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 escalat ion of cancer chemotherapy doses. Cyclophosphamide, an alkylating agen t, is an ideal candidate for dose escalation: A log-linear relationshi p between cell kill and dose has been demonstrated, and the drug spare s hematopoietic stem cells. In addition, studies suggest that granuloc yte-macrophage colony-stimulating factor (GM-CSF) can enhance the abil ity to achieve optimal dose intensity as well as ameliorating chemothe rapy-induced myelosuppression. Purpose: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclo phosphamide administered every 2 weeks with GM-CSF support. Methods: F or this trial by the Cancer and Leukemia Group B (CALGB), cohorts of p atients were treated with cyclophosphamide as a 1-hour intravenous inf usion every 14 days; GM-CSF was given subcutaneously on days 3-10. Fou r dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and th ree dose levels of GM-CSF (2.5, 5.0, and 10.0 mug/kg per day) were eva luated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 an d minimal prior radiotherapy were eligible for analysis. Drug clearanc e 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 aft er the start of the infusion. Results: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more res ulted in neutropenia (absolute neutrophil counts <100/muL) in all cycl es 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 e ffects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further thera py. Degree of myelosuppression was not correlated with cyclophosphamid e AUC or clearance. Conclusions: The recommended phase II dose of cycl ophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 mug/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to ac hieve optimal dose intensity, with reproducible blood cell count recov ery and without the need for autologous bone marrow transplantation. I mplications: Phase II studies of this intensive regimen in malignant d iseases sensitive to alkylating agents are currently being done in CAL GB.