High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer

A phase II and parmacodynamic study

E. K. Rowinsky, S. D. Baker, K. Burks, S. O'Reilly, Ross C Donehower, L. B. Grochow

Research output: Contribution to journalArticle

Abstract

Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p- glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the antitumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdinerefractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/μ1 for longer than five days in 17% of courses involving seven of 17 (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/μl were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short - 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/μl for more than five days and/or platelets <25,000/μl) had higher drug exposure than patients with less severe toxicity (P <0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.

Original languageEnglish (US)
Pages (from-to)173-180
Number of pages8
JournalAnnals of Oncology
Volume9
Issue number2
DOIs
StatePublished - Feb 1998

Fingerprint

Topotecan
Granulocyte Colony-Stimulating Factor
Colorectal Neoplasms
Maximum Tolerated Dose
Neoplasms
Pharmaceutical Preparations
Neutrophils
Blood Platelets
Pharmacokinetics
Poisons
Adjuvant Chemotherapy
Neutropenia
Platelet Count

Keywords

  • Colorectal cancer
  • Granulocyte-colony stimulating factor
  • Pharmacokinetics
  • Phase II
  • Topotecan

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer : A phase II and parmacodynamic study. / Rowinsky, E. K.; Baker, S. D.; Burks, K.; O'Reilly, S.; Donehower, Ross C; Grochow, L. B.

In: Annals of Oncology, Vol. 9, No. 2, 02.1998, p. 173-180.

Research output: Contribution to journalArticle

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title = "High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer: A phase II and parmacodynamic study",
abstract = "Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p- glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the antitumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdinerefractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/μ1 for longer than five days in 17{\%} of courses involving seven of 17 (41{\%}) patients. Severe neutropenia associated with fever occurred in 12.3{\%} of courses; and platelet counts below 25,000/μl were noted in 26.9{\%} of courses. These toxicities resulted in dose reductions in seven of 17 (41{\%}) patients. Nevertheless, 90{\%} of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short - 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/μl for more than five days and/or platelets <25,000/μl) had higher drug exposure than patients with less severe toxicity (P <0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20{\%}. Although a response rate of less than 20{\%} might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.",
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T1 - High-dose topotecan with granulocyte-colony stimulating factor in fluoropyrimidine-refractory colorectal cancer

T2 - A phase II and parmacodynamic study

AU - Rowinsky, E. K.

AU - Baker, S. D.

AU - Burks, K.

AU - O'Reilly, S.

AU - Donehower, Ross C

AU - Grochow, L. B.

PY - 1998/2

Y1 - 1998/2

N2 - Purpose: The premise for the study was that topotecan (TPT) resistance in preclinical studies is associated with low level expression of the p- glycoprotein (Pgp) multi-drug transporter conferred by the multi-drug resistant (MDR) phenotype, which might be overcome in clinical practice by administering moderately (2.3-fold) higher doses of TPT that have been shown to be feasible with granulocyte colony-stimulating factor (G-CSF) support. This phase II study evaluated the antitumor activity of TPT administered at its highest possible solid tumor dose with G-CSF in patients with fluoropyrimdinerefractory advanced colorectal carcinoma. The study also sought to identify pharmacodynamic (PD) determinants of both activity and toxicity. Patients and methods: TPT was administered as a 30-minute infusion daily for five days every three weeks at a dose of 3.5 mg/m2/day to patients with advanced colorectal carcinoma who developed progressive disease either during treatment with fluoropyrimidine-based chemotherapy for advanced disease or within six months after receiving fluoropyrimdine-based adjuvant chemotherapy. This dose of TPT was previously determined to be the maximal tolerated dose (MTD) with G-CSF support in a phase I study involving solid tumor patients with similar risk factors for myelosuppression. Plasma sampling was performed during course 1 to characterize the pharmacokinetic (PK) and PD behavior of TPT Results: Seventeen patients who received 89 courses of TPT and G-CSF were evaluable for toxicity; 16 patients were evaluable for anti-tumor response. Toxicity, particularly myelosuppression, was substantial. At the 3.5 mg/m2/day dose level, absolute neutrophil counts (ANC) were less than 500/μ1 for longer than five days in 17% of courses involving seven of 17 (41%) patients. Severe neutropenia associated with fever occurred in 12.3% of courses; and platelet counts below 25,000/μl were noted in 26.9% of courses. These toxicities resulted in dose reductions in seven of 17 (41%) patients. Nevertheless, 90% of the planned total dose of TPT was administered. No major responses were observed, though minor activity was noted in several patients. Both the median time to progression and the median survival time were short - 2.5 and four months, respectively. Although interindividual variability in the disposition of total TPT was observed, the lack of objective responses precluded PD assessments related to disease activity. Total TPT exposure was significantly higher than drug exposure achieved in similar patients at an identical dose in a previous phase I study of TPT and G-CSF, which may explain why more severe myelosuppressive effects occurred in the present study. There were no PD relationships evident between relevant PK parameters and the percent decrements in platelets and ANCs during course 1, although patients with severe toxic effects (ANC below 500/μl for more than five days and/or platelets <25,000/μl) had higher drug exposure than patients with less severe toxicity (P <0.018 and P = 0.09, respectively). Conclusions: Based on these results, the true response rate of TPT at its solid tumor MTD with G-CSF support is unlikely to approach 20%. Although a response rate of less than 20% might be viewed as significant in this disease setting and might be confirmed with sufficient statistical certainty by treating additional patients, the substantial toxicity, inconvenience, and cost associated with this high dose TPT/G-CSF regimen does not warrant the acceptance of a lower level of anti-tumor activity as a criterion for further development.

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KW - Granulocyte-colony stimulating factor

KW - Pharmacokinetics

KW - Phase II

KW - Topotecan

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