Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results

Translational relevance: Di- cycloplatin (DCP) is a novel super molecule composed of carboplatin (CBP) and 1,1-cy- clobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. The solubility and stability of platinum complexes have a direct bearing on their activity, toxicity and pharmacokinetics. Preclinical studies have shown that DCP overcomes the problem of CBP instability in aqueous solution and maintains anticancer effects. Clinical evalu- ation in a Phase I dose-escalation study in patients with tumors showed that DCP was tolerated at doses ranging from 100 to 550 mg/m 2 and had potential efficacy in Chi- nese cancer patients. DCP showed favour- able bioavailability and stability in vivo, and the recommended Phase II dosage for DCP-containing chemotherapy is 450 mg/ m 2 . DCP is currently being investigated as a monotherapy in several cancer types, such as prostatic carcinoma, and in combination with paclitaxel in a Phase II non-lung can- cer study. Purpose: Dicycloplatin (DCP) is a novel supramolecule composed of carbopla- tin (CBP) and 1,1-cyclobutane dicarboxyl- ate (CBDCA) joined by a strong hydrogen bond. DCP is stable in aqueous solution un- like CBP alone. The purpose of this study was to assess the maximally tolerated dose, safety, and pharmacokinetics of DCP in Chi- nese cancer patients. Experimental Design: 29 patients were included in this study. DCP was administered by intravenous infusion over 1 hour once every 21 days. The dose of DCP was escalated from 50 mg/m 2 to 650 mg/m 2 using a modified Fibonacci scheme. Pharmacokinetic analysis was performed in 26 patients to determine the total and ultra- filtered platinum concentrations in plasma. Results: 29 and 20 patients were evaluated for toxicities and response, respectively. The primary adverse effects were nausea/vomit- ing (58.6%), thrombocytopenia (24.1%), neutropenia (17.2%), anemia (20.7%), fa- tigue (10.3%), anorexia (10.3%), liver en- zyme elevation (10.3%) and alopecia (3.5%). There was no significant toxicity with doses up to 350 mg/m 2 . At higher doses, a variety of dose-limiting toxicities (DLTs) were ob- served, including Grade 3/4 anemia, Grade 3/4 thrombocytopenia, and Grade 3/4 emesis under antiemetic treatment. The maximum tolerated dose of DCP was 550 mg/m 2 . Two partial responses occurred in patients with non-cell lung cancer who had received cis- platin- or carboplatin-based chemotherapy. Plasma decay of total and free platinum con- centrations was best fitted by using a two- compartment analysis. The terminal plasma half-life of total platinum after DCP admin- istration ranged from 41.86 to 77.20 hours without significant dose dependency. How- ever, the terminal plasma half-life of free platinum concentrations ranged from 42.34 to 61.07 hours. Conclusions: DCP displayed a favorable safety profile at doses between 50 mg/m 2 and 550 mg/m 2 , and first efficacy signals were observed. DLTs were thrombo- cytopenia, anemia and emesis. The recom- mended starting dose for a subsequent Phase II study is 450 mg/m 2 once every 3 weeks.