Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors.

Abstract

PURPOSE:

This phase I study examined the toxicity and tolerability of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies.

EXPERIMENTAL DESIGN:

Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, Zubrod performance status 0-2, and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5 to 36 mg/m(2) and up to 10 doses of docetaxel (75 mg/m(2)) every 3 weeks. Primary endpoints were safety, toxicity, and a recommended phase II dose. Circulating arginine levels were measured before each cycle. Tumor response was measured as a secondary endpoint every 6 weeks on study.

RESULTS:

Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3 to 4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with 10 patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including 2 patients with PSA response) were documented, and 7 patients had stable disease.

CONCLUSIONS:

ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted, and expansion cohorts are now accruing for both castrate-resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m(2).

• Authors: Benjamin K Tomlinson, James A Thomson, John S Bomalaski, Monica Diaz, Taiwo Akande, Nichole Mahaffey, Tianhong Li, Mrinal P Dutia, Karen Kelly, I-Yeh Gong, Thomas Semrad, David R Gandara, Chong-Xian Pan, Primo N Lara Jr
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 11 Pg. 2480-6 (Jun 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25739672 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Taxoids
• Docetaxel
• Polyethylene Glycols
• Arginine
• Hydrolases
• ADI PEG20

Topics

• Antineoplastic Combined Chemotherapy Protocols
• Arginine (metabolism)
• Docetaxel
• Drug Administration Schedule
• Drug-Related Side Effects and Adverse Reactions (classification, pathology)
• Female
• Humans
• Hydrolases (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Neoplasm Staging
• Neoplasms (drug therapy, metabolism, pathology)
• Polyethylene Glycols (administration & dosage, adverse effects, pharmacokinetics)
• Taxoids (administration & dosage)
• Treatment Outcome