Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.

Carlos Rodriguez-Galindo, Kristine R. Crews, Clinton F. Stewart, Wayne Furman, J. Carl Panetta, Najat C. Daw, Alvida Cain, Ming Tan, Peter J Houghton, Victor M. Santana

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.

Original languageEnglish (US)
Pages (from-to)15-24
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume57
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

Fingerprint

irinotecan
Topotecan
Refractory materials
Tumors
Toxicity
Neoplasms
Appointments and Schedules
Pharmacokinetics
Maximum Tolerated Dose
Typhlitis
Camptothecin
Aptitude
Rhabdomyosarcoma

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Rodriguez-Galindo, C., Crews, K. R., Stewart, C. F., Furman, W., Panetta, J. C., Daw, N. C., ... Santana, V. M. (2006). Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors. Cancer Chemotherapy and Pharmacology, 57(1), 15-24. https://doi.org/10.1007/s00280-005-0030-7

Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors. / Rodriguez-Galindo, Carlos; Crews, Kristine R.; Stewart, Clinton F.; Furman, Wayne; Panetta, J. Carl; Daw, Najat C.; Cain, Alvida; Tan, Ming; Houghton, Peter J; Santana, Victor M.

In: Cancer Chemotherapy and Pharmacology, Vol. 57, No. 1, 01.01.2006, p. 15-24.

Research output: Contribution to journalArticle

Rodriguez-Galindo, C, Crews, KR, Stewart, CF, Furman, W, Panetta, JC, Daw, NC, Cain, A, Tan, M, Houghton, PJ & Santana, VM 2006, 'Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.', Cancer Chemotherapy and Pharmacology, vol. 57, no. 1, pp. 15-24. https://doi.org/10.1007/s00280-005-0030-7
Rodriguez-Galindo, Carlos ; Crews, Kristine R. ; Stewart, Clinton F. ; Furman, Wayne ; Panetta, J. Carl ; Daw, Najat C. ; Cain, Alvida ; Tan, Ming ; Houghton, Peter J ; Santana, Victor M. / Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors. In: Cancer Chemotherapy and Pharmacology. 2006 ; Vol. 57, No. 1. pp. 15-24.
@article{483dd27b6c104d01aa143728d6781a8d,
title = "Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.",
abstract = "PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.",
author = "Carlos Rodriguez-Galindo and Crews, {Kristine R.} and Stewart, {Clinton F.} and Wayne Furman and Panetta, {J. Carl} and Daw, {Najat C.} and Alvida Cain and Ming Tan and Houghton, {Peter J} and Santana, {Victor M.}",
year = "2006",
month = "1",
day = "1",
doi = "10.1007/s00280-005-0030-7",
language = "English (US)",
volume = "57",
pages = "15--24",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.

AU - Rodriguez-Galindo, Carlos

AU - Crews, Kristine R.

AU - Stewart, Clinton F.

AU - Furman, Wayne

AU - Panetta, J. Carl

AU - Daw, Najat C.

AU - Cain, Alvida

AU - Tan, Ming

AU - Houghton, Peter J

AU - Santana, Victor M.

PY - 2006/1/1

Y1 - 2006/1/1

N2 - PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.

AB - PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.

UR - http://www.scopus.com/inward/record.url?scp=33644696212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644696212&partnerID=8YFLogxK

U2 - 10.1007/s00280-005-0030-7

DO - 10.1007/s00280-005-0030-7

M3 - Article

C2 - 16001174

AN - SCOPUS:33644696212

VL - 57

SP - 15

EP - 24

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -