PHASE-I AND PHARMACOLOGICAL STUDY OF THE ALKYLATING AGENT MODULATOR NOVOBIOCIN IN COMBINATION WITH HIGH-DOSE CHEMOTHERAPY FOR THE TREATMENTOF METASTATIC BREAST-CANCER

Purpose: Resistance to alkylators may potentially be overcome by drugs that inhibits DNA repair, thus improving the efficacy of high-dose ch emotherapy. This trial wets performed to determine if novobiocin, an a gent that inhibits DNA repair, could be given with high-dose alkylator s. Study aims were to define the toxicities and maximal-tolerated dose (MTD) of novobiocin and the pharmacokinetics of novobiocin and high-d ose cyclophosphamide and thiotepa. Patients and Methods: Thirty-eight women with responsive metastatic breast cancer received high-dose cycl ophosphamide (3 to 6 g/m(2) over 4 days), thiotepa (400 to 800 mg/m(2) ), and novobiocin (0.5 to 5.0 g/d x 7, orally) with autologous marrow support. Toxicity was monitored, The pharmacology of novobiocin, cyclo phosphamide, and thiotepa wets evaluated. Results: there were no toxic deaths, The MTD of novobiocin was 4 g/d. All seven patients treated a t 5 g/d developed grade III/IV mucositis and vomiting, The severity of mucositis correlated with the plasma levels of novobiocin, Other seve re toxicities were not observed, Plasma novobiocin levels greater than or equal to 100 mu g/mL, which are associated with reversal of drug r esistance in animal models, were consistently seen at dose levels grea ter than 2 g. The dispositions of cyclophosphamide and thiotepa were n ot altered by novobiocin. Conclusion: Novobiocin may be given with hig h-dose alkylators in doses that produce plasma levels that augment the activity of these cytotoxics in experimental models, The pharmacology of high-dose cyclophosphamide and thiotepa is unaffected. Novobiocin 4 g/d orally for 7 days is recommended for future study. (C) 1995 by A merican Society of Clinical Oncology.