Clinical trial NCT00626483: Basiliximab in Treating Patients With Newly Diagnosed Glioblastoma Multiforme Undergoing Targeted Immunotherapy and Temozolomide-Caused Lymphopenia
Official title: REGULATory T-Cell Inhibition With Basiliximab (Simulect®) During Recovery From Therapeutic Temozolomide-induced Lymphopenia During Antitumor Immunotherapy Targeted Against Cytomegalovirus in Patients With Newly-Diagnosed Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Neoplasms Brain
Keywords: adult giant cell glioblastoma
adult gliosarcoma
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-02-29
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Monoclonal antibodies, such as basiliximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Vaccines may help the body build an effective immune response to kill tumor cells. Giving these treatments together may kill more tumor cells. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) is a powerful adjuvant capable of stimulating macrophage function, inducing proliferation and maturation of DCs, and is able to enhance T-lymphocyte stimulatory function. Intradermal administration of GM-CSF enhances the immunization efficacy at the site of administration

PURPOSE: This clinical trial is studying how well basiliximab works in treating patients with newly diagnosed glioblastoma multiforme and temozolomide-caused lymphopenia who are undergoing targeted immunotherapy.

Detailed description: 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 GM-CSF 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 extends progression-free survival compared to historical cohorts.
* 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) 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 12 courses in the absence of disease progression or unacceptable toxicity. On day 14 ± 2 days of this first cycle of TMZ, patients will receive basiliximab, which is 7 days (± 2 days) before DC vaccine #1 and 2 weeks later, a second dose of basiliximab will be given, which is also 7 days before vaccine # 2.

All patients will undergo leukapheresis again for DC generation and immunologic monitoring with specific assessment of baseline antigen-specific cellular and humoral immune responses 3 + 1 weeks after vaccine #3.

Patients will then be treated monthly with TMZ cycles for a total of 12 cycles . On day 21 ± 2 days of each TMZ cycle, patients will receive monthly vaccines for a total of 8 vaccines. Patients will have blood drawn for immunologic monitoring before basiliximab infusions and prior to vaccines 1, 2, 3, and prior to monthly vaccines and then bimonthly through TMZ cycles without receiving any other prescribed antitumor therapy until progression.

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

Eligibility 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

Primary outcomes:
measure: Functional capacity of CD4+,CD25+, CD127- T-regulatory cells
timeFrame: Approximately 26 months at time of brain tumor progression
Secondary outcomes:
measure: Safety of CMV pulsed pp65 DC vaccines
timeFrame: 2 months following last vaccine administration
measure: Effect of basilixiumab on pp65 vaccine
timeFrame: 1 year
measure: Effect of basilixiumab on immune profiles
timeFrame: 1 year
measure: Progression-free survival (PFS)
timeFrame: 1 year
measure: Characterize immune cells in recurrent tumors
timeFrame: 1 year
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Mustafa Khasraw, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mitchell DA, Cui X, Schmittling RJ, Sanchez-Perez L, Snyder DJ, Congdon KL, Archer GE, Desjardins A, Friedman AH, Friedman HS, Herndon JE 2nd, McLendon RE, Reardon DA, Vredenburgh JJ, Bigner DD, Sampson JH. Monoclonal antibody blockade of IL-2 receptor alpha during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood. 2011 Sep 15;118(11):3003-12. doi: 10.1182/blood-2011-02-334565. Epub 2011 Jul 18.