© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 16, 1319-1326,
August 1993
© 1993 Oxford University Press
Phase I Trial of Granulocyte—Macrophage Colony-Stimulating Factor Plus High-Dose Cyclophosphamide Given Every 2 Weeks: a Cancer and Leukemia Group B Study
North Shore University Hospital, Cornell University Medical College Manhasset, N.Y.
University of Chicago, III
University of Maryland Cancer Center Baltimore
Duke University Medical Center Durham, N.C.
Memorial Sloan-Kettering Cancer Center, Cornell University Medical College New York, N.Y.
Stuart M. Lichtman, M.D., Don Monti Division of Oncology, North Shore University Hospital-Cornell University Medical College, 300 Community Drive, Manhasset, NY 11030.
Background: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. Purpose: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. Methods: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3–10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 µg/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. Results: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts <100/µL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%–85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. Conclusions: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 µg/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. Implications: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB. [J Natl Cancer Inst 85:1319–1326, 1993]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. J. Ratain, A. A. Miller, H. L. McLeod, A. P. Venook, M. J. Egorin, and R. L. Schilsky The cancer and leukemia group B pharmacology and experimental therapeutics committee: a historical perspective. Clin. Cancer Res., June 1, 2006; 12(11): 3612s - 3616s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Lee, J. M. Skolnik, and P. C. Adamson Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency J. Clin. Oncol., November 20, 2005; 23(33): 8431 - 8441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Fornier, A. D. Seidman, M. Theodoulou, M. E. Moynahan, V. Currie, M. Moasser, N. Sklarin, T. Gilewski, G. D'Andrea, R. Salvaggio, et al. Doxorubicin Followed by Sequential Paclitaxel and Cyclophosphamide versus Concurrent Paclitaxel and Cyclophosphamide: 5-Year Results of a Phase II Randomized Trial of Adjuvant Dose-dense Chemotherapy for Women with Node-positive Breast Carcinoma Clin. Cancer Res., December 1, 2001; 7(12): 3934 - 3941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P A Hill, K M Dwyer, and D A Power Chronic intestinal pseudo-obstruction in systemic lupus erythematosus due to intestinal smooth muscle myopathy Lupus, July 1, 2000; 9(6): 458 - 463. [Abstract] [PDF]
|
|
|
|
|
|
C. Hudis, M. Fornier, L. Riccio, D. Lebwohl, J. Crown, T. Gilewski, A. Surbone, V. Currie, A. Seidman, B. Reichman, et al. 5-Year Results of Dose-Intensive Sequential Adjuvant Chemotherapy for Women With High-Risk Node-Positive Breast Cancer: A Phase II Study J. Clin. Oncol., April 1, 1999; 17(4): 1118 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Hudis, A. Seidman, J. Baselga, G. Raptis, D. Lebwohl, T. Gilewski, M. Moynahan, N. Sklarin, D. Fennelly, J. P.A. Crown, et al. Sequential Dose-Dense Doxorubicin, Paclitaxel, and Cyclophosphamide for Resectable High-Risk Breast Cancer: Feasibility and Efficacy J. Clin. Oncol., January 1, 1999; 17(1): 93 - 93. [Abstract] [Full Text] [PDF]
|
|