Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates

Abstract

Purpose To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies. Experimental Design Patients were treated with (in mg/m2/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days-8 through-6 and etoposide 500 (days-5 through-3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured. Results The topotecan MTD in this regimen was 64 mg/m2 (21.3 mg/m2/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose. Conclusion Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.

Convection Enhanced Delivery of Topotecan for Gliomas: A Single-Center Experience

“…Our investigational therapies have focused on topoisomerase inhibitors, specifically topotecan (TPT). TPT has a long clinical history demonstrating safety in local and systemic delivery [ 21 , 30 , 31 , 32 , 33 ]. The presence of dose limiting systemic toxicities make it an optimal candidate for local delivery.…”

Andrographolide potentiates the antitumor effect of topotecan in acute myeloid leukemia cells through an intrinsic apoptotic pathway

“…Topotecan (TP) is an anticancer drug currently used in the treatment of many types of cancers, including leukemia. 1 , 2 Being a camptothecin analog, TP acts as a topoisomerase I inhibitor by interfering with the enzymatic repair of nuclear DNA, thereby inducing cell death. Studies have shown the antiproliferative effect of TP on glioma cells, small cell lung cancer, prostate cancer cells, platinum-resistant ovarian cancers, neuroblastoma cells, and leukemic cells.…”