4406 Vol. 10, 4406 – 4411, July 1, 2004
`
`Clinical Cancer Research
`
`Dose-Ranging Study of the Safety and Pharmacokinetics of
`Atrasentan in Patients with Refractory Malignancies
`
`Christopher W. Ryan,1,2 Nicholas J. Vogelzang,1,2
`Everett E. Vokes,1,2 Hedy L. Kindler,1,2
`Samir D. Undevia,1 Rod Humerickhouse,4
`Amy K. Andre´,4 Qiang Wang,4 Robert A. Carr,4
`and Mark J. Ratain1,2,3
`1Section of Hematology/Oncology, Department of Medicine, 2Cancer
`Research Center, and 3Committee on Clinical Pharmacology and
`Pharmacogenomics, University of Chicago, Chicago, and 4Abbott
`Laboratories, Abbott Park, Illinois
`
`centration, time to maximum observed concentration, min-
`imum observed plasma concentration, area under the
`plasma concentration-time curve, and elimination rate con-
`stant.
`Conclusions: Atrasentan is well tolerated in both female
`and male cancer patients at doses of up to 60 mg/day with
`dose-limiting toxicity observed at 75 mg/day. The most fre-
`quently observed toxicities were headache, rhinitis, and
`edema. There was no statistically significant difference in
`atrasentan pharmacokinetics between sexes.
`
`ABSTRACT
`Purpose: Atrasentan is an orally bioavailable selective
`antagonist of the endothelin receptor ETA. Due to the po-
`tential activity of this agent against prostate cancer, the
`majority of subjects enrolled in prior studies had been male.
`This Phase I study sought to determine the toxicity and
`pharmacokinetics of daily atrasentan in a population of both
`female and male subjects with advanced malignancies.
`Experimental Design: Patients with refractory malig-
`nancies received atrasentan once daily at doses ranging from
`5 mg to 75 mg. At least 3 subjects were treated at each dose
`level before enrollment began at the next higher dose level.
`Enrollment for specific dose levels was expanded if any
`subject experienced serious drug-related toxicity. Plasma
`concentration profiles for atrasentan were determined after
`dosing on days 1 and 28.
`Results: Thirty-five patients received atrasentan at
`doses from 5 mg to 75 mg. The most frequent drug-related
`adverse events were headache (60%), rhinitis (49%), and
`peripheral edema (31%). These toxicities were mild to mod-
`erate in severity and reversible on cessation of treatment.
`Dose escalation was stopped at the 75-mg dose level due to
`the occurrence of three severe adverse events (2 hyponatre-
`mia and 1 hypotension). Atrasentan was rapidly absorbed
`after oral administration; mean time to maximum observed
`concentration ranged from 0.3 to 1.7 h. Terminal elimina-
`tion half-life averaged 26 h. No significant difference be-
`tween sexes was found in any atrasentan pharmacokinetic
`parameter tested, including maximum observed plasma con-
`
`Received 1/14/04; revised 3/15/04; accepted 3/29/04.
`Grant support: University of Chicago Clinical Research Center Grant
`PHS M01 RR00055.
`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
`indicate this fact.
`Requests for reprints: Christopher W. Ryan, Division of Hematology/
`Oncology, Oregon Health & Science University, CR145, Portland, OR
`97239-3098. Phone: (503) 494-8487; Fax: (503) 494-6197; E-mail:
`ryanc@ohsu.edu.
`
`INTRODUCTION
`The endothelins (ET) are 21-amino acid peptides that were
`originally identified as vasoconstrictors produced in endothelial
`cells (1). Subsequently, the ETs have been found to contribute to
`cell proliferation and hormone production through G protein-
`coupled pathways and have been detected in elevated amounts
`in several malignancies (2, 3). ETs are thought to act in endo-
`crine-responsive tissues, and hormonally influenced changes in
`circulating ET levels have been described. In cancer, dysfunc-
`tion of ET regulation has been implicated in several hormonally
`regulated cancers including prostate, ovarian, and cervical can-
`cers (4 –7). ET plasma concentrations have been shown to be
`significantly elevated in metastatic prostate cancer. ETs may act
`as an antiapoptotic factor in certain malignancies (8).
`ET-1 is the main isoform of ETs identified in mammalian
`tissues and fluids and is found in many epithelial-derived tu-
`mors. ET-1 is known to act synergistically with a number of cell
`growth factors such as platelet-derived growth factor, basic
`fibroblast growth factor, epidermal growth factor, transforming
`growth factors, and insulin-like growth factor-I thereby possibly
`influencing neoplastic growth. Two subtypes of G protein-
`coupled receptors have been identified: ETA and ETB. ETA
`binds ET-1 with a higher affinity than the other ET isoforms,
`and this system has been implicated in tumor growth, angiogen-
`esis, nociception, and bone deposition (5, 9). ETB receptors
`mediate vasomotor tone and function as a clearance receptor
`(10).
`
`Atrasentan is an orally bioavailable selective antagonist of
`the ETA receptor (11). In preclinical studies, atrasentan has
`inhibited ET-1-induced biological responses that are mediated
`through the ETA receptor, and it is postulated that the agent may
`retard the progression of cancer through the same mechanism.
`Atrasentan has been evaluated principally in patients with
`hormone-refractory prostate cancer, and safety data in female
`patients is limited. ET levels are higher in men than in women
`and seem to be influenced by sex hormones, as evidenced by
`changes in ET levels that occur during the menstrual cycle and
`pregnancy (12, 13). Additionally, the ratio and density of ET
`receptors in the vasculature may be different in men and women,
`and the ETB receptor seems to contribute differently to resting
`vascular tone in males versus females (14, 15). These differ-
`
`Amerigen Exhibit 1104
`Amerigen v. Janssen IPR2016-00286
`
`

`
`Clinical Cancer Research
`
`4407
`
`ences in ET levels and expression of ET receptors create a
`potential for sex-related differences in atrasentan toxicity. Be-
`cause dysregulation of ET regulation has been implicated in
`several female-specific or predominant malignancies including
`ovarian, cervical, and breast cancers, investigation of atrasentan
`in these diseases may be warranted (4 –7, 16). To additionally
`examine the safety, tolerability, and pharmacokinetics of this
`drug, we initiated a phase I dose-escalation study of chronic
`daily atrasentan in a population of both female and male patients
`with refractory malignancies.
`
`PATIENTS AND METHODS
`Patients. Subjects were required to have a histologically
`or cytologically documented diagnosis of a refractory malig-
`nancy, have a life expectancy ⬎3 months, and an Eastern
`Cooperative Oncology Group performance status 0 –2. Normal
`organ function was required, including WBC ⬎2,000/mm3,
`absolute neutrophil count ⬎1,000/mm3, platelet count ⬎50,000/
`mm3, hemoglobin ⬎9 g/dl, total bilirubin ⬍1.5 mg/dl, aspartate
`aminotransferase and alanine aminotransferase ⱕ3 ⫻ upper
`limit of normality, and calculated creatinine clearance ⱖ50
`ml/min. Female subjects of childbearing potential were required
`to have a negative urine pregnancy test, and all of the subjects
`and their partners were required to use two forms of contracep-
`tion until 2 months after completion of study participation.
`Patients must have had no surgery, radiotherapy, chemotherapy,
`or immunotherapy within 28 days of starting treatment. Treat-
`ment with corticosteroids within 4 weeks of treatment was not
`allowed, except for physiological replacement therapy. Subjects
`requiring opioids for pain control were required to demonstrate
`stabilization of pain before study entry. No prior therapy with
`atrasentan was allowed. Exclusion criteria included brain or
`spinal cord involvement, active hepatitis A, B, or C or HIV
`positive, recent significant history of alcoholism or drug addic-
`tion, significant intercurrent medical or psychiatric disorder, or
`history of migraine headaches or chronic headache syndrome.
`All of the subjects were ⬎18 years of age and gave written
`informed consent. Enrollment priority was given to female
`subjects.
`in hard gelatin capsule
`Treatment Plan. Atrasentan,
`strengths of 2.5 mg and 10 mg, was administered orally once
`daily until disease progression, toxicity requiring study drug
`discontinuation, or for a maximum of 12 months, whichever
`came first. Patients were admitted for 24 h to the Clinical
`Research Center at the University of Chicago on day 1. Subjects
`arrived fasted, having taken nothing orally beginning at mid-
`night. Atrasentan was administered on day 1 and withheld on
`day 2 for the purpose of pharmacokinetic sampling. Plasma
`samples for atrasentan concentrations were obtained predosing,
`and 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 10 h, 16 h,
`24 h, 30 h, and 48 h after dosing. A predose sample was
`obtained on day 14. Dosing was withheld on days 29 –31 for
`repeat pharmacokinetic sampling, including 72-h and 96-h sam-
`ples in addition to samples at above-mentioned times.
`The initial dose level was 5 mg/day, with subsequent
`planned dose levels of 10, 20, 30, 45, 60, 75, 95, 115, and 140
`mg/day. Three subjects were to be enrolled at each dose level.
`Two subjects within each dose level must have completed at
`
`least 14 days of drug administration, and the third subject must
`have completed at least 7 days of drug administration without
`any evidence of National Cancer Institute Common Toxicity
`Criteria grade 3 or 4 drug-related toxicity before dosing at the
`next higher dose level began. If 1 of the first 3 subjects in a dose
`level experienced a grade 3 or 4 drug-related toxicity, 3 addi-
`tional subjects were to be dosed at that level before dosing
`began at the next higher dose level.
`Before enrollment, patients underwent a physical exam and
`medical history, electrocardiogram, chemistry panel, complete
`blood count, urinalysis, radiographic assessment, and Brief Pain
`Inventory assessment. Physical exams were repeated every 28
`days, and laboratory studies were repeated every 14 days. Ra-
`diological assessment was repeated after 84 days.
`The quality of life of the subjects was assessed through the
`Functional Assessment Cancer Therapy questionnaire (17). Pain
`assessment for subjects requiring opioid analgesics was based
`on the daily log of pain of the subjects using the Visual Analog
`Scale (18). All of the subjects before beginning therapy (19)
`completed a Brief Pain Inventory-Short Form. Patients with pain
`requiring the use of opioids were required to enter a stabilization
`period of no more than 14 days to achieve adequate pain control
`before day 1 dosing. A subject was considered to have achieved
`adequate pain control if he/she had 2 of 3 successive days of a
`pain score ⱕ5 on the Visual Analog Scale, tolerable side effects,
`and the use of ⱕ4 rescue doses per day.
`Pharmacokinetic and Statistical Analysis. Atrasentan
`plasma concentrations were determined using a validated liquid
`chromatograph/mass spectrometer assay method. Parameter es-
`timates for atrasentan were obtained using noncompartmental
`methods. The maximum observed plasma concentration, the
`minimum concentration for the dosing interval (day 28 only),
`and time to maximum observed concentration were read directly
`from the plasma concentration-time data. 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 points was used to determine ␤. The terminal
`elimination half-life was calculated as ln(2)/␤. The area under
`the plasma concentration-time curve from time 0 to infinite time
`(AUC⬁) after dosing on day 1 was calculated as the sum of
`AUC0-last and Clast/␤, where Clast is the last measurable plasma
`concentration. AUC over a dosing interval on day 28 (AUC0 –24)
`was calculated by the linear trapezoidal method. Oral clearance
`(CL/F, where F is the bioavailability) was calculated by dividing
`the administered dose by the corresponding AUC. Apparent
`volume of distribution (V␤) was calculated by dividing CL/F by ␤.
`Atrasentan pharmacokinetic (PK) variables, including time
`to maximum observed concentration and natural logarithms of
`dose-normalized maximum observed plasma concentration and
`AUC⬁ for day 1 and time to maximum observed concentration
`and natural logarithms of dose-normalized maximum observed
`plasma concentration, minimum concentration for the dosing
`interval and AUC0 –24 for day 28, were analyzed by an analysis
`of covariance model. The analysis of covariance model was
`specified with body weight as a covariate and dose level and sex
`as classification variables, and it allowed different slopes and
`intercepts for the regression lines with body weight for the two
`sexes by including an interaction term between body weight and
`
`

`
`4408 Phase I Study of Atrasentan in Refractory Malignancies
`
`sex. Changes in logarithms of dose-normalized maximum ob-
`served plasma concentration and AUC0 –24 from day 1 to day 28,
`as well as the logarithm of dose-normalized day 1 AUC⬁ sub-
`tracted from the logarithm of dose-normalized day 28 AUC0 –24,
`were analyzed by an ANOVA model with factors of dose and
`sex.
`
`Mean changes from baseline to each visit in laboratory
`parameters, pain assessments, and quality of life were analyzed
`by an ANOVA with all of the treatment groups combined and
`with dose as the factor.
`
`RESULTS
`are
`characteristics
`Patient Characteristics. Patient
`shown in Table 1. A total of 35 patients were treated in this
`study between February 1999 and June 2000. The majority
`(54%) of subjects were female. This was a heavily pretreated
`population of patients with 74% having received ⱖ2 prior
`chemotherapy regimens. Colorectal cancer was the most com-
`mon diagnosis, and colorectal, lung, and kidney cancers ac-
`counted for the majority of enrolled patients. No prostate cancer
`patients were enrolled in this study.
`Subjects were treated at 7 different dose levels of atrasen-
`tan: 5 mg (n ⫽ 3), 10 mg (n ⫽ 3), 20 mg (n ⫽ 4), 30 mg (n ⫽
`3), 45 mg (n ⫽ 5), 60 mg (n ⫽ 8), and 75 mg (n ⫽ 9). All of
`the enrolled subjects received at least one dose of atrasentan.
`Overall, subjects in the study achieved 2045 days of exposure to
`atrasentan. The majority of subjects discontinued treatment due
`
`Table 1 Patient characteristics
`
`Characteristic
`
`Total patients
`Age (years)
`Median
`Range
`Sex
`Female
`Male
`Baseline ECOGa performance status
`0
`1
`Previous therapy
`Surgery
`Radiation
`Biologic therapy
`Radiopharmaceuticals
`Prior chemotherapy regimens
`0
`1
`2
`3⫹
`Tumor type
`Colorectal
`Lung
`Kidney
`Sarcoma
`Cervical
`Pancreatic
`Head and neck
`Esophageal
`Other
`
`a ECOG, Eastern Cooperative Oncology Group.
`
`No.
`
`35
`
`55
`26–83
`
`19
`16
`
`17
`18
`
`30
`17
`7
`1
`
`2
`7
`8
`18
`
`9
`6
`5
`2
`2
`2
`1
`1
`7
`
`to disease progression. Dose escalation was discontinued at the
`75-mg dose level due to the occurrence of dose-limiting toxicity.
`Toxicity. Adverse events occurring on this study were
`graded as mild, moderate, or severe. All of the subjects enrolled
`in the study experienced at least one adverse event during
`treatment. The most commonly reported adverse events were
`headache (23 of 35; 66%), rhinitis (18 of 35; 51%), and periph-
`eral edema (16 of 35; 46%). When stratified by attribution, the
`most common adverse events that were considered possibly or
`probably related to study drug administration remained head-
`ache (21 of 35; 60%), rhinitis (17 of 35; 49%), and peripheral
`edema (11 of 35; 31%). Adverse events that were considered
`possibly or probably related to atrasentan and experienced by
`ⱖ10% of subjects are listed in Table 2. The incidences of
`headache and rhinitis were more pronounced at higher dose
`levels with 12 of 17 (71%) of patients experiencing headache
`and 11 of 17 (65%) of patients experiencing rhinitis at the 60 mg
`and 75 mg dose levels.
`A total of 26 adverse events were graded severe as listed in
`Table 3. Six subjects experienced severe adverse events that
`were judged either possibly or probably related to atrasentan by
`the investigator or the study sponsor. These events (with the
`respective dose level) were: hypotension (75 mg), hyponatremia
`(75 mg), pleural effusion (75 mg), fractured arm (75 mg),
`central nervous system hemorrhage (30 mg), and dyspnea with
`hypotension (60 mg). Severe events were most prevalent at the
`60 and 75 mg/day dose levels, accounting for 19 of the 26
`events. Pneumonia, dyspnea, hyponatremia, cough, and head-
`ache were the most commonly reported severe events, occurring
`in ⱖ2 patients. The remaining severe events occurred as indi-
`vidual episodes. There was no significant difference in severe
`events among either sex. Four deaths occurred during the trial or
`the follow-up period. None of these deaths were considered
`related to atrasentan (2 due to disease progression and 2 due to
`infection). Twenty-seven patients discontinued treatment for
`disease progression, and 1 withdrew for personal reasons. Five
`patients were withdrawn from the study for the following ad-
`verse events: pneumonia (20 mg), nausea and vomiting (60 mg),
`edema and dyspnea (75 mg), hypotension (75 mg), and dyspnea
`(30 mg).
`Dose-Limiting Toxicity. Dose escalation was halted af-
`ter 9 subjects were treated at the 75-mg dose level. Two subjects
`at this dose level experienced hyponatremia that was graded
`as severe, and 1 subject developed hypotension that resulted in
`a serious adverse event. These events were considered dose-
`limiting; 2 additional subjects were treated at the 60-mg dose
`level after these events for additional assessment of this dose
`level.
`Laboratory Evaluation. Previous clinical studies of
`atrasentan have suggested a mild hemodilution effect as mani-
`fested by a decrease in hemoglobin/hematocrit as well as serum
`albumin and total protein (20, 21). In the current study, no
`statistically significant changes from baseline across all of the
`dose levels occurred for hemoglobin or hematocrit after 2 or 4
`weeks of atrasentan treatment. There was a mild decrease in
`albumin and total protein over the first 4 weeks of 0.25 ⫾ 0.09
`g/dl (P ⫽ 0.008) and 0.41 ⫾ 0.14 g/dl (P ⫽ 0.008), respectively.
`PKs. PK parameters are shown in Table 4. Atrasentan
`was rapidly absorbed after oral administration of 5–75 mg daily
`
`

`
`Clinical Cancer Research
`
`4409
`
`Table 2 Number (%) of subjects experiencing adverse events considered possibly or probably related to treatment and reported by ⱖ10% of 35
`subjects receiving atrasentan
`
`Atrasentan dose
`Adverse event
`
`Headache
`Rhinitis
`Peripheral edema
`Asthenia
`Hypotension
`Nausea
`Vomiting
`Anorexia
`Anemia
`
`5 mg
`n ⫽ 3
`
`1 (33)
`1 (33)
`
`1 (33)
`
`1 (33)
`
`10 mg
`n ⫽ 3
`
`1 (33)
`
`1 (33)
`2 (67)
`1 (33)
`
`20 mg
`n ⫽ 4
`
`3 (75)
`1 (25)
`1 (25)
`
`1 (25)
`
`1 (25)
`
`30 mg
`n ⫽ 3
`
`1 (33)
`2 (67)
`2 (67)
`1 (33)
`1 (33)
`1 (33)
`1 (33)
`1 (33)
`1 (33)
`
`45 mg
`n ⫽ 5
`
`3 (60)
`2 (40)
`1 (20)
`
`1 (20)
`2 (40)
`2 (40)
`1 (20)
`
`60 mg
`n ⫽ 8
`
`4 (50)
`7 (88)
`4 (50)
`3 (38)
`1 (13)
`1 (13)
`
`1 (13)
`1 (13)
`
`75 mg
`n ⫽ 9
`
`8 (89)
`4 (44)
`2 (22)
`2 (22)
`3 (33)
`3 (33)
`3 (33)
`2 (22)
`1 (11)
`
`Total
`n ⫽ 35
`
`21 (60)
`17 (49)
`11 (31)
`8 (23)
`8 (23)
`8 (23)
`6 (17)
`6 (17)
`4 (11)
`
`with mean time to maximum observed concentration values
`ranging from 0.3 to 1.7 h. After peaking, atrasentan plasma
`concentrations declined biexponentially with a terminal half-life
`that averaged 26 h. Atrasentan PKs were characterized by a
`global mean oral clearance of 21 liters/h (SD 14) and apparent
`volume of distribution of 790 liters (SD 677). Clearance was
`constant across dose groups (P ⫽ 0.13, day 1; P ⫽ 0.19, day 28)
`and between day 1 and day 28 (P ⫽ 0.54). There was no
`statistically significant difference between sexes in any atrasen-
`tan PK parameter analyzed (Table 5). The tests of different
`slopes (P ⬎ 0.07) and different averages (P ⬎ 0.06) on the
`regression lines with body weight between sexes for all of the
`analyzed PK variables were not statistically significant. Steady-
`state atrasentan plasma concentrations consistent with biological
`activity in preclinical models and expected to selectively inhibit
`ETA receptors were achieved across the range of doses studied.
`Response. No objective responses were observed in
`this study. One patient with medullary thyroid carcinoma and
`another with papillary thyroid carcinoma maintained stable
`disease for 6 months and 13 months, respectively. Sixteen
`
`patients had objective evidence of disease progression on
`follow-up radiographic imaging. Twelve subjects were with-
`drawn early from treatment with clinical evidence of progres-
`sive disease, and 2 patients died from progressive disease
`while on study. No statistically significant changes in pain
`response or analgesic use were observed during the study. No
`statistically significant changes in quality of life parameters
`as measured by the Functional Assessment Cancer Therapy
`questionnaire were observed.
`
`DISCUSSION
`This Phase I study demonstrates that chronic daily oral
`dosing of atrasentan is well tolerated in doses of up to 60
`mg/day. This is the first study of atrasentan in cancer patients to
`contain a significant proportion of female subjects. Before this
`study, atrasentan had been predominately studied in males due
`to its development for treatment of prostate cancer. No signifi-
`cant differences in toxicity or PKs between the sexes were
`observed. Given that ET dysregulation has been suggested in
`
`Table 3 Number of subjects experiencing adverse events by dose level
`
`Atrasentan dose
`Adverse event
`
`Pneumonia
`Dyspnea
`Hyponatremia
`Cough
`Headache
`Anemia
`Asthenia
`Bilirubinemia
`Chest pain
`CNSa bleed
`Confusion
`Edema
`Hepatomegaly
`Hypotension
`Nausea and vomiting
`Pathological fracture
`Peripheral edema
`Sepsis
`Shock
`Total
`
`a CNS, central nervous system.
`
`5 mg
`n ⫽ 3
`
`10 mg
`n ⫽ 3
`
`20 mg
`n ⫽ 4
`
`1
`
`1
`1
`2
`
`0
`
`1
`
`30 mg
`n ⫽ 3
`
`45 mg
`n ⫽ 5
`
`60 mg
`n ⫽ 8
`
`75 mg
`n ⫽ 9
`
`1
`
`1
`
`2
`
`1
`
`1
`
`2
`
`2
`
`1
`1
`
`1
`
`1
`
`6
`
`2
`1
`2
`1
`
`1
`
`1
`1
`1
`1
`
`1
`1
`
`13
`
`

`
`4410 Phase I Study of Atrasentan in Refractory Malignancies
`
`Mean values ⫾ SD atrasentan dose (mg).
`
`Table 4 Pharmacokinetic parameters of atrasentan in patients with refractory malignancies
`
`Parameter
`
`5
`
`10
`
`20
`
`30
`
`45
`
`60
`
`75
`
`Day 1
`Tmax(h)b
`Cmax(ng/ml)
`AUC⬁(h䡠ng/ml)
`t1/2(h)c
`CL/F (liter/h)
`Day 28
`Tmax(h)
`Cmax(ng/ml)
`Cmin(ng/ml)
`AUC0–24(h䡠ng/ml)
`t1/2(h)c
`CL/F (liter/h)
`
`n ⫽ 3
`0.8 ⫾ 0.3
`91 ⫾ 34
`646 ⫾ 344
`27.0 ⫾ 10.1
`9.5 ⫾ 5.3
`n ⫽ 3
`0.6 ⫾ 0.1
`89 ⫾ 42
`17 ⫾ 13
`580 ⫾ 360
`34.1 ⫾ 16.5
`10.6 ⫾ 4.9
`
`n ⫽ 3
`1.0 ⫾ 0.5
`62 ⫾ 53
`536 ⫾ 273
`23.2 ⫾ 5.8
`23.8 ⫾ 15.5
`n ⫽ 3
`0.8 ⫾ 0.7
`99 ⫾ 63
`19 ⫾ 11
`752 ⫾ 430
`26.4 ⫾ 8.6
`19.7 ⫾ 16.8
`
`n ⫽ 4a
`0.9 ⫾ 0.5
`217 ⫾ 268
`1089 ⫾ 940
`18.8 ⫾ 3.7
`30.4 ⫾ 23.4
`n ⫽ 3a
`0.3 ⫾ 0.1
`358 ⫾ 305
`40 ⫾ 28
`1591 ⫾ 973
`40.9 ⫾ 3.4
`20.3 ⫾ 19.0
`
`n ⫽ 3
`1.1 ⫾ 0.4
`234 ⫾ 173
`1527 ⫾ 652
`21.2 ⫾ 8.7
`22.4 ⫾ 9.9
`n ⫽ 4
`1.7 ⫾ 1.6
`242 ⫾ 197
`31 ⫾ 21
`1492 ⫾ 876
`32.0 ⫾ 8.1
`27.0 ⫾ 15.8
`
`n ⫽ 5a
`1.2 ⫾ 0.7
`396 ⫾ 207
`4326 ⫾ 2455
`19.1 ⫾ 3.7
`13.7 ⫾ 8.5
`n ⫽ 3
`1.5 ⫾ 0.9
`544 ⫾ 348
`97 ⫾ 104
`5354 ⫾ 5644
`30.0 ⫾ 5.0
`16.0 ⫾ 11.4
`
`n ⫽ 8
`0.8 ⫾ 0.3
`480 ⫾ 269
`3453 ⫾ 1502
`16.1 ⫾ 6.3
`20.1 ⫾ 8.0
`n ⫽ 4
`0.6 ⫾ 0.1
`819 ⫾ 338
`50 ⫾ 19
`3162 ⫾ 1215
`32.6 ⫾ 15.5
`22.0 ⫾ 10.8
`
`n ⫽ 9a
`0.9 ⫾ 0.4
`857 ⫾ 477
`4277 ⫾ 2584
`12.1 ⫾ 4.8
`24.4 ⫾ 16.6
`n ⫽ 2
`1.3 ⫾ 1.1
`489 ⫾ 400
`26 ⫾ 4
`2338 ⫾ 1374
`36.1 ⫾ 41.4
`38.8 ⫾ 22.8
`
`a n reduced by one for AUC⬁, t1/2, and CL/F, because t1/2 could not be determined for one of the subjects.
`b Tmax, time to maximum observed concentration; Cmax, maximum observed plasma concentration; AUC⬁, area under the plasma concentration-
`time curve from time 0 to infinite time; t1/2, terminal elimination half-life; CL/F, oral clearance; AUC0 –24, area under the plasma concentration-time
`curve over a dosing interval on Day 28.
`c Harmonic mean ⫾ pseudo SD.
`
`breast, cervical, and ovarian cancers, additional study in these
`diseases may be warranted.
`The frequently observed adverse events of rhinitis, head-
`ache, and edema have been reported previously with ET recep-
`tor antagonists and are likely attributable to the vasoactive
`properties of these agents. Data from a previous Phase I study of
`atrasentan supported 60 mg as the maximum tolerated dose due
`to increased incidence of headache coincident with higher dose
`levels (20). Another Phase I study treated patients with doses of
`up to 95 mg/day without achieving protocol-defined maximum
`tolerated dose (21). Rhinitis, headache, and peripheral edema
`were again the most frequent adverse events, and most cases
`occurred in patients taking doses of ⱖ60 mg. The majority of
`patients treated at the 60- and 75-mg dose levels in our study
`experienced headache and rhinitis. Whereas these adverse
`
`Table 5 Central value estimates of pharmacokinetic parameter
`by sex
`
`Central value estimatesa
`
`Parameter
`
`Males
`
`Females
`
`P
`
`events were not considered severe in nature, they were promi-
`nent enough to support a recommended daily dose of ⬍75 mg.
`The severe adverse events that limited dose escalation in
`this study were hypotension and hyponatremia, which likewise
`may be explainable by vasoactive changes induced by atrasen-
`tan. Whereas statistically significant decreases in blood pressure
`were observed sporadically, there were no consistent trends
`established across dose levels. Blood pressure should be mon-
`itored in subjects receiving atrasentan, and adjustment of con-
`comitant antihypertensives may be necessary. Whereas slight
`decreases in serum albumin and total protein suggest a mild
`hemodilution effect of atrasentan, no significant fall in hemo-
`globin or hematocrit was observed.
`PK analysis revealed that atrasentan is rapidly absorbed
`when orally administered and that biologically relevant steady-
`state concentrations were achieved across all of the dose levels.
`For example, the mean unbound minimum concentration for the
`dosing interval for the 10 mg daily regimen was ⬃10-fold
`greater than the Ki for the ETA receptor (0.017 ng/ml; atrasentan
`is 98.8% bound to plasma proteins). No significant differences
`in PKs between the sexes were detected. A modest increase in
`plasma ET concentrations was observed suggesting biological
`activity, perhaps through displacement of ETs from their recep-
`tors or alteration of a feedback pathway (data not shown). Because
`atrasentan is a selective ETA antagonist and ETB is thought to be
`the primary route of clearance of ETs from the plasma, marked
`changes in plasma ET concentrations would not be expected.
`In conclusion,
`this study demonstrated that atrasentan
`doses of up to 60 mg/day are well tolerated by both male and
`female subjects with advanced cancer. Observed side effects
`were consistent with vasoactive changes, likely mediated by the
`ETA receptor. The efficacy of atrasentan in the treatment of
`prostate cancer is being investigated in ongoing clinical studies.
`A dose of 10 mg daily is being used in most of these studies,
`well within the safe and tolerable range as evidenced by our
`study. Phase II evaluations of atrasentan may be warranted in
`other diseases in which ET dysregulation has been suggested as
`
`0.412
`0.120d
`0.067d
`
`0.651
`0.205d
`0.233d
`0.110d
`
`0.9
`8
`68
`
`0.8
`7
`46
`0.8
`
`1.0
`8
`58
`
`1.0
`11
`65
`1.3
`
`Day 1
`b (h)
`Tmax
`c (ng/ml/mg)
`Cmax
`c (h䡠ng/ml/mg)
`AUC⬁
`Day 28
`Tmax (h)
`c (ng/ml/mg)
`Cmax
`c (h䡠ng/ml/mg)
`AUC0–24
`c (ng/ml/mg)
`Cmin
`aAdjusted means (least-squares means) after adjusting for dose
`level and body weight in analysis of covariance for Tmax and antiloga-
`rithms of adjusted means in logarithms for others.
`b Tmax, time to maximum observed concentration; Cmax, maximum
`observed plasma concentration; AUC⬁, area under the plasma concen-
`tration-time curve from time 0 to infinite time; AUC0 –24, area under the
`plasma concentration-time curve over a dosing interval on Day 28.
`c Dose-normalized.
`d Data analyzed on transformed log scale.
`
`

`
`Clinical Cancer Research
`
`4411
`
`a factor in tumor growth. Randomized placebo-controlled Phase
`II studies demonstrated a consistent ability of atrasentan to
`attenuate the increase in markers of prostate cancer progression
`such as prostate-specific antigen, alkaline phosphatase, N-
`telopeptides, C-telopeptides, deoxypyridinoline, and lactate de-
`hydrogenase (22–24). Phase III trials comparing atrasentan to
`placebo are nearing completion.
`
`ACKNOWLEDGMENTS
`We thank Todd J. Janus, M.D., PhD., for assistance in the conduct
`of this study.
`
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