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.
OBJECTIVE
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.


METHODS
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/m(2)) and carboplatin (area under the curve, 6) administered on day 1 every 3 weeks. A fixed 10 mg daily oral dose ofAtrasentan 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 > or = 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%.


CONCLUSIONS
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.
Chiappori
Alberto A
AA
Thoracic Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. Alberto.Chiappori@moffitt.org
Haura
Eric
E
Rodriguez
Francisco A
FA
Boulware
David
D
Kapoor
Rachna
R
Neuger
Anthony M
AM
Lush
Richard
R
Padilla
Barbara
B
Burton
Michelle
M
Williams
Charles
C
Simon
George
G
Antonia
Scott
S
Sullivan
Daniel M
DM
Bepler
Gerold
G
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077868:Atrasentan; D001932:Brain Neoplasms / Q000188:drug therapy / Q000556:secondary; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000556:secondary; D065130:Endothelin A Receptor Antagonists; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D011759:Pyrrolidines / Q000008:administration & dosage; D015996:Survival Rate
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D016190:Carboplatin; D017239:Paclitaxel; D000077868:Atrasentan