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Notes: Abstract Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p-glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the anti-tumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/µl for longer than five days in 17% of courses involving seven of 17 (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/µl were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short – 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/µl for more than five days and/or platelets 〈25,000/µl) had higher drug exposure than patients with less severe toxicity (P 〈 0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.

Notes: Abstract  The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22±28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3±1.6 h in the fasting state to 2.5±1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16±51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.

Notes: Abstract Background: The objectives were to determine the dose-limiting toxicity of topotecan in combination with cisplatin, to describe the principal toxicities, and to define the maximally-tolerated doses of the drugs in previously untreated patients with advanced non-small-cell lung carcinoma. Patients and methods: The study was designed to evaluate escalated doses of topotecan (starting at 0.75 mg/m2/day) as a 30-minute infusion daily for five consecutive days with a fixed clinically-relevant dose of 75 mg/m2 cisplatin given on day 1, every three weeks. Results: Fifteen chemotherapy-naïve patients entered the study and 14 were evaluable for toxicity. All 11 patients treated at the first topotecan/cisplatin dose level of 0.75/75 mg/m2, experienced at least one episode of grade 4 neutropenia. For six patients, absolute neutrophil counts were below 500/ml for more than five days, and two of them developed a grade 4 thrombocytopenia. At the next higher topotecan/cisplatin dose level (1.0/75 mg/m2), grade 4 neutropenia lasting longer than five days occurred in all three evaluable patients, including one patient who expired due to a severe neutropenia associated with sepsis. Non-hematologic toxicities, predominantly nausea and vomiting, were mild to moderate in severity and manageable. Four patients had partial responses (30.7%; 95% confidence interval (9%–61%) of relatively short duration. Conclusion: Both severe neutropenia and thrombocytopenia precluded dose escalation of topotecan and cisplatin administered on this schedule. In previously untreated patients, the first topotecan/cisplatin dose level (0.75/75 mg/m2), was associated with intolerable myelosuppression, and, therefore, the dose levels evaluated in this study cannot be recommended for subsequent phase II investigations. The high toxicity of this schedule and the recent understanding of the pharmacokinetic interaction between those drugs may encourage the investigation of the alternate sequence of cisplatin after TPT in phase II studies.