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

Abstract

Purpose: Endothelins and their cell membrane receptors (ET A R and ET B R) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ET A R 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 CommonToxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m 2 ) and carboplatin (area under the curve, 6) administered on day 1every 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 F SD, 21.2 F 4.5 L/h versus 21.3 F 4.9 L/h) for pre-and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities z10% 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 platinumbased 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 a-helix and two disulfide bridges. They exert their effects by binding to two cell surface receptors (ET A R and ET B R), which belong to the G protein -linked family of receptors (8,9). The binding of ET-1 to ET A R 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 (b...

Anti-endothelin drugs in solid tumors

“…They appear to be well tolerated, without pharmacokinetic interaction of paclitaxel and atrasentan. Efficacy and survival have proved to be similar to those already observed in studies involving the use of chemotherapy alone in advanced NSCLC patients [80]. Phase III trials and other combination regimen trials should also be designed.…”

Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer

“…The primary end point was progression-free survival (PFS) at 6 months, with an anticipated rate of 50% in the experimental and 38% in the control arms based on previous phase II trials. 16,18,19 Other end points included overall survival, best disease response (RR), feasibility, toxicity (assessed by Common Terminology Criteria for Adverse Events, version 3.0), and additional relevant molecular investigations.…”

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

“…These data suggest that the systemic clearance of docetaxel is unlikely to be reduced by atrasentan based on metabolic inhibition. One previously published study evaluated the pharmacokinetic interaction of atrasentan on the CYP450 3A4 & 2C9 substrate, paclitaxel [23]. No significant difference in paclitaxel systemic clearance was observed, although the study was only designed to identify a comparatively large change (33%) in pharmacokinetic parameter estimates with 80 percent power [23].…”