Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: A pharmacodynamically based Phase I trial

Joseph Aisner, Rita Musanti, Stephanie Beers, Sharon Smith, Stephanie Locsin, Eric H. Rubin

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m2/day) on days 1 to 3 with etoposide (70-80 mg/m2/day) and cisplatin (20-25 mg/ m2/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/m2/day; etoposide 80 mg/m2/day; and cisplatin 25 mg/m2/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/m2/day; etoposide 70 mg/m2/ day; and cisplatin 20 mg/m2/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 μg/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 ≥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/m2/day days 1-3; etoposide 70 mg/m2/day days 8-10; and cisplatin 20 mg/m2/day days 8-10 with filgrastim at 5 μg/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

Original languageEnglish (US)
Pages (from-to)2504-2509
Number of pages6
JournalClinical Cancer Research
Volume9
Issue number7
StatePublished - Jul 1 2003

Fingerprint

Topotecan
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Etoposide
Cisplatin
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Head and Neck Neoplasms
Neutropenia
Stomach Neoplasms
Prostatic Neoplasms
Down-Regulation
Febrile Neutropenia
Camptothecin
Kidney Neoplasms
Treatment Failure
Point Mutation
Non-Small Cell Lung Carcinoma
Ovarian Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{14fb54cca5f94a98972697a19cf08418,
title = "Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance: A pharmacodynamically based Phase I trial",
abstract = "Purpose: 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. Experimental Design: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m2/day) on days 1 to 3 with etoposide (70-80 mg/m2/day) and cisplatin (20-25 mg/ m2/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/m2/day; etoposide 80 mg/m2/day; and cisplatin 25 mg/m2/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/m2/day; etoposide 70 mg/m2/ day; and cisplatin 20 mg/m2/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 μg/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 ≥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/m2/day days 1-3; etoposide 70 mg/m2/day days 8-10; and cisplatin 20 mg/m2/day days 8-10 with filgrastim at 5 μg/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.",
author = "Joseph Aisner and Rita Musanti and Stephanie Beers and Sharon Smith and Stephanie Locsin and Rubin, {Eric H.}",
year = "2003",
month = "7",
day = "1",
language = "English (US)",
volume = "9",
pages = "2504--2509",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance : A pharmacodynamically based Phase I trial. / Aisner, Joseph; Musanti, Rita; Beers, Stephanie; Smith, Sharon; Locsin, Stephanie; Rubin, Eric H.

In: Clinical Cancer Research, Vol. 9, No. 7, 01.07.2003, p. 2504-2509.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sequencing topotecan and etoposide plus cisplatin to overcome topoisomerase I and II resistance

T2 - A pharmacodynamically based Phase I trial

AU - Aisner, Joseph

AU - Musanti, Rita

AU - Beers, Stephanie

AU - Smith, Sharon

AU - Locsin, Stephanie

AU - Rubin, Eric H.

PY - 2003/7/1

Y1 - 2003/7/1

N2 - Purpose: 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. Experimental Design: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m2/day) on days 1 to 3 with etoposide (70-80 mg/m2/day) and cisplatin (20-25 mg/ m2/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/m2/day; etoposide 80 mg/m2/day; and cisplatin 25 mg/m2/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/m2/day; etoposide 70 mg/m2/ day; and cisplatin 20 mg/m2/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 μg/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 ≥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/m2/day days 1-3; etoposide 70 mg/m2/day days 8-10; and cisplatin 20 mg/m2/day days 8-10 with filgrastim at 5 μg/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

AB - Purpose: 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. Experimental Design: A dose escalating Phase I trial of topotecan (at doses of 0.75 to 1.0 mg/m2/day) on days 1 to 3 with etoposide (70-80 mg/m2/day) and cisplatin (20-25 mg/ m2/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/m2/day; etoposide 80 mg/m2/day; and cisplatin 25 mg/m2/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/m2/day; etoposide 70 mg/m2/ day; and cisplatin 20 mg/m2/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 μg/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 ≥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/m2/day days 1-3; etoposide 70 mg/m2/day days 8-10; and cisplatin 20 mg/m2/day days 8-10 with filgrastim at 5 μg/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=0037479850&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037479850&partnerID=8YFLogxK

M3 - Article

C2 - 12855624

AN - SCOPUS:0037479850

VL - 9

SP - 2504

EP - 2509

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -