High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: A phase II and pharmacodynamic study

Abstract

The premise for this 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 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-SCF in patients with fluoropyrimidine-refractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. 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 advance colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimidine-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 with performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT. 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/microliters for longer than 5 days in 17% of courses involving seven of seventeen (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/microliters 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 4 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 ANC's during course 1, although patients with severe toxic effects (ANC below 500/microliters for more than five days and/or platelets < 25,000/microliters) had higher drug exposure than patients with less severe toxicity (P < 0.018 and P = 0.09, respectively). 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.