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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]


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Malignant Neoplasms Brain

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Trial Information

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]


OBJECTIVES:

Primary

- To determine if basiliximab 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

- To evaluate the safety of basiliximab in these patients.

- To determine if basiliximab 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.

- To determine if basiliximab alters the phenotype (CD56 expression), cytokine secretion
profile, or cytotoxicity of CD3-CD56+ natural killer cells.

- To determine if basiliximab in addition to vaccination and ALT extends progression-free
survival compared to historical cohorts.

- To assess the differential ability of indium In 111-labeled DCs to track to the
inguinal lymph nodes under different skin-preparative conditions.

- To characterize immunologic cell infiltrate in recurrent tumors and seek evidence of
antigen-escape outgrowth.

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 basiliximab IV over 30 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.

Inclusion 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

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

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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Time Frame:

26 months

Safety Issue:

No

Principal Investigator

Gordana Vlahovic, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University

Authority:

United States: Food and Drug Administration

Study ID:

Pro00000581

NCT ID:

NCT00626483

Start Date:

March 2007

Completion Date:

March 2014

Related Keywords:

  • Malignant Neoplasms Brain
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • Neoplasms
  • Glioblastoma
  • Lymphopenia

Name

Location

Duke University Medical CenterDurham, North Carolina  27710