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

This study has suspended participant recruitment.
(CTEP Initiated Action)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00669669
First received: April 29, 2008
Last updated: July 15, 2014
Last verified: July 2014
  Purpose

This phase I/II trial is studying carmustine and temozolomide when given together with radiation therapy, BCNU, 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.


Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
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
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dose-Intensive Chemotherapy in Combination With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • 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 ]

Estimated Enrollment: 24
Study Start Date: August 2009
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 1 hour 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.

Radiation: radiation therapy
Undergo radiation therapy
Other Names:
  • irradiation
  • radiotherapy
  • therapy, radiation
Biological: filgrastim
Given SC
Other Names:
  • G-CSF
  • Neupogen
Drug: plerixafor
Given SC
Other Names:
  • AMD 3100
  • Mozobil
Drug: carmustine
Given IV
Other Names:
  • BCNU
  • BiCNU
  • bis-chloronitrosourea
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • 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 PBSC
  • in vitro-treated peripheral blood progenitor cell transplantation
  • PBPC transplantation, in vitro-treated
  • peripheral blood progenitor cell transplantation, in vitro-treated
Procedure: autologous hematopoietic stem cell transplantation
Undergo autologous in vitro-treated peripheral blood stem cell transplant
Drug: O6-benzylguanine
Given IV
Other Name: BG
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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 1 hour 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 therapy, patients are followed every 1-3 months for the first 2 years, every 3-6 months for 3 years, and annually thereafter for up to 15 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • Patients must be consented for MGMT promoter methylation analysis of brain tumor tissue within twenty-eight days after surgery
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00669669

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Hans-Peter Kiem Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided by Fred Hutchinson Cancer Research Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00669669     History of Changes
Other Study ID Numbers: 2000.00, NCI-2013-00701, 2000.00, 8357, P30CA015704
Study First Received: April 29, 2008
Last Updated: July 15, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Carmustine
O(6)-benzylguanine
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014