A t r a s e n t a n , a n E n d o t h e l i n - R e c e p t o r A n t a g o n i s t f o r
`R e f r a c t o r y A d e n o c a r c i n o m a s : S a f e t y a n d P h a r m a c o k i n e t i c s
`
`By Michael A. Carducci, Joel B. Nelson, M. Kathy Bowling, Theresa Rogers, Mario A. Eisenberger, Victoria Sinibaldi,
`Ross Donehower, Terri L. Leahy, Robert A. Carr, Jeffrey D. Isaacson, Todd J. Janus, Amy Andre, Balakrishna S. Hosmane,
`and Robert J. Padley
`
`Endothelin receptors, particularly the ETA
`Purpose:
`receptor, have been shown to participate in the patho-
`physiology of prostate and other cancers. Atrasentan,
`an endothelin antagonist, binds selectively to the ETA
`receptor. This study evaluated the safety, pharmacoki-
`netics, and maximum-tolerated dose of atrasentan in
`cancer patients.
`Patients and Methods: Patients who were 18 years
`or older and had histologically confirmed adenocarci-
`noma 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 vari-
`able 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 ⴝ 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-spe-
`cific treatment. Reversible hemodilution was apparent
`in laboratory findings and weight gain. Clinically sig-
`nificant headache was the dose-limiting adverse event;
`the maximum-tolerated dose was 60 mg/d. Pharmaco-
`kinetics were dose-proportional across the 10-
`to
`75-mg dose range. Atrasentan was rapidly absorbed;
`the time to maximum observed concentration was ap-
`proximately 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 atra-
`sentan can be easily and consistently dosed.
`J Clin Oncol 20:2171-2180. © 2002 by American
`Society of Clinical Oncology.
`
`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 circu-
`lating 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 differ-
`ent 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 manifes-
`tations 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
`
`From the Division of Medical Oncology, The Johns Hopkins Oncol-
`ogy Center, The Brady Urological Research Institute, The Johns
`Hopkins University School of Medicine, Baltimore, MD; and Abbott
`Laboratories, Abbott Park, IL.
`Submitted October 4, 2001; accepted January 17, 2002.
`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 consult-
`ants to Abbott Laboratories. The terms of this arrangement are being
`managed by the Johns Hopkins University in accordance with its
`conflict of interest policies.
`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@jhmi.edu.
`© 2002 by American Society of Clinical Oncology.
`0732-183X/02/2008-2171/$20.00
`
`Journal of Clinical Oncology, Vol 20, No 8 (April 15), 2002: pp 2171-2180
`10.1200/JCO.2002.08.028
`
`2171
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`AVENTIS EXHIBIT 2190
`Mylan v. Aventis IPR2016-00712
`
`

`
`2172
`
`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 le-
`sions.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, endome-
`trial, 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 pathophysio-
`logic effects of endothelin in cancer.16 Atrasentan is an
`orally bioavailable endothelin antagonist that potently (Ki ⫽
`34 pM) and selectively (1862 ⫻ ETA ⬎ ETB) binds to the
`ETA receptor.2 Atrasentan reverses or blocks the effects of
`ET-1, including its proliferative, angiogenic, bone-remod-
`eling, 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 objec-
`tives of the present trial were to evaluate further the safety,
`pharmacokinetics, and maximum-tolerated dose of atrasen-
`tan 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 per-
`formed at the Sidney Kimmel Comprehensive Cancer Cen-
`ter at Johns Hopkins and the General Clinical Research
`Center in the Johns Hopkins Hospital. Safety monitoring
`was continued in a separate extension trial.
`
`PATIENTS AND METHODS
`
`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 ⫻ 109/L (2000/mm3), absolute neutrophil count ⬎ 1.0 ⫻ 109/L
`
`CARDUCCI ET AL
`
`(1,000/mm3), platelet count ⬎ 100 ⫻ 109/L (100,000 mm3), hemoglo-
`bin concentration ⬎ 1.395 nmol/L (9 g/dL), total serum bilirubin ⬍
`25.62 ␮mol/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
`
`For this open-label, dose-escalation study, atrasentan was supplied as
`2.5-, 5-, 10-, and 25-mg capsules. The drug was administered orally
`once daily on day 1 and from days 3 through 28 at a fixed dose. It was
`withheld on day 2 to permit pharmacokinetic analyses during a 48-hour
`period. Patients were required to fast for 8 hours before dosing; food
`consumption was also prohibited for at least 2 hours after dosing on
`days 1, 7, 14, and 28.
`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 in-
`cluded an additional schedule for administering the total daily dose of
`atrasentan. Once the maximum-tolerated dose was defined, an addi-
`tional cohort of three patients were enrolled at the equivalent daily
`maximum-tolerated dose administered as a divided dose (twice daily).
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`

`
`PHASE I TRIAL OF ATRASENTAN
`
`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 atrasen-
`tan 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
`
`Before enrollment, patients underwent a complete examination,
`including medical history, physical examination, and radiographic
`assessment. Subsequent weekly evaluations included physical exami-
`nation and laboratory studies. A final radiographic assessment was
`performed within 1 week of the final study day.
`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 ⱖ 25% from baseline score for at
`least 2 consecutive weeks without a concomitant increase in opioid
`analgesic use or a reduction from baseline score of ⱖ 25% in opioid
`analgesic use for at least 2 consecutive weeks without an increase in
`pain score.
`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 symp-
`toms. 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 concentra-
`tions 1 to 3 days before initiation of treatment and weekly thereafter.
`
`Pharmacokinetic Procedures
`
`Atrasentan plasma concentrations were determined using a validated
`liquid chromatography assay method with fluorescence detection.33
`The immunoreactive ET plasma concentrations were determined using
`a validated enzyme-linked immunoassay method.29
`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
`
`Table 1. Characteristics of 31 Cancer Patients Treated With Atrasentan
`
`2173
`
`57
`42-76
`
`Characteristic
`
`Age, years
`Median
`Range
`Sex
`Male
`Female
`Type of cancer
`Prostate
`Other*
`Previous therapies
`Surgery
`Chemotherapy
`Radiotherapy
`Hormone treatment
`
`No. Patients
`(N ⫽ 31)
`
`23
`8
`
`14
`17
`
`30
`28
`20
`16
`
`*Includes cancer of the colon (n ⫽ 6), breast (n ⫽ 2), renal cell (n ⫽ 3), lung
`(n ⫽ 4), pancreas (n ⫽ 1), and unknown primary site (n ⫽ 1).
`
`immunoreactive ET. For atrasentan, the AUC was calculated from time
`0 to infinity (AUC⬁) after dosing on day 1 and during the interval after
`dosing on day 28 (AUC0 to 24). The terminal phase elimination rate
`constant (␤) was obtained using a least-squares linear regression
`analysis of the terminal log-linear portion of the plasma concentration-
`time profile. A minimum of three concentration-time data points was
`used to determine ␤. The terminal elimination half-life (t1/2) was
`calculated as ln(2)/␤. Oral clearance (CL/F) was obtained by dividing
`the dose by the AUC value. For immunoreactive ET, the AUC values
`were determined during 24 hours on days 1 and 28.
`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 per-
`formed before rounding.
`
`RESULTS
`
`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.
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
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`

`
`2174
`
`CARDUCCI ET AL
`
`Table 2.
`
`Treat-Emergent Adverse Events Reported by >10% of 31 Cancer Patients Receiving Atrasentan
`
`Atrasentan Total Daily Dose
`
`10 mg (n ⫽ 3)
`
`20 mg (n ⫽ 3)
`
`30 mg (n ⫽ 4)
`
`45 mg (n ⫽ 8)
`
`60 mg (n ⫽ 7)
`
`75 mg (n ⫽ 6)
`
`Total (n ⫽ 31)
`
`Adverse Event*
`
`No.
`
`Rhinitis
`Headache
`Asthenia
`Peripheral edema
`Anorexia
`Nausea
`Vomiting
`Nausea and vomiting
`Constipation
`Dyspnea
`Pain
`Chills
`Accidental injury
`Back pain
`Facial edema
`Dyspepsia
`Anxiety
`Insomnia
`Lung disorder
`Pneumonia
`Rash
`Any event
`
`2
`0
`1
`1
`1
`1
`1
`0
`1
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`3
`
`%
`
`67
`
`33
`33
`33
`33
`33
`
`33
`
`33
`
`100
`
`No.
`
`3
`3
`1
`1
`0
`1
`2
`0
`0
`0
`1
`0
`0
`2
`0
`0
`0
`0
`0
`0
`0
`3
`
`%
`
`100
`100
`33
`33
`
`33
`67
`
`33
`
`67
`
`100
`
`No.
`
`4
`4
`3
`0
`2
`0
`0
`1
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`1
`4
`
`%
`
`100
`100
`75
`
`50
`
`25
`
`25
`
`25
`100
`
`No.
`
`7
`4
`3
`5
`2
`1
`0
`1
`0
`3
`0
`0
`2
`0
`2
`1
`1
`0
`1
`0
`1
`7
`
`%
`
`88
`50
`38
`63
`25
`13
`
`13
`
`38
`
`25
`
`25
`13
`13
`
`13
`
`13
`88
`
`No.
`
`7
`7
`4
`4
`1
`2
`1
`2
`4
`3
`1
`1
`0
`1
`1
`2
`2
`2
`1
`2
`0
`7
`
`%
`
`100
`100
`57
`57
`14
`29
`14
`29
`57
`43
`14
`14
`
`14
`14
`29
`29
`29
`14
`29
`
`100
`
`No.
`
`6
`6
`2
`2
`4
`4
`3
`2
`1
`0
`2
`2
`0
`0
`0
`0
`0
`1
`1
`1
`1
`6
`
`%
`
`100
`100
`33
`33
`67
`67
`50
`33
`17
`
`33
`33
`
`17
`17
`17
`17
`100
`
`No.
`
`29
`24
`14
`12
`10
`9
`7
`6
`6
`6
`4
`4
`3
`3
`3
`3
`3
`3
`3
`3
`3
`30
`
`%
`
`94
`77
`45
`39
`32
`29
`23
`19
`19
`19
`13
`13
`10
`10
`10
`10
`10
`10
`10
`10
`10
`97
`
`*Adverse events were coded using COSTART terms. Each patient was counted only once for each event regardless of the number of times the event was
`experienced.
`
`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
`
`The most common adverse effects were rhinitis (94%),
`headache (77%), asthenia (45%), and peripheral edema
`(39%) (Table 2). The severity of clinical events was
`collected using a mild, moderate, or severe grading system,
`and laboratory abnormalities were graded using the NCI-
`CTC version 1. The majority of adverse events, 73%, were
`rated as mild or as NCI grade 2 or lower in intensity and
`were reversible within 7 days after discontinuation of the
`study drug. Seven patients experienced clinical adverse
`events rated as severe by the investigator; only one of these
`events, peripheral edema, was thought to be possibly related
`to atrasentan therapy. The other events were determined not
`to be related or probably not related to atrasentan therapy by
`the investigator. These events included hemoptysis and
`
`dyspnea in a lung cancer patient; nausea, vomiting, and a
`gastrointestinal obstruction in a patient with colon cancer;
`renal failure in a prostate cancer patient; nausea and
`vomiting in a prostate cancer patient; back pain in a patient
`with renal cell cancer; and a pleural effusion in a patient
`with metastatic breast cancer. Five grade 3 laboratory
`toxicities were observed, consisting of one case each of
`hyperglycemia, hypernatremia, hyperkalemia, elevated ac-
`tive partial prothrombin time, and decreased hemoglobin.
`There were no grade 4 laboratory toxicities.
`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 recum-
`bent. 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 mod-
`erate 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
`
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`
`

`
`PHASE I TRIAL OF ATRASENTAN
`
`the headache
`and photophobia were absent. Typically,
`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. Typi-
`cally, the edema was cosmetic in nature and responded to
`diuretic therapy (furosemide and hydrochlorothiazide),
`when used. No relationship was found between the occur-
`rence 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 cardiomyop-
`athy, hypertension, and dyspnea on exertion. A previous
`echocardiogram had shown moderate left ventricular hyper-
`trophy and moderate to severe left ventricular dysfunction.
`
`Dose-Limiting Toxicity
`
`Dose escalation was halted at 75 mg because of a change
`in the character of the headaches that occurred in the six
`patients in this group. The headache experienced by these
`patients was more intense and of longer duration (in some
`cases occurring throughout the 28-day period) than that
`described in patients who were on lower doses; it necessi-
`tated chronic analgesic therapy, ranging from nonsteroidal
`anti-inflammatory drugs to opioid medications. This oc-
`curred whether patients received 75 mg of atrasentan as a
`single daily dose or as 37.5 mg twice daily. The study
`investigators judged that these headaches were consistent
`with DLT. Therefore, additional patients were enrolled in
`the 45-mg and 60-mg dose groups for further assessment of
`safety and pharmacokinetics. Two patients from the 75-mg
`group elected to continue atrasentan into the extension trial
`with chronic analgesic use.
`
`2175
`
`Laboratory Evaluation
`
`After 1 week of atrasentan initiation, a mean hemoglobin
`decrease of 1.3 ⫾ 0.1 g/dL (mean ⫾ SE) was observed, with
`a corresponding decrease in hematocrit. By day 28, hemo-
`globin values stabilized across all dose groups, with a mean
`decrease of 1.9 ⫾ 0.2 g/dL from baseline. Hemoglobin
`changes were unrelated to dose levels. There was no
`evidence of hemolysis as reflected by stable serum bilirubin,
`serum lactate dehydrogenase, mean RBC volume, and mean
`cell hemoglobin concentration. Peripheral blood smears and
`urinalyses were also unchanged. Although two patients expe-
`rienced worsening anemia that required blood transfusion, the
`cause was judged to be disease related in both cases.
`Serum albumin and total protein concentrations de-
`creased 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 hema-
`tology 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 signif-
`icantly over baseline. No grade 4 toxicities were observed.
`
`Vital Signs
`
`Atrasentan produced within the first week of the study
`declines in diastolic blood pressure that were maintained
`through day 28. At day 7 and day 28, overall mean diastolic
`pressure was decreased from baseline by ⫺ 7.9 ⫾ 1.8
`mmHg (P ⬍ .001) and ⫺ 4.8 ⫾ 1.8 mmHg (P ⫽ .01),
`respectively, with the most pronounced changes occurring
`in patients who were hypertensive at baseline (systolic
`pressure ⬎ 140 mmHg or diastolic pressure ⬎ 90 mmHg).
`At day 28, the mean change in diastolic pressure from
`baseline in hypertensive patients was ⫺ 7.4 ⫾ 2.5 mmHg (n
`⫽ 11), compared with ⫺ 3.4 ⫾ 2.3 mmHg for normotensive
`patients (n ⫽ 20). Mean systolic blood pressure did not
`change significantly from baseline: ⫺ 4.4 ⫾ 3.1 mmHg at
`day 7 and ⫺ 1.5 ⫾ 2.7 mmHg at day 28. Although the
`average pulse rate increased significantly at day 7 (10.4 ⫾
`2.2 bpm; P ⬍ .001), the difference from baseline was no
`longer apparent by day 28 (⫹3.8 ⫾ 2.5 bpm). No dose-
`response relationships were observed for these changes at
`day 7 and day 28.
`There were no study discontinuations as a result of the
`blood pressure responses. One patient, who received 45 mg
`
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`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`

`
`2176
`
`CARDUCCI ET AL
`
`Fig 1. Mean plasma concentrations of atrasentan after a single dose on
`day 1.
`
`Fig 2. Mean plasma concentrations of atrasentan on day 28 after
`once-daily dosing from days 3 to 28.
`
`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 addi-
`tional 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, aver-
`aging 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
`
`After the initial dose of atrasentan (day 1) and at steady
`state (day 28), atrasentan mean plasma concentrations
`increased rapidly with a Tmax of approximately 1.5 hours
`and declined biexponentially with a terminal half-life of
`approximately 24 hours (Figs 1 and 2). The dose-normal-
`ized AUC0 to 24 values on day 28 were not different from the
`dose-normalized AUC⬁ values on day 1 (P ⫽ .15). There
`were also no differences between the day 1 and day 28
`values for the ␤ and Tmax determinations (P ⱖ .57).
`Consistent with the 24-hour half-life of atrasentan, the Cmax
`value increased approximately 70% from day 1 to day 28
`(P ⬍ .01; Table 3). Steady state was achieved by day 7 as
`evidenced by the similar concentrations of atrasentan
`measured before dosing on days 7, 14, and 21.
`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,
`
`0 to 24
`
`dose-normalized AUC⬁, or ␤) or day 28 (Tmax, dose-
`normalized Cmax, dose-normalized Cmin, dose-normalized
`, or ␤) (P ⱖ .25).
`AUC
`Immunoreactive ET plasma concentrations at baseline
`averaged 1.5 pg/mL. Mean immunoreactive ET Cmax and
`AUC
`values were 50% greater on day 28 than on day 1
`(P ⬍ .01) and rose linearly with increasing atrasentan dose
`on day 1 (P ⱕ .01) and day 28 (P ⱕ .03), as summarized in
`Table 4. Plasma
`immunoreactive ET concentrations
`achieved steady state by day 7 as reflected by the similar
`mean immunoreactive ET concentrations before dosing on
`days 7, 14, 21, and 28 (P ⬎ .16 in pair-wise comparisons).
`
`0 to 24
`
`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 ⱖ 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
`
`Thirteen patients enrolled in the extension trial to assess
`the longer-term safety of atrasentan. Duration of the exten-
`sion study ranged from 0.5 to 7.5 months. All 13 patients
`discontinued atrasentan administration at some point be-
`
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`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`

`
`PHASE I TRIAL OF ATRASENTAN
`
`Table 3. Pharmacokinetic Evaluation of Atrasentan in 31 Cancer Patients
`
`Parameter
`
`Day 1
`Tmax, hour
`Cmax, ng/mL
`AUC8, ng/h/mL
`t1/2, hour†
`CL/F, L/h
`Day 28
`Tmax, hour
`Cmax, ng/mL
`Cmin, ng/mL
`AUC8, ng/h/mL
`t1/2, hour†
`CL/F, L/h
`
`10 mg
`n ⫽ 3
`0.6 ⫾ 0.1
`46 ⫾ 4
`528 ⫾ 227
`18.4 ⫾ 9.3
`22.5 ⫾ 12.3
`n ⫽ 3
`0.5 ⫾ 0.3
`104 ⫾ 39
`15 ⫾ 11
`618 ⫾ 285
`14.3 ⫾ 1.8
`19.2 ⫾ 10.2
`
`20 mg
`n ⫽ 3*
`1.7 ⫾ 0.3
`82 ⫾ 23
`301 ⫾ 392
`22.3 ⫾ 6.5
`16.1 ⫾ 4.9
`n ⫽ 3
`2.0 ⫾ 1.8
`135 ⫾ 40
`29 ⫾ 6
`399 ⫾ 265
`23.3 ⫾ 9.1
`14.6 ⫾ 2.5
`
`NOTE. Values represented as mean ⫾ SD.
`*N ⫽ 2 for t1/2, AUC8, and CL/F.
`†Harmonic mean ⫾ pseudostandard deviation.
`‡N ⫽ 5 for t1/2.
`§N ⫽ 3 for t1/2.
`
`Atrasentan Total Daily