The development of clinically useful drugs is a priority of clinical
cancer research.
CI-973, [SP-4-3(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-
1,4- butanediamine-N,N1)
platinum, has been shown in preclinical murine and human
tumor models to have activity equivalent or superior to that of
cisplatin and
carboplatin and to exert activity against
cisplatin-resistant cell lines. In addition, preclinical testing suggests a reduced toxicity profile for
CI-973 as compared with currently available drugs, especially decreased nephrotoxicity,
ototoxicity, and gastrointestinal toxicity. A total of 29 (28 evaluable) patients with solid
tumors were treated with intravenous
CI-973 given over 30 min every 4 weeks. No routine pre- or post-treatment hydration or
antiemetic program was used. The
CI-973 doses given were 75, 150, 170, 188, 230, and 290 mg/m2. The dose-limiting toxicity was
granulocytopenia.
Nausea and
vomiting occurred in the majority of patients but was mild to moderate in severity. No renal or
auditory toxicity was seen. The maximum tolerated dose (MTD) for patients who had a good performance status, had not received prior
radiation therapy to bone marrow, and had not previously been exposed to
platinum or stem-cell toxin was 290 mg/m2. For those who had received prior
radiation therapy, had a performance status of 2 or worse, or had previously been exposed to
platinum or stem-cell toxin, the MTD was 230 mg/m2. The recommended phase II starting doses for these groups of patients are 230 and 190 mg/m2, respectively. No clinical
tumor response was seen in this phase I study.