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Astrocytoma

Neoplasms, Neuroepithelial

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Neuroectodermal Tumors, Primitive

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Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

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Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer IV over 1-5 minutes on day 22. Patients undergo surgery on day 30 of cycle 1. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-21. Treatment repeats every 42 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer intravenously IV over 1-5 minutes on day 22. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Autologous Cytomegalovirus-specific Cytotoxic T-lymphocytes

Laboratory Biomarker Analysis

Therapeutic Conventional Surgery

Shiao-Pei Weathers

This phase I/II trial studies the side effects and best dose of autologous cytomegalovirus (CMV)-specific cytotoxic T cells when given together with temozolomide and to see how well they work in treating patients with glioblastoma. Autologous CMV-specific cytotoxic T cells may stimulate the immune system to attack specific tumor cells and stop them from growing or kill them. Drugs used in chemotherapy, such as temozolomide, may work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving autologous CMV-specific cytotoxic T cells with temozolomide may be a better treatment for patients with glioblastoma.

PRIMARY OBJECTIVES:

I. To determine the maximum feasible dose (MFD) or maximum tolerated dose (MTD) and safety of cytomegalovirus (CMV)-specific T cells in combination with dose-dense temozolomide in patients with recurrent glioblastoma. (Phase I) II. To evaluate the immunological effects in resected glioblastoma after intravenous administered cytomegalovirus (CMV)-stimulated adoptive T cells in patients with recurrent glioblastoma (GBM). (Phase II: recurrent glioblastoma undergoing resection) III. To correlate 6-month progression-free survival rate (PFS6) with objective clearance of CMV antigens as measured by immunohistochemistry (IHC) and by ex vivo T-cell-specific effector responses using intracellular cytokine profiling. (Phase II: recurrent glioblastoma undergoing resection) IV. Overall survival (OS). (Phase II: newly diagnosed glioblastoma)

SECONDARY OBJECTIVES:

I. Time to progression, overall survival (OS) as well as immunological reactivity and safety. (Phase II: recurrent glioblastoma undergoing resection) II. Safety and tolerability of dose-dense temozolomide in combination with intravenous administered CMV-stimulated adoptive T cells in patients receiving adjuvant therapy after completing external beam radiotherapy with concurrent temozolomide for newly diagnosed glioblastoma. (Phase II: newly diagnosed glioblastoma) III. Overall objective response rate (ORR), median duration of response, PFS6. (Phase II: newly diagnosed glioblastoma)

EXPLORATORY OBJECTIVES:

I. To determine the persistence and expansion of adoptively-infused CMV-specific T cells by multiparameter flow cytometry in serially-sampled peripheral blood. (Phase I) II. To identify imaging characteristics such as magnetic resonance imaging (MRI) textural analysis associated with immunological changes in tumor following treatment with CMV-stimulated adoptive T cells. (Phase II: recurrent glioblastoma undergoing resection) III. To ascertain if adoptive transfer of CMV-specific T cells leads to the expansion of T cells with specificity to other glioblastoma antigens (i.e. epitope spreading) by performing longitudinally monitoring of antigen-specific T cell frequency with enzyme-linked immunosorbent spot assay (ELISPOT). (Phase II: recurrent glioblastoma undergoing resection) IV. To determine the persistence and expansion of adoptively-infused CMV-specific T cells by multiparameter flow cytometry in serially-sampled peripheral blood. (Phase II: newly diagnosed glioblastoma)

OUTLINE: This is a phase I, dose-escalation study of CMV-specific T cells followed by a phase II study. Patients are assigned to 1 of 2 treatment arms.

ARM I: Patients receive temozolomide orally (PO) once a day (QD) on days 1-21 and CMV-specific T cell transfer intravenously (IV) over 1-5 minutes on day 22. Patients undergo surgery on day 30 of cycle 1. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-21. Treatment repeats every 42 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer intravenously IV over 1-5 minutes on day 22. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 3 months.

Autologous CMV-Specific Cytotoxic T Cells and Temozolomide in Treating Patients With Glioblastoma

A Phase I/II Clinical Trial of Autologous CMV-Specific Cytotoxic T Cells for GBM Patients

The number of participants who were treated at the respective dose level without DLT

Descriptive statistics will be used to summarize immunological effect. To evaluate the tumor-mediated immune suppression at the effector location, the markers (interferon, interleukin-2, and tumor necrosis factor alpha, perforin, granzyme B) will be measured for immune responses in the tumor microenvironment rather than in the peripheral blood.

Progression-free survival (PFS) is defined as the time from study enrollment until the time of first disease progression, relapse, or death due to disease. Patients who are alive without progression or relapse will be censored at the time of last contact. The point estimate of 6-month progression-free survival (PFS6) will be analyzed. Kaplan-Meier curves will be generated and median survival time will be derived.

Overall Survival is defined as the time from definitive histological diagnosis until the time of death.

The length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body.

The number of participants with stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST).

Cox proportional hazard regression will be employed for multivariate analysis.

Progression free survival is defined as time in weeks from start of study treatment to first documentation of objective tumor progression or up to death due to any cause, whichever occurs first.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

No Phase 2 participants died and 13 out of 16 Phase 1 participants died unrelated to study treatment. For the Phase 2 newly diagnosed participants the median survival weeks was 24 at the time of last follow up.

Dose escalation component in participants with recurrent glioblastoma to determine the maximum feasible dose (MFD) or maximum tolerated dose (MTD) of CMV-specific T cells in combination with dose-dense temozolomide. We will follow a 3+3 design exploring 4 dose levels of CMV-T cells: 5 x 106, 1 x 107, 5 x 107, and 1 x 108 CMV CTLs. 4 cycles total of dose-dense TMZ and CMV-T cell infusion. Following completion of 4 cycles of dose-dense TMZ and CMV-T cell infusion, participants can receive additional 42-day cycles of dose-dense TMZ for up to 12 cycles or tumor PD.

Phase I: Recurrent Glioblastoma Dose Level 5 x 10^6

Phase I: Recurrent Glioblastoma Dose Level 1 x 10^7

Phase I: Recurrent Glioblastoma Dose Level 5 x 10^7

Phase I: Recurrent Glioblastoma Dose Level 1 x 10^8

Participants will receive 4 cycles total of dose-dense TMZ followed by adoptive CMV T cell infusion. Following completion of 4 cycles of dose-dense TMZ and CMV T cell infusion, patients can receive standard dose TMZ 200 mg/m\^ 2 days 1-5 every 28 days up to 12 cycles or tumor PD

Phase II: Newly Diagnosed Dose Level 1 x 10^8

Participants will receive a total of 3 cycles of dose-dense temozolomide (TMZ) followed by fixed doses of CMV-specific T cell infusion in the post-surgical phase, after which they can remain on dose-dense temozolomide until tumor progression, as long as there are no unacceptable toxicities or until completion of 12 cycles of treatment with dose-dense temozolomide (whichever occurs first).

Phase II: Recurrent Glioblastoma Dose Level 1 x 10^8

Participants received 4 cycles total of dose-dense TMZ followed by adoptive CMV T cell infusion. Following completion of 4 cycles of dose-dense TMZ and CMV T cell infusion, patients can receive standard dose TMZ 200 mg/m\^ 2 days 1-5 every 28 days up to 12 cycles or tumor PD.

Participants will receive a total of 3 cycles of dose-dense temozolomide followed by fixed doses of CMV-specific T cell infusion in the post-surgical phase, after which they can remain on dose-dense temozolomide until tumor progression, as long as there are no unacceptable toxicities or until completion of 12 cycles of treatment with dose-dense temozolomide (whichever occurs first).

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Shiao-Pei Weathers, MD, Associate Professor, Neuro-Oncology

Phase I: Recurrent Glioblastoma (MTD) Dose Level 1 x 10^8

Maximum Tolerated Dose (MTD) (Recurrent Glioblastoma Participant Cohort)- Phase I

Number of Participants With Immunological Effects in Tumor Tissue (Recurrent Glioblastoma Cohort)- Phase II

Progression Free Survival (PFS) (Recurrent Glioblastoma Cohort) at 6 Months- Phase II

Overall Survival (OS) (Newly Diagnosed Glioblastoma Cohort)- Phase II

Time to Progression (Recurrent Glioblastoma Cohort)- Phase II

Overall Objective Response Rate (ORR) (Newly Diagnosed Glioblastoma Cohort)- Phase II

Median Duration of Response (Newly Diagnosed Glioblastoma Cohort)- Phase II

Progression Free Survival (PFS) (Newly Diagnosed Glioblastoma Cohort)- Phase II

Participants will receive 4 cycles total of dose-dense TMZ followed by adoptive CMV T cell infusion. Following completion of 4 cycles of dose-dense TMZ and CMV T cell infusion, patients can receive standard dose TMZ 200 mg/m\^ 2 days 1-5 every 28 days up to 12 cycles or tumor PD.

Spots Global Cancer Trial Database for cytomegalovirus positive