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Clinical Cancer Research 14, 1464, March 1, 2008. doi: 10.1158/1078-0432.CCR-07-1508
© 2008 American Association for Cancer Research
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Cancer Therapy: Clinical

Phase I/II Study of Atrasentan, an Endothelin A Receptor Antagonist, in Combination with Paclitaxel and Carboplatin as First-Line Therapy in Advanced Non–Small Cell Lung Cancer

Alberto A. Chiappori1,2, Eric Haura1,2, Francisco A. Rodriguez3, David Boulware4, Rachna Kapoor4, Anthony M. Neuger5, Richard Lush2,5, Barbara Padilla2, Michelle Burton2, Charles Williams1, George Simon1,2, Scott Antonia1,2, Daniel M. Sullivan2 and Gerold Bepler1,2

Authors' Affiliations: 1 Thoracic Oncology Program, 2 Experimental Therapeutics Program, 3 Medical Oncology Fellow, 4 Biostatistics Core, and 5 Clinical Trials Laboratory Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: Alberto A. Chiappori, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-745-3050; Fax: 813-745-3027; E-mail Alberto.Chiappori{at}moffitt.org.


   Abstract
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Materials and Methods
 Results
 Discussion
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Purpose: Endothelins and their cell membrane receptors (ETAR and ETBR) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ETAR antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis. This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin.

Experimental Design: Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non–small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute Common Toxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6) administered on day 1 every 3 weeks. A fixed 10 mg daily oral dose of atrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre- and post-atrasentan) in the first 10 patients.

Results: All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean ± SD, 21.2 ± 4.5 L/h versus 21.3 ± 4.9 L/h) for pre- and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities ≥10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%.

Conclusion: Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non–small cell lung cancer were comparable with studies of chemotherapy alone.

In 2006, lung cancer remains the most frequent cause of cancer mortality in the United States (1). More than 80% of patients have non–small cell lung cancer (NSCLC) and half of them have advanced disease at diagnosis (2). In these cases, treatment mostly consists of chemotherapy with a platinum-based doublet (3). Chemotherapy, however, has reached an efficacy plateau, and newer therapies are needed (4, 5). Improved understanding of the molecular biology of NSCLC (signaling pathways, etc.) has opened a whole new field of therapeutic options, where development of many new agents targets these pathways (6, 7), such as the endothelin axis pathway (8).

The endothelins include three 21–amino acid isopeptides (ET-1, ET-2, and ET-3) characterized by a single {alpha}-helix and two disulfide bridges. They exert their effects by binding to two cell surface receptors (ETAR and ETBR), which belong to the G protein–linked family of receptors (8, 9). The binding of ET-1 to ETAR exerts pleiotropic biological effects that influence cell survival and proliferation (through activation of various kinases, namely, protein kinase C, epidermal growth factor, and insulin-like growth factor), apoptosis (by suppressing Bcl-2 and enhancing Akt phosphorylations), invasion and metastasis (through enhanced secretion of matrix-degrading proteases), and angiogenesis (through increased production of vascular endothelial growth factor by increasing levels of hypoxia-inducible factor-1{alpha}; refs. 10–13).

Many tumor types secrete ET-1 and express ETAR, suggesting the existence of autocrine and paracrine loops that perpetuate endothelin axis activation (14, 15). In NSCLC, ET-1 expression has been detected, by immunohistochemistry or in situ hybridization, predominantly in adenocarcinomas and squamous cell carcinomas (16, 17). Furthermore, expression of ET-1, measured in plasma by ELISA or in tumor tissue by immunohistochemistry or real-time PCR, seems to be a negative prognostic factor (18, 19). In addition, the lung is particularly rich in ETAR, but in comparison, the receptor seems overexpressed in lung cancer (18) and ET-1 receptor binding in lung tumor blood vessels has been deemed specific, saturable, and time dependent (20). Thus, the endothelin axis is a novel target in NSCLC where selective ETAR blockade represents a rational approach with potential therapeutic implications. Recently developed small molecules, capable of inhibiting ET-1–induced ETAR activation, offer the possibility of testing this approach in the clinical setting.

Atrasentan {(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid} is a highly potent (Ki = 0.034 nmol/L), orally bioavailable, selective inhibitor of ETAR (1,800-fold ETA > ETB) that decreases the binding affinity of ET-1 without affecting receptor density and thus competitively blocks the effects of ET-1 receptor binding (Fig. 1 ; refs. 21, 22). In phase I dose-escalation studies, the pharmacokinetics of atrasentan were linear, dose proportional, and time independent over a 2.5 to 95 mg daily dose range with steady-state plasma concentrations reaching biologically relevant levels (mean unbound CMIN for the 10 mg daily dose was 8-fold greater than the ETAR Ki; refs. 23–25).


Figure 1
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  		Fig. 1. Atrasentan molecule {(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid}.

 
Across the same dose range, atrasentan was well tolerated, with a safety profile reflective of its vasodilator properties and ETAR antagonism. The most frequently reported adverse events, headaches, rhinitis, peripheral edema, and anemia (hemodilution), were usually mild to moderate in intensity, reversible, and readily controlled with symptomatic therapy and mostly occurred at doses >60 mg (patients treated >60 mg often experienced headache and rhinitis), supporting a daily dose <75 mg (headache is considered the dose-limiting toxicity; refs. 23–25).

Here, we present the first clinical trial where endothelin axis blockade, using atrasentan, is combined with standard chemotherapy (paclitaxel-carboplatin) as treatment for advanced NSCLC. The rationale behind this study included (a) the role of the endothelin axis in tumor progression, apoptosis, and angiogenesis; (b) the prevalent expression of both ET-1 and ETAR in NSCLC; (c) the emerging importance of antiangiogenic therapies in NSCLC; and (d) the preclinical evidence of antiangiogenic and proapoptotic synergism between atrasentan and paclitaxel. Our trial followed a typical safety and efficacy design; however, distinctive characteristics of the trial included (a) pre- and post-atrasentan paclitaxel pharmacokinetic evaluations given the potential for atrasentan-mediated, cytochrome P450–mediated paclitaxel metabolism inhibition and (b) the selection of a fixed atrasentan daily oral dose.


   Materials and Methods
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Study population and patient eligibility. Patients required histologic or cytologic confirmation of advanced NSCLC (stage IIIB with malignant pleural effusion and stage IV), estimated life expectancy ≥12 weeks, Eastern Cooperative Oncology Group performance status ≤1, and one unidimensionally measurable lesion and to meet New York Heart Association class I criteria if cardiovascular disease was present. Other eligibility criteria included the following: age ≥18 years; no prior chemotherapy or biologic or immunotherapy; and adequate bone marrow (absolute neutrophil count ≥2.0 x 109 cells/L, platelet count ≥100 x 109 cells/L), renal (creatinine clearance ≥60 mL/min), and hepatic functions (bilirubin ≤1.5 upper limit of normal, alanine aminotransferase and/or aspartate aminotransferase ≤2.5x upper limit of normal, or ≤5x upper limit of normal with documented liver metastasis).

Brain metastases were allowed after definitive therapy (resection and/or whole brain irradiation) if asymptomatic and steroid-free for ≥2 weeks. Women who were pregnant, nursing, or of childbearing potential (on inadequate birth control method) and patients with hypersensitivity to cremophor or grade >1 neuropathy were excluded. Written informed consent was obtained from all subjects and an institutional review board reviewed and approved the protocol.

Study design. This open-label, phase I/II study was conducted at the H. Lee Moffitt Cancer Center and Research Institute. The phase I objective was to evaluate the safety of paclitaxel-carboplatin plus a fixed daily dose of atrasentan and to determine potential pharmacokinetic interactions between paclitaxel and atrasentan. The phase II goal was to further detail the safety of the regimen and to determine its antitumor activity, measuring the overall response rate, progression-free survival (PFS), and overall survival (median survival and 1-year survival).

Dose-limiting toxicities were recorded in all phase I patients during cycle 1 to assess the need for paclitaxel-carboplatin dose modifications before the phase II part. Pre- and post-atrasentan paclitaxel pharmacokinetic variables were calculated in all these patients, and based on intraperson paclitaxel pharmacokinetic variability (26), a change of >33% in the mean paclitaxel clearance was considered "clinically significant." If a clinically significant change and/or more than three dose-limiting toxicities were observed during phase I, the chemotherapy doses were reduced following an established schema before continuing to phase II. In the absence of such findings, the phase II was initiated at phase I starting doses for all drugs.

Prestudy evaluations included a history and physical examination, Eastern Cooperative Oncology Group performance status, complete blood count, serum chemistries, coagulation profile, and urinalysis. Women of childbearing potential required a pregnancy test. Imaging of the chest, head scan, and electrocardiogram were also done. During chemotherapy, evaluations included physical examination, performance status, complete blood count, and serum chemistries before every cycle and imaging of the chest (and other target lesions) every other cycle. After chemotherapy, patients with complete response, partial response, or stable disease were followed every 2 months until progression of disease, death, or loss to follow-up. All patients were followed for a minimum of 30 days after the last dose of atrasentan.

Treatment plan. Atrasentan was supplied by Global Pharmaceutical Research and Development, Abbott Laboratories as 10 mg gelatin capsules. Paclitaxel and carboplatin were commercially available. Study medications were administered as follows. (a) On day 1 of each cycle, and following standard premedications for hypersensitivity and emesis, paclitaxel was dosed at 225 mg/m2 as a 3-h i.v. infusion. Carboplatin was dosed to a target area under the curve of 6 mg x min/mL as a 30-min i.v. infusion immediately thereafter. (b) Atrasentan was administered continuously as a 10 mg daily oral dose, starting on day 4 of cycle 1 (to allow for off-atrasentan paclitaxel pharmacokinetic sampling). Treatments were repeated every 21 days for a total of four to six cycles, contingent to the return of all treatment-related adverse events to grade ≤1 or baseline. After completing four or more cycles of therapy, and in the absence of disease progression or intolerable toxicity, patients continued on daily, single-agent atrasentan.

Dose modifications and toxicity criteria. Chemotherapy dose reductions were planned for the transition from phase I to phase II, depending on the occurrence of clinically significant mean paclitaxel clearance changes and/or dose-limiting toxicities. Within study phases, dose modifications were implemented, after treatment was first delayed to allow its resumption once the adverse event had resolved or returned to baseline, based on hematologic and nonhematologic toxicities. Dose reescalation was not permitted. Treatment was stopped in the event that chemotherapy had to be delayed >2 weeks or if toxicities persisted despite maximum dose reductions. All toxicities were graded using the National Cancer Institute Common Toxicity Criteria version 2.0.

Pharmacokinetics. Paclitaxel pharmacokinetic plasma samples were obtained from all phase I patients on days 1 to 3 of cycles 1 and 2 (pre- and post-atrasentan, respectively). Samples were collected (a) before the start of the paclitaxel infusion (predose) and 1.5 and 3 h after the start of the infusion and (b) 0.5, 1, 2, 3, 5, 24, 48, and 72 h after the end of the infusion. Plasma samples were stored frozen at –80°C before assay. Paclitaxel was isolated through solid-phase extraction and all analyses were done by liquid chromatography-mass spectrometry methods described in the literature (27, 28) and validated by the Clinical Trials Laboratory Core.

Using selected ion monitoring, paclitaxel was targeted at m/z 854 a.m.u. with a linear range from 2.5 to 1,000 ng/mL. Quality control samples were checked at 30, 80, and 800 ng/mL, and the overall precisions, expressed as relative SD, were 9.1%, 8.2%, and 4.2%, respectively. Calibration curves were calculated by linear regression with 1/y weighting to determine the slopes, intercepts, and correlation coefficients. The average correlation coefficient (R2) for the assay runs was >0.9995.

Plasma paclitaxel concentration-time profiles were analyzed using standard noncompartmental methods. Derived variables included in the analyses were the maximum plasma concentration (CMAX), the time to CMAX (TMAX), plasma elimination half-life (t1/2), area under the curve in plasma, steady-state volume of distribution, and total body clearance.

Efficacy assessment. The Response Evaluation Criteria in Solid Tumors (29) method was used to evaluate antitumor activity. Only patients with tumor imaging after two cycles of therapy were evaluable. PFS was the time interval between the dates of the first chemotherapy and disease progression. Overall survival was the time interval between the dates of the first chemotherapy and death. Patients with neither disease progression nor death were censored at their last date known alive. Survival analysis (PFS, median survival, and 1-year survival) was done on an intent-to-treat population.

Statistical considerations. Ten patients were enrolled for the phase I component. The pre- and post-atrasentan mean paclitaxel pharmacokinetic variables were compared using Student's paired t test at the two-sided 0.05 significance level. Assuming a SD of 33% for the mean pharmacokinetic differences, a 10-patient sample size provides 80% power if the mean change in the pharmacokinetic variables is 33% (1 SD).

The primary objective of the phase II component was to reject the null hypothesis (median PFS, 3.5 months) and to accept the alternative hypothesis (median PFS, 6.5 months). To test this and to calculate the sample size, we assumed an exponential distribution. Thus, the estimated 6-month PFSs under null hypothesis and alternative hypothesis were 0.305 and 0.530, respectively. To achieve a power of 0.80, with {alpha} = 0.05, we calculated a sample size of 40 patients. Alternative hypothesis was accepted if ≥19 patients were progression-free at 6 months. The PFS and median survival distributions were estimated using the Kaplan-Meier (30) method.


   Results
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Patient characteristics. Between July 2003 and August 2005, 44 patients were enrolled (phase I, 10; phase II, 34). All patients received at least one cycle of chemotherapy and one dose of atrasentan and were evaluable for toxicity, response, and survival (intent-to-treat population). Patient demographics are shown in Table 1 . The study population included 26 (59%) men and 18 (41%) women with a median age of 61.5 years (range, 23-78). All but two patients were white (95.5%) and only nine (20.5%) had performance status of 0. The predominant histology was adenocarcinoma (21 patients, 47.7%) and 38 (86.4%) patients had stage IV disease. Seven patients with brain metastasis were enrolled (15.9%).


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  		Table 1. Patient characteristics

 
Treatment duration, safety, and tolerability. The total number of chemotherapy cycles administered was 166 (Table 1). Median number of cycles was 4 (range, 1-6). The median duration of treatment with single-agent atrasentan was 76.5 days (range, 11-385; mean ± SD, 95.5 ± 90.4). Twenty patients (45.5%) failed to go on to single-agent atrasentan (16 progressive disease, 2 stable disease, and 2 withdrawals).

All grade 3 and 4 treatment-related adverse events are reported in Table 2 . Two patients were removed from study due to excessive toxicity: one with intractable nausea and vomiting (the only study dose-limiting toxicity) and one for infection. Toxicity was tolerable with grade 3/4 ≥10%: lymphopenia (10 of 44, 22.7%), neutropenia (9 of 44, 20.5%), dyspnea (3 of 44, 11.4%), and hyperglycemia (3 of 44, 11.4%). There were no toxic deaths.


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  		Table 2. Treatment-related grade 3 and 4 toxicities (all patients, N = 44)

 
Pharmacokinetics. Data were obtained from all 10 patients enrolled during phase I. Neither clinically nor statistically significant changes in paclitaxel clearance (mean ± SD, 21.2 ± 4.5 L/h pre-atrasentan versus 21.3 ± 4.9 L/h post-atrasentan) or other pharmacokinetic variables (CMAX, t1/2, area under the curve, and volume of distribution) were observed (Fig. 2 ) and they resembled values previously described for paclitaxel (26). This allowed for transition from the phase I to the phase II components without chemotherapy dose modifications. Pre- and post-atrasentan paclitaxel plasma concentrations peaked at the end of the infusion (3 h) and mean concentrations reached >5,300 ng/mL.


Figure 2
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  		Fig. 2. Pharmacokinetics. Graph, comparison of the plasma paclitaxel concentrations (mean ± SD) versus time profiles (pre- and post-atrasentan). Symbols represent actual measured level. Pre- and post-atrasentan mean (±SD) paclitaxel pharmacokinetic variables. P values are for a paired t test of means. AUC, area under the curve; VD, volume of distribution.

 
Response and survival. Because all phase I patients received full doses of the three treatment drugs, they were counted toward the calculated phase II sample size. Efficacy results are shown in Table 3 . In the intent-to-treat population (44 patients), 0 and 8 patients achieved complete response and partial response, respectively, for an overall response rate of 18.2% [95% confidence interval (95% CI), 8.2-32.7]. Another 16 patients achieved stable disease and 20 had progressive disease. The PFS, median survival, and 1-year survival in the intent-to-treat population were 4.2 months (95% CI, 3.2-5.8), 10.6 months (95% CI, 8.8-14.5), and 43%, respectively (Table 3). After removal from study, 31 patients received second-line therapy (pemetrexed, 15; docetaxel, 2; gemcitabine-navelbine, 3; gefitinib/erlotinib, 7; and clinical trials, 4).


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  		Table 3. Efficacy

 

   Discussion
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 Materials and Methods
 Results
 Discussion
References
 
This is the first clinical trial to address the safety and efficacy of atrasentan, a selective ETAR antagonist, in combination with paclitaxel-carboplatin as first-line therapy for advanced NSCLC. Due to the distinctive characteristics of our trial, a phase I/II study design was chosen and this allowed for (a) the evaluation of the potential for atrasentan to inhibit paclitaxel metabolism [clearance primarily mediated by the cytochrome P450 system (CYP3A and CYP2C9); ref. 26], and (b) a timely determination of the safety and efficacy of the regimen.

Given the potential for atrasentan to inhibit paclitaxel metabolism [clearance primarily mediated by the cytochrome P450 system (CYP3A and CYP2C9); ref. 26], potential pharmacokinetic interactions between these drugs were also evaluated. However, because hepatic mechanisms of elimination are not significant for carboplatin, a pharmacokinetic interaction with atrasentan was neither anticipated (31) nor tested. Another distinctive characteristic of our study was the selection of a fixed, 10 mg atrasentan dose. This decision was based on pharmacokinetic studies showing that daily oral doses of atrasentan between 2.5 and 30 mg achieved plasma concentrations exceeding the Ki for the ETAR and on pharmacodynamic studies showing physiologic effects in humans at such doses. Additionally, evidence of higher adverse events and of potential loss of ETAR selectivity, with increasing doses (>20 mg) of atrasentan, also influenced the dose selection decision (32).

Because atrasentan plasma concentrations 100-fold higher (10 µmol/L) than those achieved after multiple 10 mg daily doses are required to produce a 10% inhibition of CYP-dependent enzyme activity (atrasentan concentration-dependent inhibition of CYP3A and CYP2C9 activities reached IC50 values of 3 and 35 µmol/L, respectively), no atrasentan-paclitaxel interaction was expected. Therefore, to optimize the study duration, we limited the pharmacokinetic analysis to the first 10 patients (phase I). A mean paclitaxel clearance difference of >33% was considered clinically significant, but we found no effect from daily treatment with atrasentan on the pharmacokinetics of paclitaxel (Fig. 2).

A large body of evidence indicates that the cytotoxic activity of taxanes or platinum can be enhanced by combination with atrasentan (33–35). Specifically, atrasentan ETAR blockade results in sensitization to taxane-induced (or platinum-induced) apoptosis (33), and it enhanced paclitaxel-induced vascular endothelial growth factor inhibition with additional reduction in microvessel density (34). These atrasentan properties acquire greater importance considering that a recent phase III study (E4599), where paclitaxel-carboplatin was combined with bevacizumab, an antiangiogenic monoclonal antibody against vascular endothelial growth factor, showed a superior survival in advanced NSCLC but also increased toxicities, including life-threatening pulmonary hemorrhage (36). Given the antiangiogenic and proapoptotic synergism that atrasentan has shown with taxanes or platinum and the conceptual similarities with E4599, our regimen was a logical combination to test in NSCLC.

In our study, toxicities were generally well tolerated and atrasentan did not seem to exacerbate the toxicities of paclitaxel-carboplatin. Among adverse events known to be due to atrasentan, only rhinitis and anemia were observed in >15% of patients. The former was considered drug related but with no effect on compliance. The latter was felt mostly related to chemotherapy because no major signs of hemodilution or fluid retention were seen (only six patients developed edema). Regardless of etiology, the incidence of anemia (all grades and grade 3/4) was similar to other recent studies and hematologic (neutropenia) and nonhematologic (neuropathy) toxicities observed were also in line with those described for paclitaxel-carboplatin (37, 38). No major bleeding complications were observed in our study despite allowing patients with hemoptysis, therapeutic anticoagulation, and/or brain metastasis. Only one patient developed hemoptysis while on atrasentan and an endobronchial lesion was shown as the bleeding source, which stopped spontaneously without atrasentan discontinuation.

In contrast, our efficacy results did not compare so favorably with E4599 (Table 3). Several explanations include the following: (a) the endothelin axis may not be of much importance in NSCLC and preclinical evidence from ovarian cancer studies cannot be extrapolated to NSCLC (this seems unlikely, given the vascular endothelial growth factor mode of action and its clinical importance in NSCLC); (b) although pharmacologically reasonable, 10 mg atrasentan achieves insufficient ETAR blockade at the tumor level to enhance cytotoxicity (it is known that plasma concentrations do not reflect intratumoral concentrations and that "surrogate" determinations rarely correlate with antitumor effect); and (c) given our less selective patient population (~16% brain metastasis), inferior results can be expected. In that regard, a more fair comparison would be with the Alpha Oncology trial (~15% brain metastasis; ref. 39). Here, our results compare substantially better with a median survival of 2.7 months higher (10% higher 1-year survival).

In conclusion, we believe that our inability to reject the null hypothesis in this study may reflect deficiencies in our clinical trial related to the low dose of atrasentan used and that the endothelin axis remains a potentially important pathway to target in NSCLC. Future NSCLC studies with atrasentan should explore higher atrasentan doses (maximum tolerated dose) and include methodologies to test the biological activity of the drug (pre- and post-atrasentan vascular endothelial growth factor and/or ET-1 serum levels, ET-1 and/or ETAR tumoral expression, etc.).


   Acknowledgments
 
We thank Jeannie Vaughn for her assistance in the conduction and data management of the clinical trial and Anita Bruce for providing editorial assistance.


   Footnotes
 
Grant support: Global Pharmaceutical Research and Development, Abbott Laboratories (Abbott Park, IL).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented at the 2005 American Society of Clinical Oncology Annual Meeting (Orlando, FL) and 2006 Florida Joint Cancer Centers Conference (Palm Beach, FL).

Conflict of interest: Global Pharmaceutical Research and Development, Abbott Laboratories (Abbott Park, IL) supplied the study drug atrasentan and paid for the study.

Received 6/18/07; revised 10/10/07; accepted 12/13/07.


   References
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 Abstract
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 Results
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 References
 

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106–30.[Abstract/Free Full Text]
  2. Novello S, le Chevalier T. Is there a standard strategy in the management of locally advanced non-small cell lung cancer? Lung Cancer 2001;34 Suppl 4:S9–14.[CrossRef][Medline]
  3. Hoang T, Xu R, Schiller JH, Bonomi P, Johnson DH. Clinical model to predict survival in chemonaive patients with advanced non-small-cell lung cancer treated with third-generation chemotherapy regimens based on eastern cooperative oncology group data. J Clin Oncol 2005;23:175–83.[Abstract/Free Full Text]
  4. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–8.[Abstract/Free Full Text]
  5. Carney DN, Hansen HH. Non-small-cell lung cancer—stalemate or progress? N Engl J Med 2000;343:1261–2.[Medline]
  6. Dy GK, Adjei AA. Novel targets for lung cancer therapy: part II. J Clin Oncol 2002;20:3016–28.[Abstract/Free Full Text]
  7. Dy GK, Adjei AA. Novel targets for lung cancer therapy: part I. J Clin Oncol 2002;20:2881–94.[Abstract/Free Full Text]
  8. Nelson J, Bagnato A, Battistini B, Nisen P. The endothelin axis: emerging role in cancer. Nat Rev Cancer 2003;3:110–6.[CrossRef][Medline]
  9. Levin ER. Endothelins. N Engl J Med 1995;333:356–63.[Free Full Text]
  10. Bagnato A, Natali PG. Endothelin receptors as novel targets in tumor therapy. J Transl Med 2004;2:16.[CrossRef][Medline]
  11. Bagnato A, Spinella F. Emerging role of endothelin-1 in tumor angiogenesis. Trends Endocrinol Metab 2003;14:44–50.[CrossRef][Medline]
  12. Del Bufalo D, Di Castro V, Biroccio A, et al. Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: requirement for Akt activation. Mol Pharmacol 2002;61:524–32.[Abstract/Free Full Text]
  13. Del Bufalo D, Di Castro V, Biroccio A, et al. Endothelin-1 acts as a survival factor in ovarian carcinoma cells. Clin Sci (Lond) 2002;103 Suppl 48:302–5S.
  14. Bagnato A, Salani D, Di Castro V, et al. Expression of endothelin 1 and endothelin A receptor in ovarian carcinoma: evidence for an autocrine role in tumor growth. Cancer Res 1999;59:720–7.[Abstract/Free Full Text]
  15. Carducci MA, Padley RJ, Breul J, et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003;21:679–89.[Abstract/Free Full Text]
  16. Yang X, Liu L, Qi H. [Study on endothelin-1 positive expression and quantitative analysis in lung cancer]. Zhonghua Jie He He Hu Xi Za Zhi 1998;21:111–3.[Medline]
  17. Giaid A, Hamid QA, Springall DR, et al. Detection of endothelin immunoreactivity and mRNA in pulmonary tumours. J Pathol 1990;162:15–22.[CrossRef][Medline]
  18. Boldrini L, Gisfredi S, Ursino S, et al. Expression of endothelin-1 is related to poor prognosis in non-small cell lung carcinoma. Eur J Cancer 2005;41:2828–35.[CrossRef][Medline]
  19. Arun C, DeCatris M, Hemingway DM, London NJ, O'Byrne KJ. Endothelin-1 is a novel prognostic factor in non-small cell lung cancer. Int J Biol Markers 2004;19:262–7.[Medline]
  20. Zhao YD, Springall DR, Hamid Q, Levene M, Polak JM. Localization and characterization of endothelin-1 receptor binding in the blood vessels of human pulmonary tumors. J Cardiovasc Pharmacol 1995;26 Suppl 3:S341–5.[Medline]
  21. Opgenorth TJ, Adler AL, Calzadilla SV, et al. Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. J Pharmacol Exp Ther 1996;276:473–81.[Abstract/Free Full Text]
  22. Winn M, von Geldern TW, Opgenorth TJ, et al. 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996;39:1039–48.[CrossRef][Medline]
  23. Carducci MA, Nelson JB, Bowling MK, et al. Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol 2002;20:2171–80.[Abstract/Free Full Text]
  24. Zonnenberg BA, Groenewegen G, Janus TJ, et al. Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: an endothelin receptor antagonist for refractory prostate cancer. Clin Cancer Res 2003;9:2965–72.[Abstract/Free Full Text]
  25. Ryan CW, Vogelzang NJ, Vokes EE, et al. Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignancies. Clin Cancer Res 2004;10:4406–11.[Abstract/Free Full Text]
  26. Gianni L, Kearns CM, Giani A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995;13:180–90.[Abstract/Free Full Text]
  27. Sottani C, Minoia C, D'Incalci M, Paganini M, Zucchetti M. High-performance liquid chromatography tandem mass spectrometry procedure with automated solid phase extraction sample preparation for the quantitative determination of paclitaxel (Taxol) in human plasma. Rapid Commun Mass Spectrom 1998;12:251–5.[CrossRef][Medline]
  28. Parise RA, Ramanathan RK, Zamboni WC, Egorin MJ. Sensitive liquid chromatography-mass spectrometry assay for quantitation of docetaxel and paclitaxel in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2003;783:231–6.[Medline]
  29. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205–16.[Abstract/Free Full Text]
  30. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.[CrossRef]
  31. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999;17:409–22.[Abstract/Free Full Text]
  32. Abbott Laboratories PPD, Research and Development. Atrasentan (ABT-627). Selective endothelin A (ETA) receptor antagonist. Investigator's brochure. Abbott Park (IL): Abbott Laboratories; 2004.
  33. Rosano L, Spinella F, Di Castro V, Natali PG, Bagnato A. Therapeutic targeting of the endothelin A receptor in human ovarian carcinoma: efficacy of cytotoxic agents is markedly enhanced by co-administration with atrasentan. J Cardiovasc Pharmacol 2003;44:S132–5.[CrossRef]
  34. Rosano L, Spinella F, Salani D, et al. Therapeutic targeting of the endothelin A receptor in human ovarian carcinoma. Cancer Res 2003;63:2447–53.[Abstract/Free Full Text]
  35. Salani D, Rosano L, Di Castro V, et al. ABT-627, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma growth in vitro. Clin Sci (Lond) 2002;103 Suppl 48:318–21S.
  36. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial—E4599. Proc Am Soc Clin Oncol 2005;23:LBA4.
  37. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol 2004;22:785–94.[Abstract/Free Full Text]
  38. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892–9.[Abstract/Free Full Text]
  39. Treat J, Belani CP, Edelman MJ, et al. A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC): update of the Alpha Oncology trial (A1-99002L) [abstract 7025]. Proc Am Soc Clin Oncol 2005;23:16S.



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