A phase i study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

John F. Deeken, Rebecca Slack, Glen J. Weiss, Ramesk K Ramanathan, Michael J. Pishvaian, Jimmy Hwang, Karen Lewandowski, Deepa Subramaniam, Aiwu Ruth He, Ion Cotarla, Aquilur Rahman, John L. Marshall

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Background: Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. Methods: LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m2 IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis. Results: Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m2. Two out of two patients experienced grade 4 neutropenia at the 132 mg/m2 dose level. When an additional three patients were treated at the expanded 110 mg/m2 dose level, two experienced grade 4 neutropenia. The 85 mg/m2 dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m2 with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %. Conclusion: LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m2 without G-CSF or 110 mg/m2 with G-CSF.

Original languageEnglish (US)
Pages (from-to)627-633
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

Fingerprint

docetaxel
Toxicity
Tumors
Pharmacokinetics
Granulocyte Colony-Stimulating Factor
Neoplasms
Neutropenia
Pharmaceutical Preparations
Drug Carriers
Liposomes
Solubility

Keywords

  • Clinical trial
  • Docetaxel
  • Liposomes
  • Phase I

ASJC Scopus subject areas

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

Cite this

A phase i study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. / Deeken, John F.; Slack, Rebecca; Weiss, Glen J.; Ramanathan, Ramesk K; Pishvaian, Michael J.; Hwang, Jimmy; Lewandowski, Karen; Subramaniam, Deepa; He, Aiwu Ruth; Cotarla, Ion; Rahman, Aquilur; Marshall, John L.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 3, 03.2013, p. 627-633.

Research output: Contribution to journalArticle

Deeken, JF, Slack, R, Weiss, GJ, Ramanathan, RK, Pishvaian, MJ, Hwang, J, Lewandowski, K, Subramaniam, D, He, AR, Cotarla, I, Rahman, A & Marshall, JL 2013, 'A phase i study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies', Cancer Chemotherapy and Pharmacology, vol. 71, no. 3, pp. 627-633. https://doi.org/10.1007/s00280-012-2048-y
Deeken, John F. ; Slack, Rebecca ; Weiss, Glen J. ; Ramanathan, Ramesk K ; Pishvaian, Michael J. ; Hwang, Jimmy ; Lewandowski, Karen ; Subramaniam, Deepa ; He, Aiwu Ruth ; Cotarla, Ion ; Rahman, Aquilur ; Marshall, John L. / A phase i study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 3. pp. 627-633.
@article{11f040d5c3714b35bdf776f5aac470dd,
title = "A phase i study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies",
abstract = "Background: Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. Methods: LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m2 IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis. Results: Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m2. Two out of two patients experienced grade 4 neutropenia at the 132 mg/m2 dose level. When an additional three patients were treated at the expanded 110 mg/m2 dose level, two experienced grade 4 neutropenia. The 85 mg/m2 dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m2 with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 {\%}), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 {\%}) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 {\%}. Conclusion: LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 {\%} of the patients. The recommended phase II dose of LE-DT is 85 mg/m2 without G-CSF or 110 mg/m2 with G-CSF.",
keywords = "Clinical trial, Docetaxel, Liposomes, Phase I",
author = "Deeken, {John F.} and Rebecca Slack and Weiss, {Glen J.} and Ramanathan, {Ramesk K} and Pishvaian, {Michael J.} and Jimmy Hwang and Karen Lewandowski and Deepa Subramaniam and He, {Aiwu Ruth} and Ion Cotarla and Aquilur Rahman and Marshall, {John L.}",
year = "2013",
month = "3",
doi = "10.1007/s00280-012-2048-y",
language = "English (US)",
volume = "71",
pages = "627--633",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "3",

}

TY - JOUR

T1 - A phase i study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

AU - Deeken, John F.

AU - Slack, Rebecca

AU - Weiss, Glen J.

AU - Ramanathan, Ramesk K

AU - Pishvaian, Michael J.

AU - Hwang, Jimmy

AU - Lewandowski, Karen

AU - Subramaniam, Deepa

AU - He, Aiwu Ruth

AU - Cotarla, Ion

AU - Rahman, Aquilur

AU - Marshall, John L.

PY - 2013/3

Y1 - 2013/3

N2 - Background: Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. Methods: LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m2 IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis. Results: Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m2. Two out of two patients experienced grade 4 neutropenia at the 132 mg/m2 dose level. When an additional three patients were treated at the expanded 110 mg/m2 dose level, two experienced grade 4 neutropenia. The 85 mg/m2 dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m2 with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %. Conclusion: LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m2 without G-CSF or 110 mg/m2 with G-CSF.

AB - Background: Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. Methods: LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m2 IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis. Results: Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m2. Two out of two patients experienced grade 4 neutropenia at the 132 mg/m2 dose level. When an additional three patients were treated at the expanded 110 mg/m2 dose level, two experienced grade 4 neutropenia. The 85 mg/m2 dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m2 with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %. Conclusion: LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m2 without G-CSF or 110 mg/m2 with G-CSF.

KW - Clinical trial

KW - Docetaxel

KW - Liposomes

KW - Phase I

UR - http://www.scopus.com/inward/record.url?scp=84875853658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875853658&partnerID=8YFLogxK

U2 - 10.1007/s00280-012-2048-y

DO - 10.1007/s00280-012-2048-y

M3 - Article

VL - 71

SP - 627

EP - 633

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 3

ER -