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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

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.

Purpose: Endothelins and their cell membrane receptors (ET_AR and ET_BR) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ET_AR 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.

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