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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Malignant Neoplasms Brain

Intervention / Treatment
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* Biological: RNA-loaded dendritic cell vaccine
* Drug: basiliximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CMV pp65-LAMP mRNA-loaded DC vaccination<br>Basiliximab will be safe in combination with CMV pp65-LAMP mRNA-loaded DC vaccination and GM-CSF | Biological: RNA-loaded dendritic cell vaccine<br>* Only one dose of DCs (2 x 10^7) is being assessed.<br>Drug: basiliximab<br>* Basiliximab 20 mg and 40 mg is being assessed depending on dose-cohort enrollment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional capacity of CD4+,CD25+, CD127- T-regulatory cells | Functional and quantitative recovery of regulatory T cells is measured during and following study treatment and at the time of tumor progression, which is estimated to be about 26 months from time of diagnosis based on expected progression free survival rates with standard of care therapy. | Approximately 26 months at time of brain tumor progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CMV pulsed pp65 DC vaccines | Number of patients experiencing WHO Grade 3, 4, and 5 adverse events considered possibly, probably, or definitely related to study treatment | 2 months following last vaccine administration | 
| Effect of basilixiumab on pp65 vaccine | 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 | 1 year | 
| Effect of basilixiumab on immune profiles | Determine if basiliximab alters the phenotype (CD56-expression), cytokine secretion profile, or cytotoxicity of CD3-CD56+ NK cells | 1 year | 
| Progression-free survival (PFS) | Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve. | 1 year | 
| Characterize immune cells in recurrent tumors | Characterize immunologic cell infiltrate in recurrent tumors and seek evidence of antigen escape outgrowth | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult giant cell glioblastoma, adult gliosarcoma