Comment Period Extended to 3/23/2015 for Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells in Treating Patients With Malignant Gliomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2015 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00669669
First received: April 29, 2008
Last updated: January 23, 2015
Last verified: January 2015

April 29, 2008
January 23, 2015
August 2009
December 2017   (final data collection date for primary outcome measure)
  • Incidence of dose-limiting toxicity (DLT) [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  • Incidence of replication competent retrovirus or leukemia [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]
  • Response rate [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: From the onset of temozolomide to the date at which unequivocal disease progression, assessed up to 15 years ] [ Designated as safety issue: No ]
  • Survival [ Time Frame: From the first day of treatment until death, assessed up to 15 years ] [ Designated as safety issue: No ]
  • Time to progression [ Time Frame: From the first day of treatment until unequivocal progression is documented, assessed up to 15 years ] [ Designated as safety issue: No ]
  • Gene transfer efficiency and in vivo selection, assessed by gene marking in peripheral blood and marrow [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  • Chemoprotection, assessed by the ability to increase the temozolomide dose beyond 472 mg/m^2 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Development of replication competent retrovirus or leukemia [ Designated as safety issue: Yes ]
  • Dose-limiting toxicity (hematologic and nonhematologic) of temozolomide [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00669669 on ClinicalTrials.gov Archive Site
Not Provided
  • Tumor response by MRI or contrast-enhanced CT scan [ Designated as safety issue: No ]
  • Duration of response [ Designated as safety issue: No ]
  • Time to progression [ Designated as safety issue: No ]
  • Gene transfer efficiency and in vivo selection by gene marking in peripheral blood and marrow monthly [ Designated as safety issue: No ]
  • Chemoprotection in terms of the ability to increase the temozolomide dose [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells in Treating Patients With Malignant Gliomas
Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas

This phase I/II trial studies the side effects and the best dose of temozolomide when given together with radiation therapy, carmustine, O6-benzylguanine, and an autologous stem cell 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.

PRIMARY OBJECTIVES:

I. Determine the safety and feasibility of infusing autologous 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.

PHASE I: Patients undergo radiotherapy 5 days per week for 7 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.

PHASE II: Beginning approximately 4 weeks after completion of Phase 1 of the study, patients receive O6-benzylguanine IV continuously over 48 hours followed 2 hours later by temozolomide PO. 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 the first 2 years, every 3-6 months for 3 years, and then annually thereafter for up to 15 years.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • Irradiated
    • Irradiation
    • RT
  • Biological: Filgrastim
    Given SC
    Other Names:
    • G-CSF
    • Nivestim
    • r-metHuG-CSF
  • Drug: Plerixafor
    Given SC
    Other Names:
    • AMD 3100
    • JM-3100
  • Drug: Carmustine
    Given IV
    Other Name: FDA 0345
  • Drug: Temozolomide
    Given PO
    Other Name: TMZ
  • 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
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
    Undergo autologous in vitro-treated peripheral blood stem cell transplant
    Other Name: Autologous Stem Cell Transplantation
  • Drug: O6-Benzylguanine
    Given IV
    Other Name: BG
  • Other: Laboratory Biomarker Analysis
    Correlative studies
Experimental: Treatment (chemotherapy, autologous stem cell transplant)

PHASE I: Patients undergo radiotherapy 5 days per week for 7 weeks. Patients receive filgrastim SC on days -7 to -3 and begin stem cell collection on the 4th day of filgrastim administration (up to 3 apheresis). Patients may 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 IV over 3 hours followed 2 hours later by temozolomide PO. At least twenty-four hours after completion of carmustine and temozolomide, patients undergo reinfusion of genetically-modified stem cells.

PHASE II: Beginning approximately 4 weeks after completion of phase 1 of the study, patients receive O6-benzylguanine IV continuously over 48 hours followed 2 hours later by temozolomide PO. Treatment may repeat at least every 28 days for a total of 24 courses in the absence of disease progression or unacceptable toxicity.

Interventions:
  • Radiation: Radiation Therapy
  • Biological: Filgrastim
  • Drug: Plerixafor
  • Drug: Carmustine
  • Drug: Temozolomide
  • Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
  • Drug: O6-Benzylguanine
  • Other: Laboratory Biomarker Analysis
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.
 
Recruiting
24
Not Provided
December 2017   (final data collection date for primary outcome measure)

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 an 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 an 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 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
Both
18 Years and older
No
United States
 
NCT00669669
2000.00, NCI-2013-00701, 8357, 2000.00, P30CA015704
Yes
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
Principal Investigator: Hans-Peter Kiem Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
January 2015

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