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O6-Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cell in Treating Patients With Malignant Gliomas

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00669669
Recruitment Status : Active, not recruiting
First Posted : April 30, 2008
Results First Posted : December 28, 2018
Last Update Posted : December 16, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE April 29, 2008
First Posted Date  ICMJE April 30, 2008
Results First Submitted Date  ICMJE November 7, 2018
Results First Posted Date  ICMJE December 28, 2018
Last Update Posted Date December 16, 2019
Actual Study Start Date  ICMJE February 25, 2009
Actual Primary Completion Date July 6, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 6, 2018)
  • Number of Participants Dose-limiting Toxicity (DLT) [ Time Frame: Up to 6 weeks after infusion ]
    Defined as any grade 4 nonhematopoietic toxicity that is likely related to the investigational procedures (Part I)
  • Number of Participants With Retrovirus or Leukemia [ Time Frame: Up to 2 years after infusion ]
    Replication competent retrovirus or diagnosis of leukemia
Original Primary Outcome Measures  ICMJE
 (submitted: April 29, 2008)
  • Dose-limiting toxicity (hematologic and nonhematologic) of temozolomide
  • Development of replication competent retrovirus or leukemia
Change History Complete list of historical versions of study NCT00669669 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2018)
  • Response Rate [ Time Frame: Up to 15 years ]
    Proportion of patients with reduction in tumor burden of a predefined amount
  • Duration of Response [ Time Frame: Up to 15 years ]
    From the onset of temozolomide to the date at which unequivocal disease progression, assessed up to 15 years
  • Number of Participants That Survived [ Time Frame: Up to 15 years ]
    From the first day of treatment until death, assessed up to 15 years
  • Time to Progression [ Time Frame: Up to 15 years ]
    From the first day of treatment until unequivocal progression is documented, assessed up to 15 years
  • Gene Transfer Efficiency and in Vivo Selection [ Time Frame: Up to 15 years ]
    Assessed by gene marking in peripheral blood and marrow
  • Number of Participants With Chemoprotection [ Time Frame: Up to 15 years ]
    assessed by the ability to increase the Temozolomide dose beyond 472 mg/m^2
Original Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2008)
  • Tumor response by MRI or contrast-enhanced CT scan
  • Duration of response
  • Time to progression
  • Gene transfer efficiency and in vivo selection by gene marking in peripheral blood and marrow monthly
  • Chemoprotection in terms of the ability to increase the temozolomide dose
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE O6-Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cell in Treating Patients With Malignant Gliomas
Official Title  ICMJE Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas
Brief Summary This phase I/II trial studies the side effects and best dose of temozolomide when given together with radiation therapy, carmustine, O6-benzylguanine, and patients' own stem cell (autologous) transplant in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Giving chemotherapy, such as temozolomide, carmustine, and O6-benzylguanine, and radiation therapy before a peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or plerixafor, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy or radiation therapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy and radiation therapy.
Detailed Description

PRIMARY OBJECTIVES:

I. Determine the safety and feasibility of infusing autologous granulocyte colony-stimulating factor (G-CSF) (filgrastim) mobilized stem cells transduced with a Phoenix-gibbon ape leukemia virus (GALV)-pseudotype vector expressing methylguanine methyltransferase (MGMT) (P140K).

II. Define the dose of BCNU (carmustine) that results in efficient engraftment of gene modified cells when given with peripheral blood stem cell support.

SECONDARY OBJECTIVES:

I. Determine the engraftment of gene-modified cells after conditioning with BCNU.

II. Determine the ability to select gene-modified cells in vivo with this regimen.

III. Evaluate the molecular and clonal composition of gene-modified cells after chemotherapy with temozolomide.

IV. Observe patients for clinical anti-tumor response.

V. Determine the correlation of the level of MGMT (P140K) marking with toxicity, temozolomide dose achieved, and response.

VI. Characterize the toxicity associated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of temozolomide followed by a phase II study.

PART I: Within 35 days of surgery, patients undergo 3 dimensional (3D) conformal intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy daily 5 days per week for 6 weeks. Patients receive filgrastim subcutaneously (SC) on days -7 to -3 and begin stem cell collection on the 4th day of filgrastim administration (up to 3 apheresis). Patients may also receive plerixafor SC on days -5 to -3. The CD34+ stem cells are separated from the patient's stem cells and they are transduced with Phoenix-RD114 pseudotype vector (retrovirus). One day after apheresis is completed, patients receive carmustine intravenously (IV) over 3 hours followed 2 hours later by temozolomide orally (PO). At least twenty-four hours after completion of carmustine and temozolomide, patients undergo reinfusion of genetically-modified stem cells.

PART II: Beginning approximately 4 weeks after completion of Phase 1 of the study, patients receive O6-benzylguanine IV continuously over 48 hours followed by temozolomide PO within 1 hour. Treatment may repeat at least every 28 days for a total of 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 1-3 months for 2 years, every 3-6 months for 3 years, and then annually thereafter for 10 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Gliosarcoma
Intervention  ICMJE
  • Radiation: 3-Dimensional Conformal Radiation Therapy
    Undergo 3D conformal IMRT
    Other Names:
    • 3-dimensional radiation therapy
    • 3D CONFORMAL RADIATION THERAPY
    • 3D CRT
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
    Undergo autologous in vitro-treated peripheral blood stem cell transplant
    Other Name: Autologous Stem Cell Transplantation
  • Drug: Carmustine
    Given IV
    Other Names:
    • BCNU
    • Becenum
    • Becenun
    • BiCNU
    • Bis(chloroethyl) Nitrosourea
    • Bis-Chloronitrosourea
    • Carmubris
    • Carmustin
    • Carmustinum
    • FDA 0345
    • Gliadel
    • N,N'-Bis(2-chloroethyl)-N-nitrosourea
    • Nitrourean
    • Nitrumon
    • SK 27702
    • SRI 1720
    • WR-139021
  • Biological: Filgrastim
    Given SC
    Other Names:
    • Filgrastim XM02
    • G-CSF
    • Neupogen
    • r-metHuG-CSF
    • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    • rG-CSF
    • Tbo-filgrastim
    • Tevagrastim
  • Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
    Undergo autologous in vitro-treated peripheral blood stem cell transplant
    Other Names:
    • in vitro-treated PBPC transplantation
    • in vitro-treated peripheral blood progenitor cell transplantation
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo 3D conformal IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: O6-Benzylguanine
    Given IV
    Other Names:
    • 6-O-BENZYLGUANINE
    • O(6)-Benzylguanine
  • Drug: Plerixafor
    Given SC
    Other Names:
    • AMD 3100
    • JM-3100
    • Mozobil
    • SDZ SID 791
  • Radiation: Proton Beam Radiation Therapy
    Undergo proton beam radiation therapy
  • Drug: Temozolomide
    Given PO
    Other Names:
    • CCRG-81045
    • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
    • M & B 39831
    • M and B 39831
    • Methazolastone
    • RP-46161
    • SCH 52365
    • Temcad
    • Temodal
    • Temodar
    • Temomedac
Study Arms  ICMJE Experimental: Treatment (chemotherapy, autologous stem cell transplant)
See Detailed Description
Interventions:
  • Radiation: 3-Dimensional Conformal Radiation Therapy
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
  • Drug: Carmustine
  • Biological: Filgrastim
  • Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
  • Radiation: Intensity-Modulated Radiation Therapy
  • Other: Laboratory Biomarker Analysis
  • Drug: O6-Benzylguanine
  • Drug: Plerixafor
  • Radiation: Proton Beam Radiation Therapy
  • Drug: Temozolomide
Publications * Adair JE, Johnston SK, Mrugala MM, Beard BC, Guyman LA, Baldock AL, Bridge CA, Hawkins-Daarud A, Gori JL, Born DE, Gonzalez-Cuyar LF, Silbergeld DL, Rockne RC, Storer BE, Rockhill JK, Swanson KR, Kiem HP. Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J Clin Invest. 2014 Sep;124(9):4082-92. doi: 10.1172/JCI76739. Epub 2014 Aug 8.

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 6, 2018)
12
Original Enrollment  ICMJE
 (submitted: April 29, 2008)
30
Estimated Study Completion Date  ICMJE December 31, 2027
Actual Primary Completion Date July 6, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with glioblastoma multiforme or gliosarcoma
  • The patient or legal guardian must be able to comprehend the informed consent form and sign prior to patient enrollment
  • Karnofsky performance status at time of study entry must be >= 70%
  • Life expectancy of >= 3 months
  • Patients must agree to undergo repeat clinical neurological examinations and brain magnetic resonance imaging (MRI) with appropriate contrast after every other cycle of chemotherapy
  • White blood cell (WBC) > 3000/ul
  • Absolute neutrophil count (ANC) > 1500/ul
  • Platelets > 100,000/ul
  • Hemoglobin > 10 gm/100ml
  • Total and direct bilirubin < 1.5 times upper limit of laboratory normal
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 3 times upper limit of laboratory normal
  • Alkaline phosphatase =< 3 times upper limit of laboratory normal
  • Blood urea nitrogen (BUN) < 1.5 times upper limit of laboratory normal
  • Serum creatinine < 1.5 times upper limit of laboratory normal
  • Left ventricular ejection fraction (LVEF) >= 40%, however, subjects with a LVEF in the range of 40-49% should have cardiology clearance prior to intervention
  • MGMT promoter methylation analysis of surgically resected tumor or tumor biopsy must demonstrate an unmethylated or hypomethylated MGMT promoter status

Exclusion Criteria:

  • Patients with cardiac insufficiency and a LVEF of < 40%; history of coronary artery disease or arrhythmia, which has required or requires ongoing treatment
  • Patients with active pulmonary infection and/or pulse oximetry < 90% and a corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 70% of predicted
  • Active systemic infection
  • Patients who are human immunodeficiency virus (HIV) positive
  • Pregnant or lactating women; a beta-human chorionic gonadotropin (HCG) level will be obtained from women of childbearing potential; fertile men and women should use effective contraception
  • Previous chemotherapy for any malignancy including temozolomide, dacarbazine (DTIC) or prior nitrosourea
  • Diabetes mellitus
  • Bleeding disorder
  • Methylated or hypermethylated MGMT promoter status within tumor tissue
  • Medical or psychiatric condition which in the opinion of the protocol chairman would compromise the patient's ability to tolerate this protocol
  • Prior interstitial radiotherapy, stereotactic or gamma knife surgery or implanted BCNU-wafers
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (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 NCT00669669
Other Study ID Numbers  ICMJE 2000.00
NCI-2013-00701 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
8357
2000.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Hans-Peter Kiem Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date December 2019

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