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GlioblastomaPhase 1/2NCT00669669

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

A Phase 1/2 study testing 3-Dimensional Conformal Radiation Therapy, Autologous Hematopoietic Stem Cell Transplantation and Carmustine in people with Glioblastoma and Gliosarcoma, run by Fred Hutchinson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Glioblastoma, Gliosarcoma
What is being tested?
3-Dimensional Conformal Radiation Therapy, Autologous Hematopoietic Stem Cell Transplantation and Carmustine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 siteUnited States
Study dates
25 Feb 2009to 20 Jan 2021
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: Benzylguanine-Mediated Tumor Sensitization With Chemoprotected Autologous Stem Cells for Patients With Malignant Gliomas

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

  1. 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.

Being tested
3-Dimensional Conformal Radiation Therapy, Autologous Hematopoietic Stem Cell Transplantation, Carmustine, Filgrastim, In Vitro-Treated Peripheral Blood Stem Cell Transplantation
Medical subject headings
Glioblastoma, Gliosarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 3-Dimensional Conformal Radiation TherapyRadiation

    Also called 3-dimensional radiation therapy, 3D CONFORMAL RADIATION THERAPY, 3D CRT, 3D-CRT

    Undergo 3D conformal IMRT

  • Autologous Hematopoietic Stem Cell TransplantationProcedure or surgery

    Also called Autologous Stem Cell Transplantation

    Undergo autologous in vitro-treated peripheral blood stem cell transplant

  • CarmustineDrug

    Also called BCNU, Becenum, Becenun, BiCNU

    Given IV

  • FilgrastimBiological

    Also called Filgrastim XM02, G-CSF, Neupogen, r-metHuG-CSF

    Given SC

  • In Vitro-Treated Peripheral Blood Stem Cell TransplantationProcedure or surgery

    Also called in vitro-treated PBPC transplantation, in vitro-treated peripheral blood progenitor cell transplantation

    Undergo autologous in vitro-treated peripheral blood stem cell transplant

  • Intensity-Modulated Radiation TherapyRadiation

    Also called IMRT, Intensity Modulated RT, Intensity-Modulated Radiotherapy

    Undergo 3D conformal IMRT

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • O6-BenzylguanineDrug

    Also called 6-O-BENZYLGUANINE, O(6)-Benzylguanine

    Given IV

  • PlerixaforDrug

    Also called AMD 3100, JM-3100, Mozobil, SDZ SID 791

    Given SC

  • Proton Beam Radiation TherapyRadiation

    Undergo proton beam radiation therapy

  • TemozolomideDrug

    Also called 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

    Given PO

Study groups in NCT00669669
Study groupRoleWhat they receive
Treatment (chemotherapy, autologous stem cell transplant)ExperimentalSee Detailed Description
Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants Dose-limiting Toxicity (DLT)

    Defined as any grade 4 nonhematopoietic toxicity that is likely related to the investigational procedures (Part I)

    Measured: Up to 6 weeks after infusion

  2. Number of Participants With Retrovirus or Leukemia

    Replication competent retrovirus or diagnosis of leukemia

    Measured: Up to 2 years after infusion

Secondary outcomes (8)

  1. Response Rate

    Number of patients with reduction in tumor burden of a predefined amount

    Measured: Up to 66 months

  2. Duration of Response

    From the onset of temozolomide to the date at which unequivocal disease progression, assessed up to 65 months.

    Measured: Up to 65 months

  3. Time to Progression

    From the first day of treatment (transplant) until unequivocal progression is documented, assessed up to 66 months.

    Measured: Up to 66 months.

  4. Number of Participants That Survived

    From the first day of treatment until death, assessed up to 74 months.

    Measured: Up to 74 months

  5. Number of Participants With Chemoprotection

    assessed by the ability to increase the Temozolomide dose beyond 472 mg/m^2

    Measured: Up to 66 months

  6. Number of Participants With Chemoselection

    assessed by the increase in peripheral blood Vector Copy Number (VCN), the average copies of integrated transgene per cell, after chemotherapy

    Measured: Up to 59 months

  7. Gene Transfer Efficiency

    Assessed by gene marking in peripheral blood prior to chemoselection. Gene marking is assessed in whole blood by quantitative PCR and reported as a vector copy number (VCN) or the average copies of integrated transgene per cell. The units here will be reported as copies/cell.

    Measured: Up to 59 months

  8. Gene Transfer Efficiency After Chemotherapy

    Assessed by gene marking in peripheral blood after chemoselection. Gene marking is assessed in whole blood by quantitative PCR and reported as a vector copy number (VCN) or the average copies of integrated transgene per cell. The units here will be reported as copies/cell.

    Measured: Up to 59 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Apr 2008 (estimated)
  2. Study start25 Feb 2009
  3. Primary completion6 Jul 2018
  4. Study completion20 Jan 2021

Why it stopped: Terminated due to loss in funding.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00669669
Sponsor's protocol ID
2000.00
Other IDs
NCI-2013-00701, 8357, 2000.00, RG1709046
Status last verified
Jan 2022
First submitted
29 Apr 2008
Last updated
18 May 2022
Data monitoring committee
Yes

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.

    PubMed 25105369

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing 3-Dimensional Conformal Radiation Therapy, Autologous Hematopoietic Stem Cell Transplantation and Carmustine in people with Glioblastoma and Gliosarcoma, run by Fred Hutchinson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 18 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Dec 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants Dose-limiting Toxicity (DLT) (time frame: Up to 6 weeks after infusion). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00669669, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2022.

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