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

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ClinicalTrials.gov Identifier: NCT00626483
Recruitment Status : Completed
First Posted : February 29, 2008
Last Update Posted : August 28, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Gary Archer Ph.D., Duke University

Tracking Information
First Submitted Date  ICMJE February 28, 2008
First Posted Date  ICMJE February 29, 2008
Last Update Posted Date August 28, 2019
Actual Study Start Date  ICMJE April 24, 2007
Actual Primary Completion Date July 6, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2017)
Functional capacity of CD4+,CD25+, CD127- T-regulatory cells [ Time Frame: Approximately 26 months at time of brain tumor progression ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 28, 2008)
Functional capacity of CD4+,CD25+, CD127- T-regulatory cells
Change History Complete list of historical versions of study NCT00626483 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2019)
  • Safety of CMV pulsed pp65 DC vaccines [ Time Frame: 2 months following last vaccine administration ]
    Number of patients experiencing WHO Grade 3, 4, and 5 adverse events considered possibly, probably, or definitely related to study treatment
  • Effect of basilixiumab on pp65 vaccine [ Time Frame: 1 year ]
    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
  • Effect of basilixiumab on immune profiles [ Time Frame: 1 year ]
    Determine if basiliximab alters the phenotype (CD56-expression), cytokine secretion profile, or cytotoxicity of CD3-CD56+ NK cells
  • Progression-free survival (PFS) [ Time Frame: 1 year ]
    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.
  • Characterize immune cells in recurrent tumors [ Time Frame: 1 year ]
    Characterize immunologic cell infiltrate in recurrent tumors and seek evidence of antigen escape outgrowth
Original Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2008)
Safety
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Basiliximab in Treating Patients With Newly Diagnosed Glioblastoma Multiforme Undergoing Targeted Immunotherapy and Temozolomide-Caused Lymphopenia
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malignant Neoplasms Brain
Intervention  ICMJE
  • Biological: RNA-loaded dendritic cell vaccine
    Only one dose of DCs (2 x 10^7) is being assessed.
  • Drug: basiliximab
    Basiliximab 20 mg and 40 mg is being assessed depending on dose-cohort enrollment.
Study Arms  ICMJE Experimental: CMV pp65-LAMP mRNA-loaded DC vaccination
Basiliximab will be safe in combination with CMV pp65-LAMP mRNA-loaded DC vaccination and GM-CSF
Interventions:
  • Biological: RNA-loaded dendritic cell vaccine
  • Drug: basiliximab
Publications * 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 α 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 22, 2019)
34
Original Enrollment  ICMJE
 (submitted: February 28, 2008)
6
Actual Study Completion Date  ICMJE July 6, 2016
Actual Primary Completion Date July 6, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00626483
Other Study ID Numbers  ICMJE Pro00000581
P50CA108786 ( U.S. NIH Grant/Contract )
P30CA014236 ( U.S. NIH Grant/Contract )
SPORE Project 3
CDR0000579683 ( Other Identifier: National Cancer Institute )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gary Archer Ph.D., Duke University
Study Sponsor  ICMJE Gary Archer Ph.D.
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Dina Randazzo, DO Duke University
PRS Account Duke University
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP