nk-121 and Neoplasms

Nine platinum analogs are currently in clinical development, including three that contain the diaminocyclohexane substituent and five that contain the cyclobutanedicarboxylato leaving group. Many of them have shown activity in at least one cisplatin (CDDP)-resistant cell line, most commonly L1210 murine leukemia. In addition, most were less nephrotoxic than CDDP in preclinical evaluations. While these agents share certain key structural similarities, there are important differences in their toxicity profiles that may be exploitable in future combination therapies. Though neuropathy has been a troubling toxicity with two of the three diaminocyclohexane (DACH) compounds, it differs in that it appears to be less chronic and cumulative with oxaliplatin (I-OHP), which is also associated with much less myelosuppression. Of the cyclobutanedicarboxylato compounds that are structurally related to carboplatin (CBDCA), there are several notable differences. For several compounds, isolated neutropenia has been dose-limiting and thrombocytopenia, which is common with CBDCA, has been uncommon. Like CBDCA, neurotoxicity has not been an issue with this group. Therefore, the potential for dose escalation with a colony stimulating factor (CSF) appears enhanced. Furthermore, promising early clinical leads, such as the substantial response rates in cervix and head and neck cancers with 254-S and in patients with colon cancer using circadian modulation of I-OHP, require careful evaluation. Preclinical synergy data are also cited that suggest other potential clinical leads. The development of a number of these agents has been complicated by unanticipated issues, including unexpected chronic dose-limiting neurotoxicity with ormaplatin (OP), formulation and stability problems with liposomal-neodecanoato-diaminocyclohexane platinum (II) (L-NDDP), and problematic nephrotoxicity with zeniplatin (ZP). However, several of these new compounds are likely to enter broader phase II and III development and should provide important information not only about the utility of the agents themselves but also about the predictive value of some of these preclinical models of CDDP resistance.

Topics: Animals; Antineoplastic Agents; Carboplatin; Chemistry, Pharmaceutical; Cyclobutanes; Drugs, Investigational; Forecasting; Humans; Neoplasms; Organoplatinum Compounds; Oxaliplatin

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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carboplatin; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Risk Factors

CI-973, a platinum(II) derivative with a 2-methyl-1,4-butanediamine carrier ligand, has activity in cisplatin-resistant tumor models in vitro and in vivo. In a Phase I pharmacokinetic study, 31 patients were treated with CI-973 (24 to 50 mg/m2/day for 5 days; 28-day cycles) given i.v. over 30 min without routine antiemetic prophylaxis or hydration. Of the 29 patients evaluable for maximum tolerated dose determination, most had a performance status of 0 or 1, and most had received prior chemotherapy. Neutropenia was dose limiting at 40 and 50 mg/m2/day. Recovery from neutropenia was generally rapid with nadir counts and recovery usually occurring by Days 15 and 22, respectively. Drug-associated thrombocytopenia was uncommon and never severe, even in patients with Grade 4 neutropenia. Anemia was common, but did not appear dose related. Drug-related nausea and vomiting and changes in renal function were relatively infrequent and mild. No clinically evident ototoxicity was reported, although changes in audiograms were noted in several patients. CI-973 concentrations were measured in plasma ultrafiltrate and urine by high-pressure liquid chromatography. The harmonic mean terminal half-life was 2.0 h. The mean CI-973 renal and nonrenal clearance values were 42.3 and 37.4 ml/min/m2, respectively. The mean recovery of CI-973 in urine was 53% of the administered dose. The mean ratio of CI-973 renal clearance to creatinine clearance was 0.92. Total clearance correlated with creatinine clearance (r2 = 0.63). A relationship between toxicity, expressed as the percentage of reduction in absolute granulocyte count, and area under the CI-973 plasma concentration-time curve was found in a subgroup of "good-risk" patients. This relationship, described well by a sigmoidal Emax pharmacodynamic model, did not hold for patients with extensive prior therapy or poor performance status. A model for toxicity prediction based on dose and creatinine clearance has been derived and will be validated in future studies. The recommended Phase II dose of CI-973 is 30 mg/m2/day for 5 days.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carboplatin; Drug Administration Schedule; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms

Since the introduction of Cisplatin (CDDP) into clinical practice in 1972, CDDP has assumed an important role in the treatment of various tumors. But its renal toxicity has been proved to be a dose limiting factor. Thus the total number of courses which may be given is limited. For this reason, efforts have been made to develop CDDP analogues with reduced toxicities, especially renal toxicity, and more enhanced antitumor activity, and they are now reaching the clinical testing phase. Among them Carboplatin (CBDCA), 254-S, DWA 2114R and NK 121 have been well studied. These analogues were noted to be less nephrotoxic, but more myelosuppressive than CDDP in preclinical analysis. As for cytotoxicity, their inhibitory effects on tumor growth in murine experimental system were similar or more to that of CDDP. Due to these data clinical trials have been carried out. Phase I studies have shown that these analogues are relatively free of renal toxicity as evaluated in preclinical studies and that their dose limiting factor is myelosuppression. Estimation of cross resistance to CDDP and antitumor spectrum have been studied at phase II trials which are ongoing. Interim reports have not shown that enhanced tumor activity or enlarged antitumor spectrum are expected.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Carboplatin; Cisplatin; Drug Evaluation; Drug Screening Assays, Antitumor; Humans; Kidney; Leukopenia; Mice; Neoplasms; Neoplasms, Experimental; Organoplatinum Compounds; Thrombocytopenia