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Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant
Benjamin K Tomlinson1, James A Thomson2, John S Bomalaski2
1The University of California Davis Comprehensive Cancer Center, Sacramento, California.
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).
Insights
Pegylated arginine deiminase (ADI-PEG 20) combined with docetaxel showed acceptable toxicity in advanced solid tumors. Promising activity was observed, supporting further trials in specific cancers.
Area of Science:
- Oncology
- Pharmacology
Background:
- Advanced solid malignancies present significant treatment challenges.
- Combination therapies are crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the safety and tolerability of pegylated arginine deiminase (ADI-PEG 20) with docetaxel.
- To determine a recommended Phase II dose for this combination therapy.
Main Methods:
- Phase I clinical trial involving 18 patients with advanced solid malignancies.
- Administered escalating doses of ADI-PEG 20 weekly with standard docetaxel every 3 weeks.
- Monitored safety, toxicity, arginine levels, and tumor response.
Main Results:
- The combination demonstrated reasonable toxicity, with one dose-limiting urticarial rash.
- Common toxicities included grade 3-4 leukopenia and fatigue.
- Partial responses were observed in 4 of 14 evaluable patients, with 7 achieving stable disease.
Conclusions:
- Pegylated arginine deiminase (ADI-PEG 20) is a tolerable combination partner for docetaxel in advanced solid tumors.
- The recommended Phase II dose is 36 mg/m(2) for ADI-PEG 20.
- Expansion cohorts for castrate-resistant prostate cancer and non-small cell lung cancer are ongoing.
