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


METHODS
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).
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
Benjamin K
BK
Tomlinson
Polaris Pharmaceuticals, Inc., San Diego, California.
James A
JA
Thomson
Polaris Pharmaceuticals, Inc., San Diego, California.
John S
JS
Bomalaski
Polaris Pharmaceuticals, Inc., San Diego, California.
Monica
M
Diaz
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
Taiwo
T
Akande
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
Nichole
N
Mahaffey
The University of California Davis Comprehensive Cancer Center, Sacramento, California. VA Northern California Health Care System, Mather, California.
Tianhong
T
Li
The University of California Davis Comprehensive Cancer Center, Sacramento, California. VA Northern California Health Care System, Mather, California.
Mrinal P
MP
Dutia
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
Karen
K
Kelly
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
I-Yeh
IY
Gong
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
Thomas
T
Semrad
The University of California Davis Comprehensive Cancer Center, Sacramento, California.
David R
DR
Gandara
The University of California Davis Comprehensive Cancer Center, Sacramento, California. VA Northern California Health Care System, Mather, California.
Chong-Xian
CX
Pan
The University of California Davis Comprehensive Cancer Center, Sacramento, California. primo.lara@ucdmc.ucdavis.edu.
Primo N
PN
Lara
D000971:Antineoplastic Combined Chemotherapy Protocols; D001120:Arginine / Q000378:metabolism*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
D043823:Taxoids; D000077143:Docetaxel; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20