Journal of Clinical Oncology, Vol 23, No 28 (October 1), 2005: pp. 7178-7187
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.06.502
Phase I Trial of Temozolomide Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma
Jennifer A. Quinn,
Annick Desjardins,
Jon Weingart,
Henry Brem,
M. Eileen Dolan,
Shannon M. Delaney,
James Vredenburgh,
Jeremy Rich,
Allan H. Friedman,
David A. Reardon,
John H. Sampson,
Anthony E. Pegg,
Robert C. Moschel,
Robert Birch,
Roger E. McLendon,
James M. Provenzale,
Sridharan Gururangan,
Janet E. Dancey,
Jill Maxwell,
Sandra Tourt-Uhlig,
James E. Herndon, II,
Darell D. Bigner,
Henry S. Friedman
From the Departments of Surgery, Pathology, Radiology, and Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC; Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore; National Cancer Institute, Frederick Cancer Research and Development Center, Frederick; and Investigational Drug Branch, National Cancer Institute, Bethesda, MD; Department of Medicine, Committee on Cancer Biology and Cancer Research Center, University of Chicago, Chicago, IL; Department of Cellular and Molecular Physiology, Milton S. Hershey Medical Center, Hershey, PA; Laboratory of Comparative Carcinogenesis, AOI Pharmaceuticals, Memphis, TN
Address reprint requests to Jennifer A. Quinn, MD, Brain Tumor Center at Duke, Room 047 Baker House, Trent Dr, S Hospital, Durham, NC 27710; e-mail: quinn008{at}mc.duke.edu
PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG.
PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined.
RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression.
CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.
Supported by National Institutes of Health Grants No. U01-CA62474 and NS30245. Pharmacological studies by the Pharmacology Core Facility at the University of Chicago Cancer Research Center were supported by National Cancer Institute Grant No. CA14599 (M.E.D.).
Authors' disclosures of potential conflicts of interest are found at the end of this article.

CiteULike Complore Connotea Del.icio.us Digg Facebook Reddit Technorati Twitter What's this?
This article has been cited by other articles:

|
 |

|
 |
 
J. Felsberg, M. Rapp, S. Loeser, R. Fimmers, W. Stummer, M. Goeppert, H.-J. Steiger, B. Friedensdorf, G. Reifenberger, and M. C. Sabel
Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients
Clin. Cancer Res.,
November 1, 2009;
15(21):
6683 - 6693.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. M. Horton, G. Jenkins, D. Pati, L. Zhang, M. E. Dolan, A. Ribes-Zamora, A. A. Bertuch, S. M. Blaney, S. L. Delaney, M. Hegde, et al.
Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity
Mol. Cancer Ther.,
August 1, 2009;
8(8):
2232 - 2242.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Yip, J. Miao, D. P. Cahill, A. J. Iafrate, K. Aldape, C. L. Nutt, and D. N. Louis
MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance
Clin. Cancer Res.,
July 15, 2009;
15(14):
4622 - 4629.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. R. Plummer
Chemopotentiation by Manipulation of DNA Repair: An Update on the Clinical Status and Potential Emerging Therapies
Am. Assoc. Cancer Res. Educ. Book,
April 18, 2009;
2009(1):
57 - 60.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. A. Quinn, S. X. Jiang, D. A. Reardon, A. Desjardins, J. J. Vredenburgh, J. N. Rich, S. Gururangan, A. H. Friedman, D. D. Bigner, J. H. Sampson, et al.
Phase II Trial of Temozolomide Plus O6-Benzylguanine in Adults With Recurrent, Temozolomide-Resistant Malignant Glioma
J. Clin. Oncol.,
March 10, 2009;
27(8):
1262 - 1267.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Remington, J. Chtchetinin, K. Ancheta, P. L. Nghiemphu, T. Cloughesy, and A. Lai
The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity
Neuro-oncol,
January 1, 2009;
11(1):
22 - 32.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. A. Quinn, S. X. Jiang, D. A. Reardon, A. Desjardins, J. J. Vredenburgh, J. N. Rich, S. Gururangan, A. H. Friedman, D. D. Bigner, J. H. Sampson, et al.
Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma
Neuro-oncol,
January 1, 2009;
11(5):
556 - 561.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. D. Milsom, M. Jerabek-Willemsen, C. E. Harris, A. Schambach, E. Broun, J. Bailey, M. Jansen, D. Schleimer, K. Nattamai, J. Wilhelm, et al.
Reciprocal Relationship between O6-Methylguanine-DNA Methyltransferase P140K Expression Level and Chemoprotection of Hematopoietic Stem Cells
Cancer Res.,
August 1, 2008;
68(15):
6171 - 6180.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. A. Maxwell, S. P. Johnson, R. E. McLendon, D. W. Lister, K. S. Horne, A. Rasheed, J. A. Quinn, F. Ali-Osman, A. H. Friedman, P. L. Modrich, et al.
Mismatch Repair Deficiency Does Not Mediate Clinical Resistance to Temozolomide in Malignant Glioma
Clin. Cancer Res.,
August 1, 2008;
14(15):
4859 - 4868.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Nagane, K. Kobayashi, A. Ohnishi, S. Shimizu, and Y. Shiokawa
Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide
Jpn. J. Clin. Oncol.,
December 21, 2007;
(2007)
hym132v1.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Broniscer, S. Gururangan, T. J. MacDonald, S. Goldman, R. J. Packer, C. F. Stewart, D. Wallace, M. K. Danks, H. S. Friedman, T. Y. Poussaint, et al.
Phase I Trial of Single-Dose Temozolomide and Continuous Administration of O6-Benzylguanine in Children with Brain Tumors: a Pediatric Brain Tumor Consortium Report
Clin. Cancer Res.,
November 15, 2007;
13(22):
6712 - 6718.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. C. Rice, C. W. Stevens, A. M. Correa, A. A. Vaporciyan, A. Tsao, K. M. Forster, G. L. Walsh, S. G. Swisher, W. L. Hofstetter, R. J. Mehran, et al.
Outcomes After Extrapleural Pneumonectomy and Intensity-Modulated Radiation Therapy for Malignant Pleural Mesothelioma
Ann. Thorac. Surg.,
November 1, 2007;
84(5):
1685 - 1693.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. L. Eoff, K. C. Angel, M. Egli, and F. P. Guengerich
Molecular Basis of Selectivity of Nucleoside Triphosphate Incorporation Opposite O6-Benzylguanine by Sulfolobus solfataricus DNA Polymerase Dpo4: STEADY-STATE AND PRE-STEADY-STATE KINETICS AND X-RAY CRYSTALLOGRAPHY OF CORRECT AND INCORRECT PAIRING
J. Biol. Chem.,
May 4, 2007;
282(18):
13573 - 13584.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. J. Hansen, R. Nagasubramanian, S. M. Delaney, L. D. Samson, and M.E. Dolan
Role of O6-methylguanine-DNA methyltransferase in protecting from alkylating agent-induced toxicity and mutations in mice
Carcinogenesis,
May 1, 2007;
28(5):
1111 - 1116.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Yoshimoto, C. K. Augustine, J. S. Yoo, P. A. Zipfel, M. A. Selim, S. K. Pruitt, H. S. Friedman, F. Ali-Osman, and D. S. Tyler
Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents
Mol. Cancer Ther.,
May 1, 2007;
6(5):
1492 - 1500.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Weingart, S. A. Grossman, K. A. Carson, J. D. Fisher, S. M. Delaney, M. L. Rosenblum, A. Olivi, K. Judy, S. B. Tatter, and M. E. Dolan
Phase I Trial of Polifeprosan 20 With Carmustine Implant Plus Continuous Infusion of Intravenous O6-Benzylguanine in Adults With Recurrent Malignant Glioma: New Approaches to Brain Tumor Therapy CNS Consortium Trial
J. Clin. Oncol.,
February 1, 2007;
25(4):
399 - 404.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. Rice
Reply
Ann. Thorac. Surg.,
December 1, 2006;
82(6):
2337 - 2338.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. A. Maxwell, S. P. Johnson, J. A. Quinn, R. E. McLendon, F. Ali-Osman, A. H. Friedman, J. E. Herndon II, K. Bierau, J. Bigley, D. D. Bigner, et al.
Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma.
Mol. Cancer Ther.,
October 1, 2006;
5(10):
2531 - 2539.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. Tentori, C. Leonetti, M. Scarsella, A. Muzi, E. Mazzon, M. Vergati, O. Forini, R. Lapidus, W. Xu, A. S. Dorio, et al.
Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma
FASEB J,
August 1, 2006;
20(10):
1709 - 1711.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. A. Reardon, J. N. Rich, H. S. Friedman, and D. D. Bigner
Recent Advances in the Treatment of Malignant Astrocytoma
J. Clin. Oncol.,
March 10, 2006;
24(8):
1253 - 1265.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|