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

NCT ID: NCT00669669

Last Updated: 2022-05-18

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-25
• Study Completion Date: 2021-01-20

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.

Conditions

Glioblastoma; Gliosarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (chemotherapy, autologous stem cell transplant)

See Detailed Description

Group Type: EXPERIMENTAL

3-Dimensional Conformal Radiation Therapy

Intervention Type: RADIATION

Undergo 3D conformal IMRT

Autologous Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo autologous in vitro-treated peripheral blood stem cell transplant

Carmustine

Intervention Type: DRUG

Given IV

Filgrastim

Intervention Type: BIOLOGICAL

Given SC

In Vitro-Treated Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo autologous in vitro-treated peripheral blood stem cell transplant

Intensity-Modulated Radiation Therapy

Intervention Type: RADIATION

Undergo 3D conformal IMRT

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

O6-Benzylguanine

Intervention Type: DRUG

Given IV

Plerixafor

Intervention Type: DRUG

Given SC

Proton Beam Radiation Therapy

Intervention Type: RADIATION

Undergo proton beam radiation therapy

Temozolomide

Intervention Type: DRUG

Given PO

Interventions

3-Dimensional Conformal Radiation Therapy

Undergo 3D conformal IMRT

Intervention Type: RADIATION

Autologous Hematopoietic Stem Cell Transplantation

Undergo autologous in vitro-treated peripheral blood stem cell transplant

Intervention Type: PROCEDURE

Carmustine

Given IV

Intervention Type: DRUG

Filgrastim

Given SC

Intervention Type: BIOLOGICAL

In Vitro-Treated Peripheral Blood Stem Cell Transplantation

Undergo autologous in vitro-treated peripheral blood stem cell transplant

Intervention Type: PROCEDURE

Intensity-Modulated Radiation Therapy

Undergo 3D conformal IMRT

Intervention Type: RADIATION

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

O6-Benzylguanine

Given IV

Intervention Type: DRUG

Plerixafor

Given SC

Intervention Type: DRUG

Proton Beam Radiation Therapy

Undergo proton beam radiation therapy

Intervention Type: RADIATION

Temozolomide

Given PO

Intervention Type: DRUG

Other Intervention Names

3-dimensional radiation therapy; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; Autologous Stem Cell Transplantation; 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; Filgrastim XM02; G-CSF; Neupogen; r-metHuG-CSF; Recombinant Methionyl Human Granulocyte Colony Stimulating Factor; rG-CSF; Tbo-filgrastim; Tevagrastim; in vitro-treated PBPC transplantation; in vitro-treated peripheral blood progenitor cell transplantation; IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; 6-O-BENZYLGUANINE; O(6)-Benzylguanine; AMD 3100; JM-3100; Mozobil; SDZ SID 791; 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

Eligibility 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
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hans-Peter Kiem

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 25105369 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2013-00701

Identifier Type: REGISTRY

Identifier Source: secondary_id

8357

Identifier Type: -

Identifier Source: secondary_id

2000.00

Identifier Type: OTHER

Identifier Source: secondary_id

RG1709046

Identifier Type: OTHER

Identifier Source: secondary_id

2000.00

Identifier Type: -

Identifier Source: org_study_id