Phase I study of docosahexaenoic acid-paclitaxel: A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile

Antonio C Wolff, Ross C Donehower, M. Katherine Carducci, Michael A Carducci, Julie Brahmer, Yelena Zabelina, Matthews O. Bradley, Forrest H. Anthony, Charles S. Swindell, Philip A. Witman, Nigel L. Webb, Sharyn D. Baker

Research output: Contribution to journalArticle

Abstract

Purpose: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs). Experimental Design: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel. Results: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m2). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m2); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m2. Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m2, DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, β half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m2 were: Cmax, 282 (46) ng/ml; AUC, 10,705 (60) ng/ml × h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented ≤0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed. Conclusions: The starting dose recommended for subsequent studies is 1100 mg/m2. DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/ m2). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.

Original languageEnglish (US)
Pages (from-to)3589-3597
Number of pages9
JournalClinical Cancer Research
Volume9
Issue number10 I
StatePublished - Oct 1 2003

Fingerprint

Fatty Acids
Paclitaxel
Pharmacology
Pharmacokinetics
Neutropenia
Area Under Curve
Half-Life
Taxoids
Febrile Neutropenia
taxane
docosahexaenoyl-paclitaxel
Alopecia
Prodrugs
Peripheral Nervous System Diseases
Research Design
Urine
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I study of docosahexaenoic acid-paclitaxel : A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile. / Wolff, Antonio C; Donehower, Ross C; Carducci, M. Katherine; Carducci, Michael A; Brahmer, Julie; Zabelina, Yelena; Bradley, Matthews O.; Anthony, Forrest H.; Swindell, Charles S.; Witman, Philip A.; Webb, Nigel L.; Baker, Sharyn D.

In: Clinical Cancer Research, Vol. 9, No. 10 I, 01.10.2003, p. 3589-3597.

Research output: Contribution to journalArticle

Wolff, AC, Donehower, RC, Carducci, MK, Carducci, MA, Brahmer, J, Zabelina, Y, Bradley, MO, Anthony, FH, Swindell, CS, Witman, PA, Webb, NL & Baker, SD 2003, 'Phase I study of docosahexaenoic acid-paclitaxel: A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile', Clinical Cancer Research, vol. 9, no. 10 I, pp. 3589-3597.
Wolff, Antonio C ; Donehower, Ross C ; Carducci, M. Katherine ; Carducci, Michael A ; Brahmer, Julie ; Zabelina, Yelena ; Bradley, Matthews O. ; Anthony, Forrest H. ; Swindell, Charles S. ; Witman, Philip A. ; Webb, Nigel L. ; Baker, Sharyn D. / Phase I study of docosahexaenoic acid-paclitaxel : A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 10 I. pp. 3589-3597.
@article{d4a000a527c74101ad5a0c2b96d27669,
title = "Phase I study of docosahexaenoic acid-paclitaxel: A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile",
abstract = "Purpose: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs). Experimental Design: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel. Results: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m2). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21{\%}/53{\%} of courses at 1100 mg/m2); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m2. Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m2, DHA-paclitaxel had a mean (CV{\%}) volume of distribution of 7.5 (64) liters, β half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m2 were: Cmax, 282 (46) ng/ml; AUC, 10,705 (60) ng/ml × h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented ≤0.06{\%} of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed. Conclusions: The starting dose recommended for subsequent studies is 1100 mg/m2. DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/ m2). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.",
author = "Wolff, {Antonio C} and Donehower, {Ross C} and Carducci, {M. Katherine} and Carducci, {Michael A} and Julie Brahmer and Yelena Zabelina and Bradley, {Matthews O.} and Anthony, {Forrest H.} and Swindell, {Charles S.} and Witman, {Philip A.} and Webb, {Nigel L.} and Baker, {Sharyn D.}",
year = "2003",
month = "10",
day = "1",
language = "English (US)",
volume = "9",
pages = "3589--3597",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "10 I",

}

TY - JOUR

T1 - Phase I study of docosahexaenoic acid-paclitaxel

T2 - A taxane-fatty acid conjugate with a unique pharmacology and toxicity profile

AU - Wolff, Antonio C

AU - Donehower, Ross C

AU - Carducci, M. Katherine

AU - Carducci, Michael A

AU - Brahmer, Julie

AU - Zabelina, Yelena

AU - Bradley, Matthews O.

AU - Anthony, Forrest H.

AU - Swindell, Charles S.

AU - Witman, Philip A.

AU - Webb, Nigel L.

AU - Baker, Sharyn D.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Purpose: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs). Experimental Design: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel. Results: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m2). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m2); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m2. Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m2, DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, β half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m2 were: Cmax, 282 (46) ng/ml; AUC, 10,705 (60) ng/ml × h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented ≤0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed. Conclusions: The starting dose recommended for subsequent studies is 1100 mg/m2. DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/ m2). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.

AB - Purpose: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs). Experimental Design: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel. Results: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200-1100 mg/m2). Median number of cycles was 2 (range, 1-8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m2); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m2. Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m2, DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, β half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m2 were: Cmax, 282 (46) ng/ml; AUC, 10,705 (60) ng/ml × h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented ≤0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed. Conclusions: The starting dose recommended for subsequent studies is 1100 mg/m2. DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/ m2). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.

UR - http://www.scopus.com/inward/record.url?scp=12444330550&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12444330550&partnerID=8YFLogxK

M3 - Article

C2 - 14506145

AN - SCOPUS:12444330550

VL - 9

SP - 3589

EP - 3597

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 10 I

ER -