Pharmacokinetic And Pharmacodynamic Analysis Of Topotecan Administered In Combination With Ps 341 In Patients With Advanced Malignancy.

2033 Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m2. Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted. No significant financial relationships to disclose.