Phase I clinical evaluation of [SP-4-3(R)]-[1,1-cyclobutanedicarboxylato(2-)](2-methyl-1,4-butanediamine-N,N 1) platinum in patients with metastatic solid tumors

Abstract

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.

The status of platinum anticancer drugs in the clinic and in clinical trials

“…73, 74 Two Phase I trials were completed with sebriplatin as a daily ¥ 5 and a once monthly IV infusion. 75,76 In the multiple dosing trial neutropenia was the DLT, but was rapidly recoverable, with mild/infrequent vomiting and nausea. 75 The MTD was determined to be 40-50 mg m -2 from which a Phase II dose of 30 mg m -2 day -1 for 5 days was recommended.…”

“…75 In the once monthly trial a MTD of 290 mg m -2 was determined with granulocytopenia as the DLT for patients previously untreated with platinum, radiation or stem cell toxin therapy, and a MTD of 230 mg m -2 for those who had previously been treated with at least one of these regimes. 76 Doses of 230 and 190 mg m -2 were recommended for Phase II trials in these groups of patients.…”

A Phase 2 study of cisplatin analog CI-973 in the treatment of patients with refractory, advanced ovarian cancer

“…There was also no evidence of neurotoxicity. Phase I studies in patients with solid tumors established that neutropenia was the doselimiting toxicity, and confirmed that CI-973 was not seriously nephrotoxic, neurotoxic, or ototoxic (7)(8)(9). Furthermore, it did not cause severe thrombocytopenia, even in patients who developed Grade IV neutropenia.…”

“…in vitro and in vivo (4)(5)(6). Phase I studies in patients with solid tumors indicate that, unlike cisplatin, CI-973 does not appear to cause serious renal toxicity, neurotoxicity, or ototoxicity (7)(8)(9). CI-973 is myelosuppressive, causing dose-limiting neutropenia, but is not associated with the dose-limiting thrombocytopenia characteristic of carboplatin therapy.…”

Platinum-Based Compounds for the Treatment of Metastatic Breast Cancer

“…CI-973, a water-soluble platinum diamine complex, showed activity equivalent or superior to that of cisplatin and carboplatin and was active against cisplatin-resistant tumors in phase I trials, with lower side effects [26]. In a phase II trial on 26 previously treated patients with MBC, CI-973 was administered intravenously at a dose of 230 mg/m 2 over 30 min at 3-week intervals.…”