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

Alternate Title

Daclizumab in Treating Patients With Newly Diagnosed Glioblastoma Multiforme Undergoing Targeted Immunotherapy and Temozolomide-Caused Lymphopenia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
No phase specified	Diagnostic, Treatment	Closed	18 and over	NCI	DUMC-PRO00000581 Pro00000581, SPORE Project 3, NCT00626483

Special Category: SPORE trial

Objectives

Primary

1. To determine if daclizumab inhibits the functional and numeric recovery of T-regulatory cells after therapeutic temozolomide (TMZ)-induced lymphopenia in the context of vaccinating adult patients with newly diagnosed glioblastoma multiforme (GBM) using cytomegalovirus (CMV) pp65-lysosomal-associated membrane protein (LAMP) mRNA-loaded dendritic cells (DCs) with autolymphocyte therapy (ALT) in patients who are seropositive and seronegative for CMV.

Secondary

1. To evaluate the safety of daclizumab in these patients.
2. To determine if daclizumab enhances the magnitude or character of pp65-specific vaccine-induced cellular or humoral immune responses, inhibits or enhances activation-induced cell death, or induces immunologic or clinical evidence of autoimmunity.
3. To determine if daclizumab alters the phenotype (CD56 expression), cytokine secretion profile, or cytotoxicity of CD3-CD56+ natural killer cells.
4. To determine if daclizumab in addition to vaccination and ALT extends progression-free survival compared to historical cohorts.
5. To assess the differential ability of indium In 111-labeled DCs to track to the inguinal lymph nodes under different skin-preparative conditions.
6. To characterize immunologic cell infiltrate in recurrent tumors and seek evidence of antigen-escape outgrowth.

Entry Criteria

Disease Characteristics:

• Histopathologically confirmed glioblastoma multiforme
  • WHO grade IV disease



• Must undergo leukapheresis ≤ 4 weeks after definitive resection



• Residual radiographic contrast enhancement on post-resection CT scan or MRI must not exceed 1 cm in diameter in two perpendicular axial planes
  • Patients with evidence of contrast enhancement exceeding 1 cm in diameter in two perpendicular axial planes after radiation will not be a candidate for the vaccine despite being previously enrolled and will be removed from the study and replaced



• No radiographic or cytologic evidence of leptomeningeal or multicentric disease

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior daclizumab
• No other prior conventional therapeutic intervention except for steroids, radiation, or temozolomide
• No prior inguinal lymph node dissection, radiosurgery, brachytherapy, or radiolabeled monoclonal antibodies
• No concurrent corticosteroids, with the exception of nasal or inhaled steroids, at a dose above physiologic levels
• • Patients requiring an increase in corticosteroids, with the exception of nasal or inhaled steroids, such that at the time of first vaccination they require a dose above physiologic levels, will be removed from the study and replaced (physiologic dose will be defined as < 2 mg of dexamethasone/day)
  • Once vaccinations have been initiated, if patients subsequently require increased steroids, they will still be permitted to remain on the study, but every effort will be made to minimize steroid requirements
• No prior allogeneic solid organ transplantation

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
• No unexplained febrile (>101.5°F) illness
• No known immunosuppressive disease or known HIV infection
• No unstable or severe intercurrent medical conditions such as severe heart or lung disease
• No allergy to temozolomide (TMZ) or otherwise unable to tolerate TMZ for reasons other than lymphopenia
  • Patients who are found after enrollment to be unable to tolerate TMZ will not be a candidate for the vaccine despite being previously enrolled and will be removed from the study and replaced
• No prior allergic reaction to daclizumab or one of its components

Expected Enrollment

Outcomes

Functional capacity of CD4+,CD25+, CD127- T-regulatory cells

Safety

Outline

Patients undergo leukapheresis for generation of dendritic cells (DCs) and autolymphocyte therapy (ALT) within 4 weeks after resection. After initial leukapheresis, all patients undergo stereotactic radiotherapy (RT) on days 1-5 and concurrent temozolomide (TMZ) IV on days 1-7 for 6.5 weeks in the absence of disease progression or unacceptable toxicity.

Beginning 3 weeks after completion of RT, patients receive TMZ IV on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Beginning on day 21 of the first course of TMZ, patients receive pp65-LAMP mRNA-loaded mature DCs every 2 weeks for 3 vaccinations. Concurrently with the first DC vaccination, patients receive ALT IV over 15 minutes and daclizumab IV over 15 minutes.

On day 21 of the second course of post-radiation TMZ, patients receive indium In 111-labeled DCs (fourth vaccination) and randomly assigned skin preparations (unpulsed DCs vs imiquimod cream applied to the vaccination site 6-24 hours before vaccination). Single-photon emission computed tomography (SPECT) images are used to quantitate migration to the inguinal lymph nodes.

After completion of study treatment, patients are followed every 2 months.

Trial Contact Information

Trial Lead Organizations

Duke Comprehensive Cancer Center

Duane Mitchell, MD, PhD, Protocol chair		Ph: 919-684-9041

Registry Information
Official Title		REGULATory T-Cell Inhibition with Daclizumab (Zenapax®) during Recovery from Therapeutic Temozolomide-induced Lymphopenia during Antitumor Immunotherapy Targeted Against Cytomegalovirus in Patients with Newly-Diagnosed Glioblastoma Multiforme [REGULATe]
Trial Start Date		2007-03-21
Trial Completion Date		2009-03-21 (estimated)
Registered in ClinicalTrials.gov		NCT00626483
Date Submitted to PDQ		2008-02-22
Information Last Verified		2008-12-21
NCI Grant/Contract Number		CA108786, CA14236

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