Phase I Trial of Granulocyte—Macrophage Colony-Stimulating Factor Plus High-Dose Cyclophosphamide Given Every 2 Weeks: a Cancer and Leukemia Group B Study

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 × 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