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© 2002 American Society for Clinical Oncology Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and PharmacokineticsByFrom the Division of Medical Oncology, The Johns Hopkins Oncology Center, The Brady Urological Research Institute, The Johns Hopkins University School of Medicine, Baltimore, MD; and Abbott Laboratories, Abbott Park, IL. Address reprint requests to Michael A. Carducci, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1M89 Bunting-Blaustein, 1650 Orleans St, Baltimore, MD 21231-1000; email: carducci{at}jhmi.edu
PURPOSE: Endothelin receptors, particularly the ETA receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ETA receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan’s pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.
THE ENDOTHELIN FAMILY is composed of three isopeptides, ET-1, -2, -3, which mediate pleiotropic activities in a wide array of tissues.1,2 Initially identified as a product of endothelial cells with potent vasoconstrictive and mitogenic properties, ET-1 is the most common circulating form of endothelin and is also found in many epithelial-derived tumors.3-5 ET-1 actions are mediated via two G-protein–coupled receptors, ETA and ETB, which are distinguished by different binding affinities for the endothelins. The ETB receptor binds the three isotypes with equal affinity, functioning as a clearance receptor and modulator of ET-1 secretion.6 In contrast, the caveolae-based ETA receptor binds ET-1 with a higher affinity than the other isoforms, directly stimulates proliferative responses in neoplastic and normal cells, and potentiates other growth factors commonly implicated in malignant growth.5-8 ET-1 activation of the ETA receptor also prevents apoptosis.9 There are multiple pathways whereby the ET-1/ETA axis may contribute to the manifestations of cancer, including the modulation of angiogenesis, blood flow, nociception, and bone deposition.10-15 A dysregulation of the endothelin axis leading to increased ET-1 production favors tumor growth. This finding was initially described in prostate cancer patients in whom increased plasma ET-1 concentrations were greatest with metastatic, hormone-refractory disease.16 Furthermore, prostate cancer cell lines, primary tumors, and metastatic prostate cancer lesions express increased amounts of ET-1.8,16 Concomitant with increased local ET-1 expression in prostate cancer, there is a diminished capacity for endothelin clearance: prostate cancer cells downregulate the expression of neutral endopeptidase, a key endothelin degradation enzyme, and also the ETB clearance receptor.8,17 ET-1 overexpression is accompanied by increased ETA receptor expression in prostate tumor cells, which correlates with increasing stage and grade of prostate cancer lesions.8,18 Similar observations about derangement of the ET-1/ETA receptor system have been made in ovarian cancer as well as in tumors of the cervix and brain.19-23 Additional evidence from breast, colon, hepatic, endometrial, and pancreatic neoplastic and stromal tissues suggests a wider participation of the endothelin axis in human cancers.24,25 Taken together, activation of the endothelin axis in prostate and other cancers may favor autonomous tumor growth and progression via an ET-1 paracrine/autocrine loop. Selective blockade of endothelin receptors represents a rational, targeted approach to abrogating the pathophysiologic effects of endothelin in cancer.16 Atrasentan is an orally bioavailable endothelin antagonist that potently (Ki = 34 pM) and selectively (1862 x ETA > ETB) binds to the ETA receptor.2 Atrasentan reverses or blocks the effects of ET-1, including its proliferative, angiogenic, bone-remodeling, and blood-flow effects.8,26-29 On the basis of the potential of a selective ETA receptor antagonist to block the ET-1/ETA receptor pathway activity in multiple tumor types, a phase I dose-escalation trial of atrasentan, administered as a once-daily dose for 4 weeks, was performed in patients with refractory adenocarcinomas. Phase I trials in healthy volunteers have demonstrated that the side effects of atrasentan are limited and only mild to moderate in severity in doses up to 40 mg/d,29,30 with headache and rhinitis being the most common. The objectives of the present trial were to evaluate further the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. Initial evidence of the antitumor activity of atrasentan was also examined in these patients. This phase I, open-label, dose-escalation trial was performed at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the General Clinical Research Center in the Johns Hopkins Hospital. Safety monitoring was continued in a separate extension trial.
Patients Patients were eligible for enrollment if they had a histologically confirmed diagnosis of an adenocarcinoma that was refractory to standard therapy or for which no standard therapy was available. Patients had to be at least 18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and have a life expectancy of at least 3 months. Additional eligibility criteria included the following: WBC count > 2.0 x 109/L (2000/mm3), absolute neutrophil count > 1.0 x 109/L (1,000/mm3), platelet count > 100 x 109/L (100,000 mm3), hemoglobin concentration > 1.395 nmol/L (9 g/dL), total serum bilirubin < 25.62 µmol/L (1.5 mg/dL), serum AST and ALT no more than 1.5 times the upper limit of normal, and a calculated creatinine clearance of at least 0.48 mL/sec/m2 (50 mL/min). Patients who had surgery, radiotherapy, or chemotherapy in the 28 days before study initiation must have had full recovery from treatment toxicity. Patients who had received corticosteroids within 4 weeks before the trial initiation or had a history of migraine headaches, CNS metastases, or active infection were excluded. Patients had to be able to take oral medication. Because the potential blood pressure response to antihypertensive drugs combined with atrasentan is unknown, patients had to be discontinued from antihypertensive therapies other than a diuretic at least 7 days before the first dose of atrasentan. Adequate cardiac function was required as assessed by an echocardiogram or multigated acquisition scan showing no signs of severe left ventricular dysfunction. Patients who had prostate cancer and had not undergone bilateral orchiectomy were maintained on therapy with a luteinizing hormone–releasing hormone agonist. Withdrawal of antiandrogen therapy with a subsequent rise in prostate-specific antigen was required, with a minimum withdrawal period of 4 weeks for flutamide and 8 weeks for bicalutamide or nilutamide. Additional concomitant therapy for the management of prostate cancer was not permitted. The institutional review board at The Johns Hopkins Hospital approved the study. The protocol was in accordance with an assurance filed with and approved by the Department of Health and Human Services. All patients gave written informed consent before any study-related procedures were initiated.
Study Protocol Successive cohorts of patients (three per group) were started on fixed doses of atrasentan at an initial dose of 10 mg/d. Subsequent planned dose levels were 20, 30, 45, 60, 75, 95, 115, and 140 mg/d, although the protocol stipulated that dose escalation would be halted when a maximum-tolerated dose was reached. The maximum-tolerated dose was defined as one dose level below that at which dose-limiting toxicity (DLT) was observed in one third or more of the patients. When DLT occurred in any single patient, drug administration was stopped in that patient until the toxicity resolved or the patient’s baseline status was restored. If desired, the patient could continue therapy at the next lower dose, remaining there for the 28-day duration of the study unless DLT recurred, in which case the patient was discontinued from the study. (Participation of any patient in a cohort at a higher dose level was prohibited.) When one of three patients in a cohort experienced a DLT, three more patients were added to the cohort. Then, when no additional DLTs were observed in the group after 28 days, an additional cohort of three patients were enrolled at the next higher dose. For studying the relationship of pharmacokinetic parameters and safety, the trial included an additional schedule for administering the total daily dose of atrasentan. Once the maximum-tolerated dose was defined, an additional cohort of three patients were enrolled at the equivalent daily maximum-tolerated dose administered as a divided dose (twice daily). In general, adverse events were graded as mild, moderate, or severe. DLTs and laboratory abnormalities were graded using the National Cancer Institute common toxicity criteria (NCI-CTC), version 1. DLT was defined as any drug-related adverse event that qualified as severe or as NCI grade 3 or 4. Blood samples were drawn for pharmacokinetic analysis of atrasentan and immunoreactive ET concentrations before the initial dose on days 1 and 28 and at the following intervals thereafter: 15, 30, and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 30, 36, and 48 hours. Predose samples were also drawn on days 7, 14, and 21. An extension trial was planned to assess the longer-term safety of atrasentan. To be eligible, patients were required to complete the 28-day study, demonstrate tumor regression or stable disease, and have no worsening of pain during the 28-day period. Patients who elected to enter the extension trial continued at their previous dose on a once-daily schedule of administration.
Clinical Assessments
Changes in cancer-related pain were evaluated using the Brief Pain Inventory–Short Form,31 which was administered at baseline and weekly thereafter. For establishing valid baseline data, patients who required opioid analgesics had their medications stabilized for 4 weeks before the initiation of treatment. Patients had to have adequate pain control to be enrolled in the study, defined as 2 of 3 consecutive days with a pain score of 4 or less, tolerable side effects from analgesics, and the use of no more than four rescue doses of analgesic per day. During the study, each patient rated the average level of pain for every 24-hour period using integers on the Numeric Rating Scale;32 analgesic use was recorded in a diary at bedtime. A positive pain response to treatment was defined as either a reduction of A complete tumor response was defined as the disappearance of all known disease; a partial response was defined as a decrease of 50% or more in bidimensionally measurable lesions without an increase in any other lesions. Progressive disease was defined as an increase in the size of existing lesions, the appearance of new lesions on imaging studies (computed topography or magnetic resonance imaging), the appearance of new cancer-related symptoms, or the worsening of existing symptoms. In patients with documented elevations in a tumor marker (prostate-specific antigen, CA-125, CA 19-9, CA 15-3, or CEA), biologic response was evaluated by measurement of serum concentrations 1 to 3 days before initiation of treatment and weekly thereafter.
Pharmacokinetic Procedures
With the use of standard noncompartmental methods, the maximum and minimum observed concentrations (Cmax and Cmin), time to maximum observed concentration (Tmax), and area under the plasma concentration-time curve (AUC) were determined for atrasentan and immunoreactive ET. For atrasentan, the AUC was calculated from time 0 to infinity (AUC To test for the dose proportionality of pharmacokinetic parameters, we performed analyses of covariance on atrasentan pharmacokinetic values with body weight as the covariate. In these analyses, the primary test was designed to have good power for a trend with dose and was performed on a linear contrast orthogonal to the dose. To test for time independence, analyses of variance with dose as the only factor were performed on the difference between day 1 and day 28 pharmacokinetic measures. To assess the time when steady state occurs, we used repeated measures analyses with body weight as the covariate to compare the dose-normalized atrasentan predose concentrations on days 7, 14, 21, and 28. In the framework of these analyses, the change from day 7 to day 28 was also tested. The same analyses were performed for the immunoreactive ET parameters. All analyses used the procedures GLM of SAS/STAT (SAS Institute Inc, Gary, NC) version 6.12. P < .05 was considered to be statistically significant. All calculations were performed before rounding.
Patient Characteristics Thirty-one patients were enrolled onto this trial between July 1997 and April 1999. Table 1 lists the patients’ characteristics. Overall, patients had good performance status; eight patients had an ECOG performance status of 0, and 23 patients had an ECOG performance status of 1. All patients had previously received a combination of therapies.
The 31 patients were treated daily with oral atrasentan at six different doses: 10, 20, 30, 45, 60, and 75 mg. Cohorts consisted of three, three, four, eight, seven, and six patients, respectively. Of the 31 patients, 24 completed the study. Seven patients were withdrawn prematurely, six because of disease progression and one because of the adverse events of dyspnea and peripheral edema. No deaths occurred during the study.
Safety
Rhinitis, manifesting as rhinorrhea and upper airway congestion, was the most common toxicity and often led to subjective complaints of dyspnea. Rated as mild in 24 patients and moderate in 5 patients, it resulted in no study withdrawals. Rhinitis worsened when patients were recumbent. When necessary, symptoms were managed with over-the-counter medications such as topical decongestants or antihistamines. The rhinitis was not dose related, occurring across all dose levels. Headache was considered mild in 16 patients and moderate in 8 patients and caused no patients to discontinue treatment. Symptoms were described as having the features of a vascular headache. Although the headaches were of mild to moderate intensity and similar to a migraine, nausea and photophobia were absent. Typically, the headache began with the initiation of therapy and resolved after several days of atrasentan treatment. Onset and duration were not dose related. These headaches were controlled, as necessary, with standard analgesic therapy. Mild asthenia was reported in 10 patients, and moderate asthenia was reported in 4 patients. It resulted in no study discontinuations, and no specific therapy was required. Mild peripheral edema was experienced by 10 patients, moderate edema was experienced by two patients, and severe edema was experienced by one patient. The edema occurred principally at the 45-mg dose and above. Typically, the edema was cosmetic in nature and responded to diuretic therapy (furosemide and hydrochlorothiazide), when used. No relationship was found between the occurrence of peripheral edema and patients’ medical history, cardiopulmonary status, concomitant medications, or site of metastatic disease. One of seven patients who received 60 mg/d atrasentan experienced an episode of severe peripheral edema and moderate dyspnea. This 52-year-old man with metastatic lung cancer developed bilateral leg edema and worsening dyspnea after 14 days of atrasentan. Although the patient responded to diuretics and withdrawal of the drug, a similar episode occurred on rechallenge with 45 mg of atrasentan. The patient subsequently withdrew from the study with spontaneous resolution of his symptoms. Review of the patient’s medical records revealed a history of cardiomyopathy, hypertension, and dyspnea on exertion. A previous echocardiogram had shown moderate left ventricular hypertrophy and moderate to severe left ventricular dysfunction.
Dose-Limiting Toxicity
Laboratory Evaluation Serum albumin and total protein concentrations decreased in parallel with the changes in hemoglobin. At week 4, albumin and total protein concentrations had declined by 0.27 ± 0.06 g/dL and 0.48 ± 0.09 g/dL, respectively. The changes in hemoglobin and serum proteins were unrelated to dose levels. When atrasentan was stopped for 1 week before the extension trial, the acute decreases in chemistry and hematology values returned toward baseline values. Rechallenge with atrasentan in the extension trial reproduced the initial responses in laboratory values observed on first exposure, with subsequent stabilization after 2 weeks. Serum hepatic transaminase and creatinine values did not increase significantly over baseline. No grade 4 toxicities were observed.
Vital Signs There were no study discontinuations as a result of the blood pressure responses. One patient, who received 45 mg of atrasentan, experienced an adverse event of asthenia concomitant with a blood pressure of 124/47 mmHg, a 22-mmHg decrease in diastolic blood pressure compared with baseline. The event resolved in less than 24 hours without intervention, and the patient experienced no additional episodes. Concomitant with the hematologic, serum chemistry, and blood pressure changes, all dose groups experienced a mean weight gain without correlation to dose. The weight gain peaked within the first week of atrasentan exposure, averaging 1.3 ± 0.4 kg over baseline values (P = .002). At week 4, mean weight change was not statistically different from baseline (0.33 ± 0.4 kg; P = .42).
Pharmacokinetics
Atrasentan pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. There was no significant trend for a change with dose for any pharmacokinetic variable tested on day 1 (Tmax, dose-normalized Cmax, dose-normalized AUC  , or ß) or day 28 (Tmax, dose-normalized Cmax, dose-normalized Cmin, dose-normalized AUC0 to 24, or ß) (P  .25).
Immunoreactive ET plasma concentrations at baseline averaged 1.5 pg/mL. Mean immunoreactive ET Cmax and AUC0 to 24 values were 50% greater on day 28 than on day 1 (P < .01) and rose linearly with increasing atrasentan dose on day 1 (P
Clinical Response Of the 15 patients with tumor-related pain, 5 (33%) experienced alleviation of pain during the 28-day treatment period as defined by a 25% decrease in the Numeric Rating Scale score or in the patient’s analgesic dosage. For patients with prostate cancer, decreases in serum prostate–specific antigen values ranged from 4% to 47% in 5 of 11 patients who had at least two observations while on study drug. No dose response was observed for these declines. Decreases were also noted in other biochemical tumor markers, including plasma CEA, CA15-3, CA-125, and CA19-9 values. According to radiographic criteria, no complete or partial responses were noted in the 24 patients who completed the initial 28-day study.
Extension Trial Adverse events did not increase in severity with extended dosing. The most common adverse events, rhinitis in 12 of 13 patients and headache in seven of 13 patients, were reportedly better tolerated and less intense with prolonged dosing than during initial atrasentan exposure. Particular improvement in symptomatology was noted in two patients who developed moderate headaches at 75 mg/d through the initial 28-day exposure period. In the extension trial, four patients experienced serious adverse events, all attributed to disease progression.
This phase I study is the first evaluation of an ETA receptor antagonist in oncology patients. The results of this study indicate that atrasentan achieves biologically relevant plasma concentrations with oral once-daily dosing. The safety profile of atrasentan in cancer patients, across the 10- to 60-mg dose range, is consistent with that observed in healthy volunteers and reflects the physiologic antagonism of ETA receptors. In addition, the observed improvements in cancer-related pain and the observed decreases in prostate-specific antigen and other tumor markers suggest that atrasentan has antitumor activity. The adverse effects of headache, rhinitis, and peripheral edema were attributable to the vasoactive pharmacology of this class of compounds. These effects were mild to moderate in intensity, reversible, and, when necessary, readily controlled with symptomatic treatment. Similar effects were previously observed in normal subjects who received up to 40 mg of atrasentan once daily and have also been reported with administration of other endothelin antagonists.34,35 Headache was the DLT in our cancer patients, resembling that described in normal subjects.29,30 Although not qualifying as dose limiting according to the NCI criteria, the moderate headaches in patients who received 75 mg of atrasentan were of sufficient intensity and duration to warrant halting additional dose escalation. Thus, 60 mg was determined to be the maximum-tolerated dose of the drug. Notably, patients in the trial tolerated doses 50% higher than that at which the headache DLT was observed in healthy male subjects.29,30 Whether this difference is due to inherently different characteristics of the populations, a differential regulation of the ET system in a pathologic state, or patients’ motivation remains to be determined. No differences in atrasentan pharmacokinetics were found between the two populations to explain the contrast in tolerability. Although doses of up to 60 mg/d were tolerated in our patient population, additional studies of atrasentan that are being designed or are under way will use doses no higher than 30 mg/d to circumvent the risk of nonspecific toxicities. Concomitant changes in laboratory values and body weight were consistent with a mild, self-limited hemodilution effect caused by atrasentan. Patients exhibited a reversible hemodilution of the same magnitude noted in normal subjects who achieved steady-state concentrations of atrasentan.30 In the present study, the hemodilution effect did not increase with patients’ age, underlying disease state, or dose of atrasentan. A similar hemodilution effect has been noted in patients who have hypertension and heart failure and are receiving nonselective endothelin antagonists.34,36 Although patients who received atrasentan had, on average, statistically significant decreases in diastolic blood pressure compared with baseline values, this effect largely reflected individuals who were hypertensive. The observed decrease in diastolic blood pressure in hypertensive patients was similar to that seen with other endothelin antagonists,34 although the changes observed in this study are difficult to interpret given the lack of a control arm and the small cohorts of patients studied at each dose. Conversely, normotensive patients exhibited no meaningful changes in blood pressure. A unifying explanation for the observed effects of atrasentan is the pharmacologic activity of ETA receptor antagonists. Selective ETA receptor antagonists produce vasodilation through multiple mechanisms, including direct antagonism of ET-1 and nitric oxide production.37 Vasodilation via endothelial activation has been proposed in the cause of certain types of headaches.38 Agents that generate nitric oxide, such as nitroglycerin, produce this effect. Similarly, a vasomotor component to rhinitis that could account for the upper airway symptoms noted in this study has been previously described39. The increased weight, hemodilution, peripheral edema, and blood pressure effects seen in our patients probably reflect the vasodilatory activity of atrasentan demonstrated previously.29,40 These vasodilatory effects may account for the experience of the patient in our study who had underlying cardiac dysfunction and withdrew prematurely because of dyspnea and peripheral edema. Two recent studies of nonselective endothelin antagonists in heart failure patients found that high doses of these agents, used without an appropriate dose-titration schedule, can exacerbate heart failure symptoms.36,41 Taken together, these data suggest that endothelin antagonists should be used cautiously in patients who have a history of heart failure. The pharmacokinetics of atrasentan in oncology patients were linear, dose proportional, and time independent over the range of 10 to 75 mg/d. Steady-state plasma concentrations attained biologically relevant levels that were at least 10-fold greater than the Ki for the ETA receptor with once-daily dosing.2 Furthermore, the pharmacokinetics were consistent with the profile described previously in normal subjects.42 Congruent with dose-related ETA receptor antagonism, plasma-immunoreactive ET concentrations were linearly related to those of atrasentan.29 Whether the increases in immunoreactive ET concentrations over baseline were due to ligand displacement or antagonism of an inhibitory feedback pathway has yet to be determined. Preclinical studies of atrasentan metabolism and transport indicate that atrasentan is a substrate for cytochrome P-450 3A4 and for the P-glycoprotein transporter. No specific drug interactions were identified in this atrasentan clinical trial; however, potential interactions with cytochrome P-450 3A4 substrates, inhibitors, and inducers and with P-glycoprotein substrates and inhibitors such as digoxin and verapamil require investigation. The potential for drug-drug interactions will be evaluated in future pharmacokinetic trials. With the pleiotropic effects of ET-1 described in prostate, ovarian, cervical, and other malignancies, there is an opportunity with atrasentan to define the activity of the endothelin system in the growth and morbidity of numerous neoplastic diseases. With generally mild to moderate side effects, predictable pharmacokinetics, and suggestion of clinical benefit, atrasentan is an appropriate candidate, either as monotherapy or in combination with traditional cytotoxic agents, to determine the therapeutic potential of this class of agents in cancers that manifest an upregulated endothelin system. Future studies of atrasentan are being planned or are in progress for patients with hormone-refractory prostate cancer; glioma; and ovarian, lung, breast, and renal carcinomas.
Supported in part by National Institutes of Heath (NIH)/National Center for Research Resources grant no. M01-RR00052 to the Johns Hopkins University School of Medicine, CaPCure, and NIH grant nos. CA65525, CA74090-01, and SPORE CA58236. Also supported by Abbott Laboratories, Abbott Park, IL. M.A.C. and J.B.N. are consultants to Abbott Laboratories. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
.01) and day 28 (P 
