Eur J Conccr Ch Oncol, \‘ol. 25, No. 4, pp 627632, 1989. Printed in Great Britain 0277-.;379/R9$3.cil + 0.00 0 1989 Prrqaman Press plc Phase I Studies of Rodorubicin Single Bolus and Daily Times Five, Once Every Three Weeks in Patients with Advanced Solid Tumors zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ JAAP VERWEIJ,* MARIA E.L. VAN DER BURG,* WIM L. VAN PUTTEN,? SONJA C. HENZEN-LOGMANS,: ERICH SALEWSKI,§ HANS P. KRAEMERtj and GERRIT STOTER* zyxwvutsrqpon *Department of Medical Oncology, Rotterdam Cancer Institute, TDepartment of Statistics, Rotterdam Cancer Institute, :Department of Pathology, Rotterdam Cancer Institute, The Netherlands, and §Behringwerke AG, Marburg, F.R.G. Abstract-Rodorubicin (Cytorhodin S, HLB 8 17) is a new tetraglycosidic anthracycline with interesting predinical antitumor a&iv@. We have performed two sequential phase I studies with the drug. In the first study Rodorubicin was administered as a single iv. administration over 30-360 min, once every 3 weeks. The second study concerned a da+ timeshue i.v. bolus schedule. Thirty patients entered these studies. Regardless of schedule, the dose limiting toxicity appeared to beproteinuria, which was reversible after discontinuation of the drug. Phlebitis was a cumbersome side-effect and it was initially considered to determine the MTD in the once every 3 weeks schedule, butjnally it could be prevented by giving the drug as a bolus injection into a rapidly running infusion. Nausea and vomiting were infrequent and mild. Neither myelotoxicity nor alopecia were observed. However, even at low cumulative doses the drug was found to be cardiotoxic using both schedules of administration. Seven out of 12 patients developed grade 1-3 cardiotoxicity, most of them above a cumulative dose of more than 4000 l.r&rn’. These side-effects preclude a dose recommendation for phase II studies with these schedules. INTRODUCTION zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA ANTHRACYCLINES are among the most commonly used cytotoxic drugs in cancer treatment. Their widespread use, their toxicity and the frequent development of resistance of tumor cells against anthracyclines has prompted research for analogs with equal or improved antitumor activity and less toxicity. Rodorubicin (Cytorhodin S; HLB 817) (Fig. 1) is the first compound of a group of tetraglycosidic anthracycline derivatives [ 11. It is a strong intercal- ator acting by nucleic acid synthesis inhibition. The drug is soluble in water and normal saline. In the usual pre-screen the drug was active against L1210 leukemia in vitro, and against B16 melanoma in vivo. In that model it was inactive against other tumors. However, in the human tumor stem cell assay in vitro the drug was found to be active in doxorubicin-sensitive lung cancers and in doxorubicin-resistant breast cancer, ovarian cancer, colon cancer, gastric cancer and pancreatic cancer. Accepted 21 October 1988. Address for correspondence: J. Verweij, M.D., Ph.D., Depart- ment of Medical Oncology, Rotterdam Cancer Institute, Greene Hilledijk 301, 3075 EA Rotterdam, The Netherlands. Besides it was active in vivo in the subcutaneously implanted colon and pancreatic tumors in nude mice. In acute toxicity experiments, mice and rats showed pathological changes in kidney, spleen and heart. In subchronic toxicity studies in rats receiving 5, 16 or 50 p.g/kg/day for 30 days, increases in creatinine were seen in the highest dose group. Renal changes consisted of glomerular and tubular epithelial damage, while cardiac changes were located in the myocardial cells. Subchronic toxicity in beagle dogs with a dose of 5, 16 or 50 *g/kg/day for 30 days only revealed changes in the highest dose group. Serum creatinine became increased which was related to glomerular and tubular dam- age at histology. The ECG showed a prolonged QT interval while at histology signs of cardiac insufficiency were noted. There was no myelo- suppression. The LD,o in mice was 2610 pg/m’. Because of its different antitumor spectrum in preclinical studies as compared to doxorubicin and an expected lower rate of cardiotoxicity, Rodorubicin was selected for clinical studies. We have performed two phase I studies of Rodorubicin which are the subject of this report. 627