Phase I Trial of Intraperitoneal Docetaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity: Dose-Limiting Toxicity and Pharmacokinetics

Robert J. Morgan, James H. Doroshow, Timothy Synold, Dean Lim, Stephen Shibata, Kim Margolin, Roderich Schwarz, Lucille Leong, George Somlo, Przemyslaw Twardowski, Yun Yen, Warren Chow, Paul Lin, Benjamin Paz, David Chu, Paul Frankel, Susan Stalter

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Abstract

Purpose: The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. Experimental Design: Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. Results: Tumor types included gastric adenocarcinoma (n = 7), ovarian cancer (n = 4), other gastrointestinal primaries (n = 3), and other cancers (n = 7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m 2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m 2 i.p. docetaxel of 3.14 and 6.33 μM·h (ranges, 1.02-5.88 and 3.97-12.70 μM·h), respectively; the mean peritoneal AUCs were 315 and 1063 μM·h (ranges, 250-373 and 239-2222 μM·h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m 2 i.p. docetaxel were 0.46 and 0.66 μM, and the mean peak peritoneal concentrations at those doses were 59 and 81 μM, respectively. The median and mean pharmacological advantage calculations (AUC peritoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 μM (range, 0.2-1.6 μM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 μM was 31.2 h (range, 27-36.5 h). Conclusions: i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.

Original languageEnglish
Pages (from-to)5896-5901
Number of pages6
JournalClinical Cancer Research
Volume9
Issue number16 I
Publication statusPublished - Dec 1 2003
Externally publishedYes

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docetaxel
Peritoneal Cavity
Pharmacokinetics
Neoplasms
Maximum Tolerated Dose
Sepsis
Therapeutics
Pharmacology
Stomatitis
Ileus
Glomerulonephritis
Neutropenia
Ovarian Neoplasms
Renal Insufficiency
Stomach
Adenocarcinoma
Research Design
Catheters
Carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase I Trial of Intraperitoneal Docetaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity : Dose-Limiting Toxicity and Pharmacokinetics. / Morgan, Robert J.; Doroshow, James H.; Synold, Timothy; Lim, Dean; Shibata, Stephen; Margolin, Kim; Schwarz, Roderich; Leong, Lucille; Somlo, George; Twardowski, Przemyslaw; Yen, Yun; Chow, Warren; Lin, Paul; Paz, Benjamin; Chu, David; Frankel, Paul; Stalter, Susan.

In: Clinical Cancer Research, Vol. 9, No. 16 I, 01.12.2003, p. 5896-5901.

Research output: Contribution to journalArticle

Morgan, RJ, Doroshow, JH, Synold, T, Lim, D, Shibata, S, Margolin, K, Schwarz, R, Leong, L, Somlo, G, Twardowski, P, Yen, Y, Chow, W, Lin, P, Paz, B, Chu, D, Frankel, P & Stalter, S 2003, 'Phase I Trial of Intraperitoneal Docetaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity: Dose-Limiting Toxicity and Pharmacokinetics', Clinical Cancer Research, vol. 9, no. 16 I, pp. 5896-5901.
Morgan, Robert J. ; Doroshow, James H. ; Synold, Timothy ; Lim, Dean ; Shibata, Stephen ; Margolin, Kim ; Schwarz, Roderich ; Leong, Lucille ; Somlo, George ; Twardowski, Przemyslaw ; Yen, Yun ; Chow, Warren ; Lin, Paul ; Paz, Benjamin ; Chu, David ; Frankel, Paul ; Stalter, Susan. / Phase I Trial of Intraperitoneal Docetaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity : Dose-Limiting Toxicity and Pharmacokinetics. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 16 I. pp. 5896-5901.
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abstract = "Purpose: The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. Experimental Design: Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. Results: Tumor types included gastric adenocarcinoma (n = 7), ovarian cancer (n = 4), other gastrointestinal primaries (n = 3), and other cancers (n = 7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m 2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m 2 i.p. docetaxel of 3.14 and 6.33 μM·h (ranges, 1.02-5.88 and 3.97-12.70 μM·h), respectively; the mean peritoneal AUCs were 315 and 1063 μM·h (ranges, 250-373 and 239-2222 μM·h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m 2 i.p. docetaxel were 0.46 and 0.66 μM, and the mean peak peritoneal concentrations at those doses were 59 and 81 μM, respectively. The median and mean pharmacological advantage calculations (AUC peritoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 μM (range, 0.2-1.6 μM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 μM was 31.2 h (range, 27-36.5 h). Conclusions: i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.",
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TY - JOUR

T1 - Phase I Trial of Intraperitoneal Docetaxel in the Treatment of Advanced Malignancies Primarily Confined to the Peritoneal Cavity

T2 - Dose-Limiting Toxicity and Pharmacokinetics

AU - Morgan, Robert J.

AU - Doroshow, James H.

AU - Synold, Timothy

AU - Lim, Dean

AU - Shibata, Stephen

AU - Margolin, Kim

AU - Schwarz, Roderich

AU - Leong, Lucille

AU - Somlo, George

AU - Twardowski, Przemyslaw

AU - Yen, Yun

AU - Chow, Warren

AU - Lin, Paul

AU - Paz, Benjamin

AU - Chu, David

AU - Frankel, Paul

AU - Stalter, Susan

PY - 2003/12/1

Y1 - 2003/12/1

N2 - Purpose: The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. Experimental Design: Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. Results: Tumor types included gastric adenocarcinoma (n = 7), ovarian cancer (n = 4), other gastrointestinal primaries (n = 3), and other cancers (n = 7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m 2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m 2 i.p. docetaxel of 3.14 and 6.33 μM·h (ranges, 1.02-5.88 and 3.97-12.70 μM·h), respectively; the mean peritoneal AUCs were 315 and 1063 μM·h (ranges, 250-373 and 239-2222 μM·h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m 2 i.p. docetaxel were 0.46 and 0.66 μM, and the mean peak peritoneal concentrations at those doses were 59 and 81 μM, respectively. The median and mean pharmacological advantage calculations (AUC peritoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 μM (range, 0.2-1.6 μM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 μM was 31.2 h (range, 27-36.5 h). Conclusions: i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.

AB - Purpose: The purpose of this Phase I study was to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of i.p. docetaxel and to determine the peritoneal pharmacokinetics and pharmacological advantage of this agent. Experimental Design: Twenty-one patients with peritoneal carcinomatosis received docetaxel administered via an implanted i.p. catheter at doses of 40, 80, 100, 125, or 156 mg/m2 every 3 weeks. DLTs on course 1 were used to define the maximum tolerated dose. Results: Tumor types included gastric adenocarcinoma (n = 7), ovarian cancer (n = 4), other gastrointestinal primaries (n = 3), and other cancers (n = 7). Sixty cycles of i.p. docetaxel (median, 2; range, 1-11) were delivered. DLTs occurred in two patients at the 156 mg/m2 dose level; both developed an ileus, and one patient died of neutropenic sepsis. One of five evaluable patients treated with 125 mg/m 2 docetaxel i.p. developed grade 4 neutropenic sepsis and stomatitis; another patient developed renal failure attributable to glomerulonephritis and grade 3 thrombocytopenia that was not judged to be dose-limiting. One of six patients receiving 100 mg/m2 D, the recommended Phase II dose, developed grade 4 neutropenia lasting <5 days. Other non-DLT treatment-related toxicities included dehydration requiring i.v. fluids, emesis, stomatitis, constipation, and abdominal pain. Best response on protocol therapy included 7 of 18 patients with stable disease for a median of 5 cycles (range, 2-11); 11 patients progressed by the first evaluation after a median of 2 cycles (range, 1-3). There were three patients inevaluable for response who received only one cycle of i.p. docetaxel (two because of patient preference and one because of adhesion formation). Pharmacokinetic evaluation revealed mean plasma areas under the curves (AUC) at 100 and 125 mg/m 2 i.p. docetaxel of 3.14 and 6.33 μM·h (ranges, 1.02-5.88 and 3.97-12.70 μM·h), respectively; the mean peritoneal AUCs were 315 and 1063 μM·h (ranges, 250-373 and 239-2222 μM·h), respectively. The mean peak plasma concentrations at 100 and 125 mg/m 2 i.p. docetaxel were 0.46 and 0.66 μM, and the mean peak peritoneal concentrations at those doses were 59 and 81 μM, respectively. The median and mean pharmacological advantage calculations (AUC peritoneal/AUCplasma) across all dose levels were 152 and 181, respectively (range, 18.8-367.4). The mean peritoneal 24- and 96-h concentrations were 0.9 μM (range, 0.2-1.6 μM) and <0.1 nM, respectively. The mean time that the concentration was >0.1 μM was 31.2 h (range, 27-36.5 h). Conclusions: i.p. docetaxel can be safely delivered at a dose of 100 mg/m2 i.p. every 3 weeks. This route of administration provides a significant peritoneal pharmacological advantage while delivering systemic concentrations consistent with the administration of standard i.v. doses.

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