Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme Recovering From Lymphopenia Caused by Temozolomide

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Biomarker/Laboratory analysis, Diagnostic, Treatment Active 18 and over NCI DUMC-PRO00000580 PRO00000580, DUMC-SPORE Project 3, NCT00627224

Special Category: SPORE trial

Objectives

Primary

1. To determine if vaccination with cytomegalovirus (CMV) pp65--LAMP mRNA-loaded dendritic cells (DCs) (CMV-DCs) during recovery from therapeutic temozolomide (TMZ)-induced lymphopenia enhances the T-cell response after autologous lymphocyte transfer (ALT) with CMV pp65-activated T cells in patients who are seropositive for CMV and who have newly diagnosed glioblastoma multiforme.

Secondary

1. To evaluate the safety of ALT with CMV pp65-activated T cells in these patients.
2. To determine if the dose of CMV pp65-activated T cells enhances the T-cell response in these patients.
3. To determine if ALT with CMV-specific T cells with or without vaccination with CMV pp65-LAMP mRNA-loaded DCs extends progression-free survival of these patients when compared with historical cohorts.
4. To assess the differential ability of ¹¹¹Indium(In)-labeled DCs transfected with chemokine receptor 7 RNA to track to the inguinal lymph nodes.
5. To characterize immunologic cell infiltrate in recurrent tumors and seek evidence of antigen escape outgrowth in recurrent or progressive tumors.
6. To assess the trafficking of ¹¹¹In-labeled CMV-specific T-cells.
7. To conduct a pilot study in a subset of patients to assess persistence, proliferation, and anatomic localization of CMV-specific T-cells ex vivo labeled with deuterated glucose.
8. To evaluate the trafficking of DCs injected intratumorally to the deep cervical lymph nodes on the tumor-bearing side.

Entry Criteria

Disease Characteristics:

• Histopathologic diagnosis of glioblastoma multiforme
  • Newly diagnosed WHO grade IV disease
• Have undergone definitive resection ≤ 4 weeks prior to leukapheresis
• Residual radiographic contrast enhancement on post-resection CT scan or MRI must not exceed 1 cm in diameter in two perpendicular axial planes
• Human cytomegalovirus seropositive
• No radiographic or cytologic evidence of leptomeningeal or multicentric disease at any time prior to vaccination

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior conventional antitumor therapy other than steroids, radiotherapy, or temozolomide
• No prior inguinal lymph node dissection
• No prior radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies
• No concurrent corticosteroids, with the exception of nasal or inhaled steroids, at a dose above physiologic levels (defined as < 2 mg of dexamethasone/qd)

Patient Characteristics:

• Karnofsky performance status 80-100%
• Curran Group status I-IV
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection requiring treatment or unexplained febrile (> 101.5º F) illness
• No known immunosuppressive disease or HIV infection
• No unstable or severe intercurrent medical conditions such as severe heart or lung disease
• No demonstrated allergy or intolerance to temozolomide for reasons other than lymphopenia

Expected Enrollment

Outcomes

T-cell response after autologous lymphocyte transfer (ALT)

Safety of ALT with cytomegalovirus (CMV) pp65-activated T cells as assessed by NCI CTCAE v3.0
Association between dose of CMV pp65-activated T cells and T-cell response
Progression-free survival
Differential ability of indium I-111-labeled dendritic cells (DCs) transfected with chemokine receptor 7 RNA to track to the inguinal lymph nodes
Immunologic cell infiltrate in recurrent tumors
Evidence of antigen escape outgrowth in recurrent or progressive tumors
Persistence, proliferation, and anatomic localization of CMV-specific T-cells ex vivo labeled with deuterated glucose
Trafficking of DCs injected intratumorally to the deep cervical lymph nodes on the tumor-bearing side

Outline

Patients undergo leukapheresis within 4-6 weeks after surgical resection to obtain peripheral blood lymphocytes (PBLs) for human cytomegalovirus (CMV)-autologous lymphocyte transfer (ALT) and CMV-dendritic cell (DC) generation. Patients then undergo external beam radiotherapy (RT) once daily, 5 days a week, for up to 7 weeks. Beginning on day 1 of RT, patients receive oral temozolomide once daily for up to 49 days. Patients with progressive disease during RT, dependence on steroids above physiologic levels, intolerance to TMZ, or failure to meet cell release criteria for DCs or PBLs are removed from study.

Beginning within 3-4 weeks after completion of concurrent RT and TMZ, patients receive oral TMZ once daily on days 1-5. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 21-23 of course 1, patients also receive an intradermal immunization and are randomized to 1 of 2 vaccine treatment arms.

• Arm I: Patients receive CMV-ALT IV over 10-15 minutes and CMV pp65-LAMP mRNA-loaded DC (CMV-DC) vaccine intradermally and administered in equal portions to each inguinal region. Treatment repeats every 2-3 weeks for up to 3 vaccines in the absence of unacceptable toxicity or inferior CMV pp65-specific immune response.



• Arm II: Patients receive CMV-ALT as in arm I and saline injection administered intradermally in equal portions to each inguinal region.

If the initial dose of CMV-ALT is considered to be safe and the combination of CMV-DCs is safe and does not produce an inferior CMV pp65-specific immune response, a third cohort of 3 patients is enrolled and receives a higher dose of CMV-ALT along with vaccine with CMV-DCs. In the event that the combination is considered to be unsafe or inferior, only the CMV-ALT is given. If the higher dose of CMV-ALT is considered to be safe, a fourth cohort of patients is enrolled receiving the same treatment as the third cohort except the T-cells are ¹¹¹indium-labeled and cultured ex vivo with deuterated glucose and their migration followed by MRI and single photon emission computed tomography.

At approximately 4-6 weeks after the third vaccination, all patients undergo follow-up leukapheresis to obtain peripheral blood mononuclear cells for immunologic monitoring and additional DCs for continued vaccinations. Leukapheresis may be performed monthly, if needed, but will likely be performed every 4 months throughout the study to generate enough DCs to continue monthly vaccinations.

Prior to the fourth vaccination, patients in both arms and patients with disease progression determined prior to the first scheduled vaccination are stratified according to side of inguinal injection (left vs right) and randomized to 1 of 2 treatment arms.

• Arm I: Patients receive a vaccination with 1 x 10⁷ pp65 mRNA-loaded, ¹¹¹indium-labeled DCs in one inguinal region.



• Arm II: Patients receive a vaccination in the opposite inguinal region with 1 x 10⁷ pp65 mRNA-loaded, ¹¹¹indium (In)-labeled DCs, which have also been loaded with mRNA encoding the chemokine receptor CCR7.

Patients then undergo gamma camera imaging to compare DC migration from the inguinal intradermal injection sites to the inguinal lymph nodes. If the first six injections of CCR7-transfected DCs show increased migration toward the lymph nodes, the next six patients are randomized by side to have one inguinal vaccination site pre-treated with unpulsed DCs or topical imiquimod before receiving the CCR7-transfected DCs.

After completion of TMZ therapy, patients continue receiving vaccinations in the absence of disease progression.

Patients undergo blood collection periodically after the first vaccination for immunologic studies. Samples are examined for antigen-induced T-cell proliferation; cytokine secretion (by enzyme-linked immunosorbent assay, fluorescent cytometry, and tetramer analysis); and CMV pp65 quantitation in genomic DNA by reverse transcriptase-polymerase chain reaction. Patients may also undergo stereotactic biopsy or tumor resection to confirm tumor progression histologically and to assess by immunohistochemistry and polymerase chain reaction immunologic cell infiltration and pp65 antigen escape at the tumor site. Patients consenting to biopsy or resection may undergo intratumoral vaccination with CMV pp65 LAMP-loaded, ¹¹¹In-labeled DCs at the time of surgery to determine if the cells migrate to cervical lymph nodes. Lymph node drainage of the human brain using ¹¹¹In-labeled DCs injected intratumorally is also evaluated. T-cell proliferation, persistence, and anatomic localization will be monitored in a subset of patients with ¹¹¹In- and deuterated glucose-labeled T cells. Single photon emission computed tomography images are used to quantitate and compare migration to the inguinal lymph nodes.

Quality of life is assessed by the Functional Assessment of Cancer Therapy-Brain questionnaire at initial leukapheresis, at the first vaccine, after the third vaccine at the time of post-vaccine leukapheresis, and then with every even-numbered vaccination thereafter.

After completion of study therapy, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

Duke Comprehensive Cancer Center

Duane Mitchell, MD, PhD, Principal investigator		Ph: 919-684-9041

U.S.A.
North Carolina
	Durham
	Duke Comprehensive Cancer Center
		Duane Mitchell, MD, PhD	Ph:  919-684-5301

Registry Information
Official Title		Evaluation of Recovery From Drug-Induced Lymphopenia Using Cytomegalovirus-Specific T-Cell Adoptive Transfer [ERaDICATe]
Trial Start Date		2007-09-14
Trial Completion Date		2010-09-14 (estimated)
Registered in ClinicalTrials.gov		NCT00627224
Date Submitted to PDQ		2008-02-22
Information Last Verified		2008-03-30
NCI Grant/Contract Number		CA108786, CA14236