A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors

C. W. Taylor, Robert T Dorr, P. Fanta, Evan M Hersh, S. E. Salmon

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Purpose: To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors. Methods: A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2. Results: The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma. Conclusions: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.

Original languageEnglish (US)
Pages (from-to)83-88
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume47
Issue number1
DOIs
StatePublished - 2001

Fingerprint

Pharmacodynamics
Asparaginase
Tumors
Asparagine
Neoplasms
Toxicity
Assays
Serum
Intramuscular Injections
Amylases
Melanoma
Lipase
Fatigue of materials
Anorexia
Multiple Myeloma
Venous Thrombosis
Pancreatitis
Nausea
Vomiting
Fatigue

Keywords

  • Asparaginase
  • Asparagine
  • Clinical trial
  • Melanoma
  • Phase I

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors. / Taylor, C. W.; Dorr, Robert T; Fanta, P.; Hersh, Evan M; Salmon, S. E.

In: Cancer Chemotherapy and Pharmacology, Vol. 47, No. 1, 2001, p. 83-88.

Research output: Contribution to journalArticle

@article{d41d7d812a754cf782120f00a75b9e62,
title = "A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors",
abstract = "Purpose: To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors. Methods: A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2. Results: The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma. Conclusions: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.",
keywords = "Asparaginase, Asparagine, Clinical trial, Melanoma, Phase I",
author = "Taylor, {C. W.} and Dorr, {Robert T} and P. Fanta and Hersh, {Evan M} and Salmon, {S. E.}",
year = "2001",
doi = "10.1007/s002800000207",
language = "English (US)",
volume = "47",
pages = "83--88",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors

AU - Taylor, C. W.

AU - Dorr, Robert T

AU - Fanta, P.

AU - Hersh, Evan M

AU - Salmon, S. E.

PY - 2001

Y1 - 2001

N2 - Purpose: To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors. Methods: A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2. Results: The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma. Conclusions: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.

AB - Purpose: To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-L-asparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors. Methods: A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2. Results: The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma. Conclusions: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.

KW - Asparaginase

KW - Asparagine

KW - Clinical trial

KW - Melanoma

KW - Phase I

UR - http://www.scopus.com/inward/record.url?scp=0034924041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034924041&partnerID=8YFLogxK

U2 - 10.1007/s002800000207

DO - 10.1007/s002800000207

M3 - Article

C2 - 11221967

AN - SCOPUS:0034924041

VL - 47

SP - 83

EP - 88

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 1

ER -