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

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 4.5–36 mg/m(2), and up to ten doses of docetaxel 75 mg/m(2) every three weeks. Primary endpoints were safety, toxicity and a recommended phase II dose. Circulating arginine levels were measured prior to each cycle. Tumor response was measured as a secondary endpoint every six 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 1(st) dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3–4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with ten patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including two patients with PSA response) were documented and seven 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)

Transient and Persistent Metabolomic Changes in Plasma following Chronic Cigarette Smoke Exposure in a Mouse Model

<div><p>Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (<i>p</i>-value≤0.05) and fold change ≥1.5). Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease.</p></div

Inter-relation of pathways.

<p>Biological relationships among chemical classes of compounds showing the regulation of one group of metabolites and its effects on other biological classes down- or up-stream. Pathway was adapted from KEGG, Lipid Maps, and SMPDB. Metabolites within this pathway passed p-value≤0.05 and fold change ≥1.5 filters. ↓ indicates the number of differentially regulated metabolites which decreased due to smoking, ↑indicates the number of differentially regulated metabolites which increased due to smoking for a particular chemical class of compounds, ^NDno data was available for these compounds in this dataset.</p

(A) Nicotine pathway and heat maps of CS metabolites in (B) four month and (C) six month comparisons.

<p>CS = cigarette smoke. Pathway diagram reprinted with permission from Hukkanen et al. Circled compounds represent the metabolites identified in the plasma of mouse samples in the current study. For each heat map, blue represents a decrease in mean metabolite abundance, and yellow/beige represents an increase in mean metabolite abundance. For example, nicotine glucuronide is increased in smoking in both the 4- and 6- month smoking mice. Samples were analyzed on an Agilent 6410 ESI-TOF in positive ionization mode, data was processed using Mass Profiler Professional, and quantitative data was obtained using Mass Hunter Quantitative analysis software. Tentative identification was performed using ID Browser within the Mass Profiler Professional software. ID Browser in-house database is comprised of Metlin, Lipid Maps and HMDB. * indicates <i>p</i>-value≤0.05 between the air control and cigarette smoking groups. Differences between other nicotine pathway metabolites are also shown but did not reach statistical significance.</p

Heat map of differentially regulated steroids and derivatives.

<p>Statistical analysis was performed using Mass Profiler Professional software (Agilent) with <i>p</i>-value cutoff ≤0.05. The mean abundance levels for each of the differentially regulated metabolites detected is shown. Blue represents a decrease in mean metabolite abundance, and yellow/beige represents an increase in mean metabolite abundance.</p

Metabolites which were (A) reversibly decreased and (B) reversibly increased with smoking.

<p>In panel A (top), differentially regulated metabolites were higher in air controls, decreased with smoking, and increased toward air control levels following smoking cessation. In panel A (bottom), differentially regulated metabolites were higher in air controls, decreased with smoking, and surpassed air control levels following smoking cessation. In panel B (top) differentially regulated metabolites were lower in air controls, increased with smoking, and decreased following smoking cessation. In panel B (bottom), differentially regulated metabolites were lower in air controls, increased with smoking, and decreased beyond air control levels following smoking cessation. Samples and data were analyzed as described in the methods section. TG = triglyceride, CDP = cytidine-diphosphate, DG = diglyceride, PC = phosphatidylcholine, PS = phosphatidylserine, TG = triglyceride, PA = phosphatidic acid. Fold change ≥1.5; <i>p</i>-value≤0.05, x-axis = Log2 normalized abundance scale; Error bars represent 95% confidence; Significance values *≤0.05, **≤0.01, ***≤0.001.</p