PHASE-I STUDY OF THE NOVEL DISTAMYCIN DERIVATIVE TALLIMUSTINE (FCE-24517)

Background: Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds t o A-T rich regions of DNA in the minor groove producing highly sequenc e-specific alkylations. Its main preclinical features are a significan t antitumour activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in an imals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. Patients and methods: Forty adult patients (pt s) with solid malignancies were entered in the study. The drug was adm inistered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week fo llowing the first cycle. From the starting dose of 50 mu g/m(2), corre sponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there we re increases through 10 dose levels, with reliance only on the feature s of the myelotoxicity observed. Results: The main toxic effect was ne utropenia which was dose-limiting, selective and short-lasting. Only p reviously-untreated pts received doses of 750 mu g/m(2) or more, with grade 4 neutropenia occurring in greater than or equal to 75% of the c ycles. The maximally tolerable dose (MTD) was defined as 1250 mu g/m(2 ), with 3 of 3 pts developing febrile neutropenia requiring TV antibio tics. A platelet count of < 100 x 10(3)/mu l was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharma cokinetic studies performed at 1000 mu g/m(2) and 1250 mu g/m(2) showe d a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previous ly-untreated pt with cutaneous recurrences of malignant mesothelioma. Conclusions: The report of some antitumour efficacy, the high selectiv ity of neutropenia, the lack of significant nonhematological toxic eff ects and the occurrence of detectable but still low plasma drug concen trations suggest that further clinical evaluation of higher doses of t allimustine in combination with colony-stimulating factors would be ju stified.