Peptide Targets for Glioblastoma Against Novel Cytomegalovirus Antigens

NCT02864368 | Terminated Phase 1 Results DMC

• 2 other identifiers: Pro00034208_12R42CA153845-02
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Glioblastoma; Glioblastoma Multiforme

Keywords

PERFORMANCE; Pro00034208; Cytomegalovirus; Ashley

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Treatment-related Adverse Events

  To assess the safety of PEP-CMV vaccination in combination with adjuvant TMZ, the percentage of patients with unacceptable toxicity will be estimated within each arm. All patients who received any PEP-CMV vaccine will be included in these analyses.

  2 weeks after the 3rd vaccine, which is approximately 12 weeks after consent

• Immunologic Response as Measured by Peak Number of T Cells That Secrete IFNγ by ELISPOT in Response to Component A of PEP-CMV

  The primary analysis will focus on patients who have follow-up immunologic monitoring after the 3rd vaccination with component A alone and before initiation of the second TMZ/vaccine cycle. Such a patient is considered "evaluable" for the immunologic response primary analyses. The Wilcoxon rank sum test will compare treatment groups with regard to the median peak number of T cells that secrete IFNγ by ELISPOT in response to component A of PEP-CMV. Analyses will include only those patients who have an assessment of immune response after receiving 3 vaccinations.

  Through study completion, an average of 1.5 years

Secondary Outcomes (1)

• Antigen Loss

  Through study completion, an average of 1.5 years

Study Arms (5)

5-day TMZ: Components A and B

EXPERIMENTAL

All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.

Drug: 5-day TMZ; Biological: PEP-CMV: Component A; Drug: Tetanus-Diphtheria booster; Drug: Tetanus Pre-Conditioning; Biological: PEP-CMV: Component B

21-day TMZ: Components A and B

EXPERIMENTAL

All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of dose-intensified TMZ (75-100 mg/m\^2/day on days 1-21 of each 28 day cycle) with PEP-CMV vaccination on day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.

Drug: 21-day TMZ; Biological: PEP-CMV: Component A; Drug: Tetanus-Diphtheria booster; Drug: Tetanus Pre-Conditioning; Biological: PEP-CMV: Component B

5-day TMZ: Safety Cohort

EXPERIMENTAL

All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine. Vaccine components A and B were administered separately, with a delay between them, to determine if it was an individual component or a combination of the components that resulted in adverse reactions.

Drug: 5-day TMZ; Biological: PEP-CMV: Component A; Drug: Tetanus-Diphtheria booster; Drug: Tetanus Pre-Conditioning; Biological: PEP-CMV: Component B

5-day TMZ: Component A Alone

EXPERIMENTAL

All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of standard TMZ (150-200 mg/m\^2/day on days 1-5 of each 28 day cycle) with PEP-CMV vaccination on Day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.

Drug: 5-day TMZ; Biological: PEP-CMV: Component A; Drug: Tetanus-Diphtheria booster; Drug: Tetanus Pre-Conditioning

21-day TMZ: Component A Alone

EXPERIMENTAL

All patients receive Tetanus-Diphtheria booster vaccine at time of enrollment. Cycles of dose-intensified TMZ (75-100 mg/m\^2/day on days 1-21 of each 28 day cycle) with PEP-CMV vaccination on day 23 (-1 day, + 2 days) of each TMZ cycle and tetanus pre-conditioning the day before the first vaccine.

Drug: 21-day TMZ; Biological: PEP-CMV: Component A; Drug: Tetanus-Diphtheria booster; Drug: Tetanus Pre-Conditioning

Interventions

5-day TMZ DRUG

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

Also known as: temozolomide, Temodar

5-day TMZ: Component A Alone; 5-day TMZ: Components A and B; 5-day TMZ: Safety Cohort

21-day TMZ DRUG

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)

Also known as: temozolomide, Temodar

21-day TMZ: Component A Alone; 21-day TMZ: Components A and B

PEP-CMV: Component A BIOLOGICAL

500 µg of PEP-CMV Component A (a synthetic long peptide) mixed with Montanide ISA-51 intradermally administered

21-day TMZ: Component A Alone; 21-day TMZ: Components A and B; 5-day TMZ: Component A Alone; 5-day TMZ: Components A and B; 5-day TMZ: Safety Cohort

Tetanus-Diphtheria booster DRUG

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)

Also known as: Td, tetanus

21-day TMZ: Component A Alone; 21-day TMZ: Components A and B; 5-day TMZ: Component A Alone; 5-day TMZ: Components A and B; 5-day TMZ: Safety Cohort

Tetanus Pre-Conditioning DRUG

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

Also known as: Td, Tetanus-Diphtheria, tetanus

21-day TMZ: Component A Alone; 21-day TMZ: Components A and B; 5-day TMZ: Component A Alone; 5-day TMZ: Components A and B; 5-day TMZ: Safety Cohort

PEP-CMV: Component B BIOLOGICAL

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

21-day TMZ: Components A and B; 5-day TMZ: Components A and B; 5-day TMZ: Safety Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years.
• Histopathologically proven newly-diagnosed primary glioblastoma with complete or partial surgical resection. Biopsy not acceptable.
• Patients must be cytomegalovirus (CMV) seropositive.
• The tumor must be supratentorial.
• Karnofsky performance status of ≥ 70.
• 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.
• Hematology: absolute neutrophil count (ANC) ≥ 1500 cells/µL, Platelet count ≥ 100,000 cells/µL, Hemoglobin ≥ 9.0 g/dl
• 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.)

You may not qualify if:

• Radiographic or cytologic evidence of leptomeningeal or multifocal disease at any time prior to study entry.
• Prior conventional antitumor therapy, other than steroids, RT or TMZ therapy given for glioblastoma.
• Pregnant or need to breast feed during the study period.
• Not adhering to pregnancy prevention recommendations.
• Active infection requiring intravenous antibiotics or an unexplained febrile (\> 101.5 F) illness.
• Immunosuppressive disease or human immunodeficiency virus infection.
• Patients with unstable or severe intercurrent medical conditions such as severe heart or lung disease.
• Patients with previous inguinal lymph node dissection, radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies.
• Prior allogeneic solid organ transplant.
• Currently receiving or ever received immunosuppressive therapy for an autoimmune disorder or an organ transplant.

Sponsors & Collaborators

• Eric Thompson, M.D.: lead
• Annias Immunotherapeutics, Inc.: collaborator
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

The Preston Robert Tisch Brain Tumor Center at Duke

Durham, North Carolina, 27710, United States

Location

Related Links

• The Preston Robert Tisch Brain Tumor Center at Duke
• Duke Cancer Institute

MeSH Terms

Conditions

Glioblastoma

Interventions

Temozolomide; Tetanus Toxoid

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Toxoids; Vaccines; Biological Products; Complex Mixtures

Results Point of Contact

• Title: Principal Investigator
• Organization: Duke University Medical Center

dukebrain1@duke.edu

(919) 684-5301

Study Officials

• David Ashley, MBBS, FRACP, PhD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Neurosurgery

Study Record Dates

• First Submitted: July 26, 2016
• First Posted: August 12, 2016
• Study Start: December 7, 2016
• Primary Completion: June 15, 2020
• Study Completion: June 15, 2020
• Last Updated: June 9, 2022
• Results First Posted: November 9, 2021

Record last verified: 2022-06

Locations

US (1)