title: Phase I clinical trial of the novel platin complex dicycloplatin: clinical and pharmacokinetic results.
abstract: TRANSLATIONAL RELEVANCE: Dicycloplatin (DCP) is a novel super molecule composed of carboplatin (CBP) and 1,1-cyclobutane 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 evaluation 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 Chinese cancer patients. DCP showed favourable 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 cancer study.
  
  
  OBJECTIVE
  Dicycloplatin (DCP) is a novel supramolecule composed of carboplatin (CBP) and 1,1-cyclobutane dicarboxylate (CBDCA) joined by a strong hydrogen bond. DCP is stable in aqueous solution unlike CBP alone. The purpose of this study was to assess the maximally tolerated dose, safety, and pharmacokinetics of DCP in Chinese cancer patients.
  
  
  METHODS
  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 ultrafiltered platinum concentrations in plasma.
  
  
  RESULTS
  29 and 20 patients were evaluated for toxicities and response, respectively. The primary adverse effects were nausea/vomiting (58.6%), thrombocytopenia (24.1%), neutropenia (17.2%), anemia (20.7%), fatigue (10.3%), anorexia (10.3%), liver enzyme 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 observed, 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 cisplatin- or carboplatin-based chemotherapy. Plasma decay of total and free platinum concentrations was best fitted by using a twocompartment analysis. The terminal plasma half-life of total platinum after DCP administration ranged from 41.86 to 77.20 hours without significant dose dependency. However, 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 thrombocytopenia, anemia and emesis. The recommended starting dose for a subsequent Phase II study is 450 mg/m(2) once every 3 weeks.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Beijing, China.
authors.forename: Su
authors.initials: S
authors.lastname: Li
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Hai
authors.initials: H
authors.lastname: Liao
authors.forename: Jing
authors.initials: J
authors.lastname: Zhan
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.forename: Ben-Yan
authors.initials: BY
authors.lastname: Zou
authors.forename: Wen-Qi
authors.initials: WQ
authors.lastname: Jiang
authors.forename: Zhong-Zhen
authors.initials: ZZ
authors.lastname: Guan
authors.forename: Xu-Qing
authors.initials: XQ
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016190:Carboplatin / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy; D002681:China; D003503:Cyclobutanes / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D003998:Dicarboxylic Acids / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010984:Platinum / Q000097:blood; D013921:Thrombocytopenia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
chemical_list: C509875:1,1-cyclobutane dicarboxylate; D000970:Antineoplastic Agents; D003503:Cyclobutanes; D003998:Dicarboxylic Acids; D004338:Drug Combinations; D010984:Platinum; D016190:Carboplatin