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Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Atrasentan: an Endothelin Receptor Antagonist for Refractory Prostate Cancer1

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Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Atrasentan: an Endothelin Receptor Antagonist for Refractory Prostate Cancer1 Vol. 9, 2965–2972, August 1, 2003 Clinical Cancer Research 2965 Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Atrasentan: An Endothelin Receptor Antagonist for Refractory Prostate Cancer1 Bernard A. Zonnenberg,2 Gerard Groenewegen, Conclusions: Atrasentan is well tolerated, with no dose- Todd J. Janus, Terri W. Leahy, limiting adverse events observed up to 95 mg. Adverse events are consistent with the vasodilatory effect of the drug. Rod A. Humerickhouse, Jeffrey D. Isaacson, PK are linear and dose-proportional; the half-life is appro- Robert A. Carr, and Emile Voest, priate for once-daily dosing. Department of Internal Medicine, University Hospital, 3584 CX Utrecht, the Netherlands [B. A. Z., G. G., E. V.], and Abbott INTRODUCTION Laboratories, Abbott Park, Illinois [T. J. J., R. A. H., J. D. I., R. A. C., 3 T. W. L.] The ETs, a family of three 21-amino acid isopeptides (ET-1, ET-2, and ET-3), were first identified in 1988 as secre- tory products of vascular endothelial cells with potent, sustained ABSTRACT vasoconstrictor activity (1). ET-1, the main isoform, is produced Purpose: Evidence suggests that endothelin (ET)-1 and by endothelial and epithelial cells and has been recognized as a mediator of growth and survival signal in both normal physiol- its primary receptor, the ETA receptor, may contribute to the progression of prostate and other cancers. Atrasentan ogy and tumor growth (2–4). ET-1 is also produced by many epithelial-derived human tumors (3, 5) and is considered to be a (ABT-627) is a highly potent, selective ETA receptor antag- onist. This study assessed safety, maximum tolerated dose, mediator and an autocrine and a paracrine growth factor for and pharmacokinetics (PK) in patients with refractory ad- local cancer and stromal cells (6, 7). enocarcinomas, primarily prostate cancer. The action of ET-1 is thought to be mediated via two Experimental Design: This 28-day, single-center Phase I G-protein-coupled receptors, ETA and ETB, which are distin- guished by different binding affinities for the ETs. The ET trial evaluated the safety and PK of escalating oral atrasen- B receptor binds the three isotypes with equal affinity and func- tan doses (2.5–95 mg) given daily (except day 2) to eligible tions primarily as both a clearance receptor and a modulator of patients >18 years old with an adenocarcinoma proven ET-1 expression (8). In contrast, the ET receptor binds ET-1 resistant to standard therapy. Priority was given to patients A with a higher affinity than the other isoforms. Binding of ET-1 with hormone-refractory prostate cancer. After 28 days, to the ET receptor stimulates vasoconstriction in normal vas- patients without objective signs of tumor progression were A cular endothelium, stimulates proliferative responses in normal eligible to continue atrasentan in an extension study. and neoplastic cells, and potentiates other growth factors in Results: Thirty-nine patients (30 of whom had prostate malignant growth (2, 8–10). Recently, ET-1 has also been found cancer) were treated in cohorts of three patients each with to prevent apoptosis (11). escalating atrasentan doses (2.5, 5, 10, 20, 30, 45, 60, 75, and Secreted by normal prostate epithelial cells (12), ET-1 is 95 mg). The most common adverse events were rhinitis, found in human semen in the highest concentrations thus far headache, and peripheral edema. Anemia consistent with a observed in any body fluid (13). A dysregulation of the ET axis reversible hemodilution effect was observed. No maximum leading to increased ET-1 production was first reported in tolerated dose was found in the dose range studied. Atra- prostate cancer; ET-1 concentrations were found to be signifi- sentan PK were characterized by rapid absorption (mean cantly elevated in patients with metastatic hormone-refractory ؎ ؎ ؍ Tmax 0.9 h), mean SD oral clearance of 24 15 liters/h, disease (14). The tumor-promoting effects of ET-1 in prostate -and volume distribution of 726 ؎ 477 liters. PK were ap cancer were observed to occur via ETA receptors (15), with ETA proximately dose-proportional and time independent across receptors predominating (10). Tumor growth was shown to be doses. promoted by increased production of ET-1, decreased ET-1 clearance, and ETA overexpression (10, 16). ET-1 expression correlates well with the stage and grade of human prostatic cancer (10, 14, 17). Received 7/29/02; revised 4/1/03; accepted 4/2/03. 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 3 The abbreviations used are: ET, endothelin; AUC, area under the indicate this fact. curve; Cmax, maximum observed plasma concentration; Cmin, minimum 1 Supported by a grant from Abbott Laboratories. observed plasma concentration; DLT, dose-limiting toxicity; ECG, elec- 2 To whom requests for reprints should be addressed, at Department of trocardiogram; iET, immunoreactive endothelin-1; MTD, maximum Medical Oncology, University Medical Centre, Heidelberglaan 100, tolerated dose; NCI, National Cancer Institute; PK, pharmacokinetics; 3584 CX Utrecht, the Netherlands. Phone: 31-30-250-6680; Fax: 31- Tmax, time to maximum observed plasma concentration; t1/2, terminal 30-254-2531; E-mail: [email protected]. elimination half-life. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2003 American Association for Cancer Research. 2966 Phase I Study of Atrasentan Pharmacokinetics and Safety A dysregulation of the ET-1/ETA receptor system similar written informed consent before undergoing any study-related to that in prostatic cancer has been reported for ovarian and procedures. human papilloma virus-associated cervical carcinomas (18–20), Study Design. This dose-escalation study was designed in which functional ETA receptors are overexpressed. Selective to enroll successive cohorts of patients (3 patients/cohort), each antagonism of ETA receptors, but not ETB receptors, has been to be started on a fixed dose of atrasentan. The initial protocol found to inhibit ET-1-mediated growth effects in various tumor specified 10 mg/day for the first cohort. Planned dose levels for models (18–20). Additional evidence in support of ET-1 and/or subsequent cohorts were 20, 30, 45, 60, 75, and 95 mg/day. The protocol was later amended to include 2.5- and 5-mg doses so ETA receptor expression in human cancers suggests a wider participation of the ET axis in both human tumor cells and that more safety and pharmacokinetic data could be collected at normal stromal cells (21, 22). these lower doses. Atrasentan was administered once daily on Selective blockade of the ET-1 receptor represents a day 1 and days 3–28; the drug was withheld on day 2 to allow targeted approach to abrogating the pathophysiological ef- for pharmacokinetic analyses over a 48-h period. The drug was fects of ET in cancer (14). Atrasentan, a p.o. bioavailable supplied as capsules (2.5, 5, 10, and 25 mg) for oral adminis- ϭ ϭ tration. The patients took the capsules under fasting conditions drug, is a potent (Ki 0.034 nM) and selective (KiETB on study days 1, 7, 14, and 28. 63.3 nM)ETA receptor antagonist (23, 24). This Phase I dose-escalation study was designed to evaluate the safety and Dose escalation was to be halted when the MTD was tolerability of atrasentan (ABT-627), estimate the MTD, and reached; MTD was defined as one dose level below that at characterize the PK of the drug after once-daily oral admin- which DLT was observed in one-third or more of the patients. If one of the three patients in a dose cohort experienced a DLT, istration in patients with refractory adenocarcinomas, partic- three more patients were added to the cohort. If no further DLTs ularly those with hormone-refractory prostate cancer requir- were observed in the group after 28 days, an additional cohort of ing pain relief with opioids. three patients was enrolled at the next higher dose. Toxicities were graded using the NCI Common Toxicity PATIENTS AND METHODS Criteria (version 2). If a NCI grade did not apply, the adverse Patients. Patients selected for this single-center open- event was graded as mild, moderate, or severe. DLT was defined label Phase I study had an adenocarcinoma (documented cyto- as any atrasentan-related adverse event qualifying as NCI grade logically or histologically) refractory to standard therapy, with 3or4. preferred enrollment offered to patients with hormone-refrac- Health status assessments, conducted weekly, included physical examination, 12-lead ECG (days 7 and 28), blood tory prostate cancer requiring pain relief with opioid analgesics. chemistry, hematology, and urinalysis. Participants had to be at least 18 years old, have an Eastern Pharmacokinetic Analyses. Blood samples were col- Cooperative Oncology Group performance status of 0–2, and lected for pharmacokinetic analysis of atrasentan concentra- have a life expectancy of at least 3 months. Women with tions before the initial dose on days 1 and 28 and at the child-bearing potential were required to have a negative preg- following intervals thereafter: 15, 30, and 45 min and 1, 1.5, nancy test. Patients were excluded from the study if they had 2, 4, 6, 8, 12, 16, 24, 30, 36, and 48 h. Blood samples were brain metastases, severe left ventricular dysfunction (assessed collected over a dosing interval on days 1 and 28 for deter- by ECG or multigated acquisition), clinically significant ECG mination of the plasma concentrations of iET. In addition, a Ն abnormalities, history of migraines, total bilirubin 25.6 mM, predose sample was collected on day 14. Patients were re- Ն ϫ aspartate transaminase or alanine transaminase 1.5 the quired to fast for 8 h before dosing and, on days 1 and 28, for upper limit of the reference range, calculated creatinine clear- at least 2 h afterward.
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