Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed WHO Grade IV Unmethylated Glioma

NCT03927222 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: Pro00090683
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) on overall survival of patients newly diagnosed with World Health Organization (WHO) Grade IV glioblastoma who have undergone definitive tumor resection, are cytomegalovirus (CMV) positive and unmethylated, and completed standard temozolomide (TMZ) and radiation treatment. After completion of the standard of care radiotherapy with concurrent TMZ, patients will receive 1 cycle of dose-intensified TMZ followed by pp65-loaded dendritic cell (DC) vaccination beginning on day 23.

Conditions

Glioblastoma

Keywords

Glioblastoma; Dendritic cells; Temozolomide; Tetanus; Khasraw; Immunotherapy; Vaccine

Outcome Measures

Primary Outcomes (1)

• Median Overall Survival (OS) of Subjects Receiving Td Pre-conditioning With GM-CSF

  Time in months from the start of study treatment to date of death due to any cause. Patients alive as of the last follow-up has OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.

  duration of the study (up to 3 years and 4.5 months)

Secondary Outcomes (5)

• Migration and Survival From Vaccine 4

  5 years

• Chemokine (C-C Motif) Ligand 3 (CCL3) and Survival From Vaccine 4

  5 years

• Polyfunctionality and Survival From Vaccine 4

  5 years

• Maximum Peak Increase From Vaccine 1 in Percent Regulatory T Cells (TReg) of CD4+ T Cells

  1 year

• Number of Participants With Unacceptable Toxicity

  1 year

Study Arms (1)

DC vaccination with Td preconditioning and GM CSF

EXPERIMENTAL

This single-arm phase II study will assess the impact of tetanus pre-conditioning and adjuvant GM-CSF on overall survival of newly diagnosed glioblastoma (GBM) patients who have undergone definitive resection, are unmethylated, and completed standard temozolomide and radiation treatment. All enrolled patients will undergo a leukapheresis for the generation of DCs. Patients will then receive approximately 6 weeks of standard of care radiation therapy (RT) and concurrent TMZ. A single post-RT cycle of dose intensified TMZ (100 mg/m2/day for 21 days) will then be given. On day 23 (± 2 days) of the cycle, patients will receive the first of 3 pp65 DC vaccines every 2 weeks. All patients will receive up to a total of 10 DC vaccines

Biological: Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF; Drug: Temozolomide; Biological: Tetanus-Diphtheria Toxoid (Td); Biological: GM-CSF; Biological: 111-Indium-labeling of Cells for in vivo Trafficking Studies

Interventions

Human CMV pp65-LAMP mRNA-pulsed autologous DCs containing GM CSF BIOLOGICAL

2x10\^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.

Also known as: CMV-specific dendritic cell vaccine, DCs

DC vaccination with Td preconditioning and GM CSF

Temozolomide DRUG

Temozolomide is a chemotherapy drug given to all enrolled patients at the post-RT clinic visit as dose-intensified TMZ (100 mg/m2/day for 21 days).

Also known as: Temodar, TMZ, Temodal

DC vaccination with Td preconditioning and GM CSF

Tetanus-Diphtheria Toxoid (Td) BIOLOGICAL

Before the first DC vaccination, patients will receive 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Prior to pp65 DC vaccination #4,(3±1) weeks after leukapheresis 2 the vaccine site will receive a pre-conditioning intradermal injection of Td (1 flocculation unit (Lf), in 0.3 mL of saline for a total of 0.4 mL).

Also known as: Td pre-conditioning, Td toxoid

DC vaccination with Td preconditioning and GM CSF

GM-CSF BIOLOGICAL

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a sterile, white, preservative-free lyophilized powder in a vial containing 250 mcg that will be reconstituted in 0.5 mL of sterile water for injection and used as an adjuvant with the DC vaccine.

Also known as: LEUKINE®, Sargramostim

DC vaccination with Td preconditioning and GM CSF

111-Indium-labeling of Cells for in vivo Trafficking Studies BIOLOGICAL

111-In-labeled DCs are 2 x 10\^7 pp65-LAMP mRNA loaded mature DCs labeled with 111-In (50 μCi / 5 x 10\^7 DCs) and given i.d. as the fourth vaccine. In up to 16 patients, the fourth vaccine will be labeled with 111-In (50 μCi / 5 x 10\^7 DCs) prior to injection.

DC vaccination with Td preconditioning and GM CSF

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
• Newly diagnosed World Health Organization (WHO) Grade IV Glioma with definitive resection prior to the consent, with a residual radiographic contrast enhancing disease on the postoperative computed tomography (CT) or Magnetic Resonance Imaging (MRI) of \<1 cm in maximal diameter in any plane.
• Able to receive standard of care radiation and chemotherapy for approximately 6 weeks duration and of more than 54 Gray (GY)
• MRI post radiation therapy (RT) does not show progressive disease outside the radiation field
• Enough tumor tissue available for determination of methylguanine-DNA methyltransferase (MGMT) gene promoter status (must be unmethylated) or prior pathology report available confirming MGMT gene promoter status
• Cytomegalovirus (CMV) Seropositive
• Karnofsky Performance Status (KPS) of ≥ 70%
• Hemoglobin ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥ 1,000 cells/µl, platelets ≥ 100,000 cells/µl prior to starting TMZ cycle 1 (patient must meet these criteria within 4 weeks after the end of XRT/TMZ to be eligible)
• Serum creatinine ≤ 3 times institutional upper limit of normal (ULN) for age, aspartate aminotransferase (AST) ≤ 3 times institutional upper limit of normal for age
• Bilirubin ≤ 1.5 times upper limit of normal prior to starting TMZ cycle 1 (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.)
• Signed informed consent approved by the Institutional Review Board
• Female patients must not be pregnant or breastfeeding. Female patients of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, \[i.e. with a failure rate of \< 1% per year\] are implants, injectables, combined oral contraceptives, intrauterine device \[IUD; only hormonal\], sexual abstinence or vasectomized partner) during the trial and for a period of \> 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhea for the last 24 months) must have a negative serum pregnancy test within 48 hours prior to first study procedure (leukapheresis).
• Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control \[i.e. with a failure rate of \< 1% per year\] include a female partner using implants, injectables, combined oral contraceptives, intrauterine devices (IUDs) \[only hormonal\], sexual abstinence or prior vasectomy) during the trial and for a period of \> 6 months following the last administration of trial drugs.

You may not qualify if:

• Pregnant or breastfeeding.
• Women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception.
• Patients with known potentially anaphylactic allergic reactions to gadolinium- diethylenetriamine penta-acetic acid (DTPA).
• Patients who cannot undergo MRI or SPECT due to obesity or to having certain metal in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods, or plates).
• Patients with evidence of tumor in the brainstem, cerebellum, or spinal cord, radiological evidence of multifocal disease, or leptomeningeal disease.
• Severe, active comorbidity, including any of the following:
• Unstable angina and/or congestive heart failure requiring hospitalization;
• Transmural myocardial infarction within the last 6 months;
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study initiation;
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness r requiring hospitalization or precluding study therapy;
• Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
• Known Human Immunodeficiency Virus (HIV) and Hepatitis C positive status;
• 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 opinion of the treating physician, may put the patient at high risk for radiation toxicity.
• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids

Sponsors & Collaborators

• Mustafa Khasraw, MBChB, MD, FRCP, FRACP: lead

Study Sites (1)

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Links

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

MeSH Terms

Conditions

Glioblastoma; Tetanus

Interventions

Temozolomide; Granulocyte-Macrophage Colony-Stimulating Factor; sargramostim

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; Clostridium Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Mustafa Khasraw, MD
• Organization: Duke University

mustafa.khasraw@duke.edu

919-684-5301

Study Officials

• Mustafa Khasraw, MBChB, MD, FRCP, FRACP

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurosurgery

Model Details: Newly-diagnosed WHO Grade IV glioma patients with their tumor resected and found to be MGMT unmethylated will be accrued to this study before the standard of care chemoradiation with the goal of treating with dose-intensified TMZ and pp65 loaded dendritic cell vaccine after completion of the standard of care chemoradiation.

Study Record Dates

• First Submitted: April 19, 2019
• First Posted: April 25, 2019
• Study Start: September 30, 2019
• Primary Completion: February 10, 2023
• Study Completion: February 10, 2023
• Last Updated: April 8, 2024
• Results First Posted: April 8, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)