Phase I pharmacokinetic and pharmacodynamic study of Carboplatin and topotecan administered intravenously every 28 days to patients with malignant solid tumors.

PURPOSE: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors. EXPERIMENTAL DESIGN: In part 1, patients received carboplatin on day 1 and topotecan on days 1, 2, and 3 (C-->T schedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T-->C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue. RESULTS: Forty-one patients were included. Dose-limiting toxicities during the C-->T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m(2)/d). Dose-limiting toxicities during the T-->C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m(2)/d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C-->T schedule. CONCLUSION: The T-->C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.

Safety and efficacy of patupilone in patients with advanced ovarian, primary fallopian, or primary peritoneal cancer: a phase I, open-label, dose-escalation study.

PURPOSE To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with resistant or refractory ovarian, fallopian, or peritoneal cancer. PATIENTS AND METHODS Patients received patupilone (6.5 to 11.0 mg/m(2)) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m(2)/week; N = 53; OR, 5.7%). CONCLUSION Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m(2). Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m(2) dose.

Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer.

PURPOSE: To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC). PATIENTS AND METHODS: We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis. RESULTS: After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk. CONCLUSION: Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

Urinary and fecal excretion of topotecan in patients with malignant solid tumours.

PURPOSE: The objectives of the study were to determine the pharmacokinetics and routes of excretion of topotecan following intravenous or oral administration to patients with refractory solid tumours. METHODS: Patients were randomized to receive either oral (2.3 mg/m(2)) or intravenous (1.5 mg/m(2)) topotecan once daily for 5 days in course 1. Patients who received in course 1 oral topotecan received in course 2 intravenous topotecan on day 1 followed by oral topotecan on days 2 to 5. Patients who received in course 1 intravenous topotecan received in course 2 oral topotecan once daily for 5 days. Plasma pharmacokinetics were performed on day 1 of course 1 (all patients) and course 2 (only patients receiving intravenous topotecan on that day). In course 1, urine and feces were collected for up to 9 days after the first dosage. The amounts of topotecan and N-desmethyl topotecan in plasma, urine and feces were determined by validated high-performance liquid chromatographic assays. RESULTS: A total of 11 patients were enrolled in the study. Nine patients were evaluable for pharmacokinetics. Plasma pharmacokinetics were similar to those previously reported. The principal route of excretion was the urine, with approximately 49% of the intravenously administered topotecan dose and 20% of the oral dose collected in the urine as parent drug. Approximately 18% and 33% of the intravenous and oral dose, respectively, were recovered unchanged in the feces. Only small amounts of N-desmethyl topotecan were found in the excreta. CONCLUSIONS: Fecal and urinary excretion of unchanged topotecan were the major routes of topotecan elimination. Approximately 28% of the intravenous dose and 43% of the oral dose of topotecan were unaccounted for and eliminated through other routes.

Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin.

PURPOSE: To investigate the safety and pharmacokinetics of a new liposomal formulation of cisplatin, SPI-77, in patients with advanced malignancies. PATIENTS AND METHODS: Patients with histologically proven malignancies not amenable to other treatment were eligible for this study. The starting dose of SPI-77 (cisplatin in Stealth liposomes) was 40 mg/m(2) administered every 4 weeks in a 2-h infusion, and doses were escalated up to 420 mg/m(2). Pharmacokinetic monitoring was performed in all patients and samples were analysed for platinum content by atomic absorption spectroscopy. Platinum-DNA (Pt-DNA) adduct levels in leucocytes (white blood cells, WBC) and tumour tissue were quantified using a sensitive (32)P-postlabelling assay. RESULTS: A total of 27 patients were accrued. The main toxicities observed were infusion-related reactions, which could be prevented by lowering the initial infusion rate, and anaemia. The pharmacokinetics of SPI-77-derived platinum were strikingly different from standard cisplatin. Free platinum levels in plasma ultrafiltrate samples were undetectable at the lowest dose levels (40 and 80 mg/m(2)), and low but highly variable at higher doses of SPI-77. Plasma pharmacokinetics of total platinum were linear with small interpatient variability. The total body clearance of SPI-77 varied from 14 to 30 ml/h and was significantly lower than reported clearance values for cisplatin of 20 l/m(2) per h, due to the slow release of cisplatin from the liposomes. Pt-DNA adduct levels in WBC ranged from 0.02 to 4.13 fmol/microg DNA for intrastrand Pt-GG (guanine-guanine) adducts and from 0.02 to 1.27 fmol/microg DNA for intrastrand Pt-AG (adenosine-guanine) adducts, which is more than tenfold lower than after administration of a comparable dose of non-liposomal cisplatin. In tumour samples obtained from two patients treated at the highest dose-levels, relatively low levels of Pt-DNA adducts were observed. CONCLUSIONS: The results of this phase I trial show that the pharmacokinetic behaviour of cisplatin is significantly altered by its encapsulation in Stealth liposomes. The pharmacokinetics of SPI-77 are mainly dominated by the liposomal properties, resulting in high cholesterol concentrations and relatively low concentrations of (free) platinum in plasma, WBC and tumour tissue, which may explain the observed differences between the toxicity profiles of SPI-77 and cisplatin.

Topoisomerase I levels in white blood cells of patients with ovarian cancer treated with paclitaxel-cisplatin-topotecan in a phase I study.

Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily x 5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 microg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R = -0.64, p = 0.026), in contrast with Topo I levels prior to (R = -0.25, p = 0.4) and after (R = -0.30, p = 0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48 +/- 27%, mean +/- SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0 +/- 4.7 and 2.7 +/- 3.6%, respectively) (p = 0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily x 5 schedule of treatment with topotecan.