Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial.
OBJECTIVE
Resistance to topoisomerase (TOP) 1 and 2 inhibitors is a potentially important reason for treatment failure, and may be related, in part, to a down-regulation of the specific TOP target. Investigators in our laboratories previously noted such a down-regulation of the target, along with a reciprocal up-regulation of the alternate TOP. Therefore, sequencing TOP inhibitors may provide a means for overcoming resistance to the TOP I and II inhibitors. Furthermore, point mutations in TOP I, which confer resistance to TOP I inhibitors, were associated with collateral sensitivity to cisplatin.


METHODS
A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m(2)/day) on days 1 to 3 with etoposide (70-80 mg/m(2)/day) and cisplatin (20-25 mg/m(2)/day) on days 8 to 10. The timing of the drug sequence was based on the prior Phase I pharmacokinetic and pharmacodynamic studies of camptothecin and etoposide, and the level of the TOP targets in peripheral blood monocytes.


RESULTS
Fifteen patients (7 males and 8 females) received 40 courses of therapy across three dose levels. The median age was 56 (range, 39-77), and the median performance status was 1 (range, 0-2). The diagnoses included: non-small cell lung cancer (7), head and neck cancer (2), cancer of unknown primary (2), and 1 each of ovarian cancer, prostate cancer, gastric cancer, and renal cancer. Level 1 (topotecan 1.0 mg/m(2)/day; etoposide 80 mg/m(2)/day; and cisplatin 25 mg/m(2)/day) produced severe and prolonged febrile neutropenia in the first patient treated, and the subsequent patients were then entered onto a reduced dose level (cohort 2: topotecan 0.75 mg/m(2)/day; etoposide 70 mg/m(2)/day; and cisplatin 20 mg/m(2)/day). Three of 6 patients on cohort 2 experienced grade IV neutropenia >5 days, and a decision was then made to add filgrastim at 5 micro g/kg rather than additionally reduce the dosages (cohort 3). Eight patients were then treated on cohort 3, and 1 of the 8 patients experienced a grade 4 neutropenia. Thus, cohort level three was considered the recommended dose for Phase II studies. Twelve of the 15 patients had disease assessable for response to therapy. Seven achieved stable disease for >/==" BORDER="0">2 months, whereas 5 showed continued progression of their disease.


CONCLUSIONS
These data show that sequencing TOP 1 and 2 inhibitors is feasible, and topotecan 0.75 mg/m(2)/day days 1-3; etoposide 70 mg/m(2)/day days 8-10; and cisplatin 20 mg/m(2)/day days 8-10 with filgrastim at 5 micro g/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.
Aisner
Joseph
J
Division of Medical Oncology, Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Jersey 08903, USA.
Musanti
Rita
R
Beers
Stephanie
S
Smith
Sharon
S
Locsin
Stephanie
S
Rubin
Eric H
EH
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D019772:Topotecan / Q000008:administration & dosage*; D016896:Treatment Outcome
D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D019772:Topotecan; D002945:Cisplatin