0022-5347/05/1733-0790/0
`THE JOURNAL OF UROLOGY®
`Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
`
`Vol. 173, 790–796, March 2005
`Printed in U.S.A.
`DOI: 10.1097/01.ju.0000147013.09157.8e
`
`A RANDOMIZED, PHASE II TRIAL OF KETOCONAZOLE PLUS
`ALENDRONATE VERSUS KETOCONAZOLE ALONE IN PATIENTS WITH
`ANDROGEN INDEPENDENT PROSTATE CANCER AND BONE
`METASTASES
`
`WILLIAM D. FIGG,* YINONG LIU, PHILIP ARLEN, JAMES GULLEY, SETH M. STEINBERG,
`DAVID J. LIEWEHR, MICHAEL C. COX, SUOPING ZHAI, SERGE CREMERS, ALLYSON PARR,
`XIAOWEI YANG, CLARA C. CHEN, ELIZABETH JONES AND WILLIAM L. DAHUT
`From the Center for Cancer Research, National Cancer Institute (WDF, YL, PA, JG, SMS, DJL, MCC, SZ, AP, XY, WLD) and
`Departments of Nuclear Medicine (CCC) and Diagnostic Radiology (EJ), Warren Grant Magnuson Clinical Center, National Institutes of
`Health, Bethesda, Maryland, and Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center (SC), Leiden,
`The Netherlands
`
`ABSTRACT
`Purpose: Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix
`metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole
`(KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we
`determined whether KT plus AL produced acceptable disease responses compared with KT alone.
`As the experimental design, 72 patients with progressive AIPC metastatic to bone were random-
`ized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40
`mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used
`to determine the proportion of patients with a PSA decrease, time to progression and response
`duration. The pharmacokinetics of KT and AL were characterized and changes in circulating
`angiogenic factors were assessed.
`Results: At a median potential followup of 23.9 months the proportion of patients with a
`greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%,
`respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H
`groups, respectively (p ⫽ 0.125). Median progression-free survival was not significantly pro-
`longed in the KT/H/AL group (4.6 vs 3.8 months, p ⫽ 0.27). There was no significant difference
`in overall survival between the 2 treatment arms but there was a trend toward improved survival
`in the KT/H arm (p ⫽ 0.074). Toxicity in the 2 groups was mild and there were no clear
`associations between changes in circulating angiogenic factor levels and clinical outcomes in
`either treatment arm.
`Conclusions: There were no statistically significant differences in response rate, progression-
`free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients
`with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable
`safety profile compared with treatment with KT/H alone. However, the addition of AL offers no
`survival benefit in patients with AIPC.
`KEY WORDS: prostate, prostatic neoplasms, ketoconazole, alendronate, pharmacokinetics
`
`Prostate cancer is currently the second leading cause of
`cancer related deaths with 28,900 deaths estimated in 2004.1
`Although the majority of patients with advanced prostate
`cancer respond to hormonal therapy, androgen independence
`eventually occurs and it is ultimately fatal. Single agent or
`combination chemotherapy may lead to improved quality of
`life and survival2 but not without toxicities. Therefore, new
`therapeutic modalities for the treatment of prostate cancer
`are warranted.
`Bisphosphonates inhibit osteoclast mediated bone resorp-
`tion.3 They may decrease bone pain and skeletal complica-
`tions in patients with metastatic cancer4⫺6 and improve sur-
`vival in multiple myeloma.7 The bisphosphonate alendronate
`Submitted for publication August 26, 2004.
`Study received National Cancer Institute institutional review
`board approval.
`Supported by the United States Government Intramural Program
`of the National Cancer Institute.
`* Correspondence: National Cancer Institute, 10 Center Dr.,
`Building 10, Room 5A-01, Bethesda, Maryland 20892 (telephone:
`301-402-3622; FAX: 301-402-8606; e-mail: wdfigg@helix.nih.gov).
`
`(AL) has been shown to inhibit osteoclast activity, block the
`establishment of bone metastases8, 9 and inhibit the secretion
`of matrix metalloproteinase (MMP)-2, which in turn may
`block angiogenesis.
`The antimycotic agent ketoconazole (KT) is a potent inhib-
`itor of adrenal steroid synthesis and it is used as second line
`hormonal treatment in patients with androgen independent
`prostate cancer (AIPC). The rate of a prostate specific anti-
`gen (PSA) decrease of greater than 50% with KT treatment
`ranges from 30% to 80%.10, 11 We have reported that KT has
`an antiproliferative effect on prostate cancer cells in vitro,12
`which may be mediated through cytochrome P450 enzymes
`other than those responsible for steroidogenesis. These ob-
`servations suggest that there is a direct cytotoxic effect of KT
`on tumor cells rather than simply an effect of androgen
`regulation. Based on these data a randomized, phase II trial
`of KT in combination with AL vs KT alone in patients with
`AIPC and bone metastases was initiated to assess the clinical
`efficacy of this combination.
`790
`
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`

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`PROSTATE CANCER, KETOCONAZOLE AND ALENDRONATE
`
`791
`
`PATIENTS AND METHODS
`Protocol objectives. The primary objective was to determine
`if KT plus AL produced acceptable disease responses com-
`pared with KT alone. Other objectives were to characterize
`the pharmacokinetics and pharmacodynamics of
`the 2
`agents, and determine the extent of angiogenesis inhibition.
`Patient eligibility. All patients had AIPC metastatic to
`bone and had progressed after combined androgen blockade
`and antiandrogen withdrawal. Each patient had 1) a histo-
`logical diagnosis of adenocarcinoma of the prostate, 2) in-
`creasing PSA despite continued testicular suppression and/or
`progression on computerized tomography (CT) or bone scan
`and 3) an Eastern Cooperative Oncology Group performance
`status of 2 or less. There were no limits on prior radiation or
`chemotherapy.
`Study design. This was an open label, randomized, phase II
`study of KT (400 mg 3 times daily with 20 mg hydrocortisone
`every morning and 10 mg hydrocortisone every evening) plus
`AL (40 mg daily) vs KT with hydrocortisone (H) as described
`alone in patients with AIPC. The trial was designed to enroll
`36 patients per arm to permit the study to conclude whether
`the response proportion on each arm was 40% or greater as
`opposed to 20% with 10% types I and II error probabilities.
`The study used a new method of interim evaluation of re-
`sponses, which would have permitted the study to terminate
`early in the event that 1 arm had far superior responses than
`the other at a midpoint.13 This study was approved by the
`institutional review board of the National Cancer Institute
`and all patients provided informed consent.
`Concomitant administration of drugs that decrease gastric
`acid output or increase gastric pH were prohibited. PSA,
`standard chemistry and hematological tests were obtained
`monthly. Radiographic studies (CT of the chest, abdomen
`and pelvis, and 99mtechnetium bone scintigraphy) were re-
`peated every 2 months. Therapy continued if there were no
`significant toxicities or evidence of disease progression. In
`addition, patients who had not undergone bilateral orchiec-
`tomy continued to receive luteinizing hormone-releasing hor-
`mone agonist.
`The dose of KT was decreased by 200 mg daily and that of
`AL was decreased by 10 mg daily in patients who experienced
`Common Toxicity Criteria, version 2.0, grade 2 side effects
`until they subsided. Patients who experienced grades 3 to 4
`toxicity had the drug withheld until toxicity resolved to grade
`2 or less. Patients were allowed to resume treatment at a
`decreased dose within 2 months provided that the side effect
`had resolved or decreased in severity to grade 2 or less.
`Patients in whom symptoms did not decrease after a 2-month
`hiatus off treatment were withdrawn from further study
`participation.
`
`Response evaluation. Standard objective criteria were used
`to assess soft tissue lesion changes.14 Disappearance of
`greater than 50% of the number of metastatic lesions on bone
`scan was also considered a positive response. PSA criteria for
`response and progression were based on Working Group Con-
`sensus of PSA criteria.15 Briefly, PSA response was defined
`as a decrease in PSA of 50% or greater (confirmed by a second
`value at 4 weeks or greater after the first one) with no other
`evidence of disease progression. Progressive disease was de-
`fined by any of certain criteria, including 1) a greater than
`25% increase in the size of all soft tissue masses and/or the
`appearance of new masses, 2) the need for radiation therapy
`and 3) 2 consecutive increasing PSA measurements by 50%
`or greater of nadir PSA in patients with a PSA response, by
`25% or greater of nadir or baseline (whichever was lower)
`PSA in patients without a PSA response or by new lesions
`consistent with AIPC. Patients were not declared to have
`disease progression until PSA had increased by an absolute
`value of 5 ng/ml or greater.
`KT pharmacokinetic analysis. Serial blood samples were
`collected following a single dose and KT plasma concentra-
`tions were determined using high performance liquid chro-
`matography assay.15 Data were analyzed by noncompart-
`mental and compartmental analysis (ADAPT II, version 4,
`University of Southern California, Los Angeles, California).
`A 1 compartment model with absorption delay was applied.
`AL pharmacokinetic analysis. Urine concentrations of
`alendronate were analyzed by high performance liquid chro-
`matography assay with a limit of quantitation of 4 ng/ml.16
`Assessment of changes in circulating angiogenic growth
`factors. Plasma was collected for the determination of vascu-
`lar endothelial growth factor (VEGF) and basic fibroblast
`growth factor (bFGF) levels prior to study and at each clinic
`visit thereafter. From each arm of the trial 10 patients with
`a PSA decrease of 50% or greater and 10 without a PSA
`decrease serving as controls were assayed for VEGF and
`bFGF levels using enzyme-linked immunosorbent assay
`(ELISA) kits (R and D Systems, Minneapolis, Minnesota).17
`Changes in MMP-2 and MMP-9 were also examined. (Amer-
`sham Pharmacia Biotech, Piscataway, New Jersey). All anal-
`yses were performed in duplicate and the absolute values
`obtained from each ELISA plate were back calculated from
`the ELISA kit standard curve.
`Assessment of changes in bone resorption. Serum levels of
`cross-linked N-telopeptides of type I collagen (NTx) were
`measured using an ELISA assay (Osteomark Serum NTx
`ELISA kit, Wampole Laboratories, Princeton, New Jersey).18
`Final assay results are reported as nanomoles of bone colla-
`gen equivalents (BCE)/l.
`Statistical analysis. All patients who received any experi-
`
`TABLE 1. Demographics of patients enrolled
`KT/H
`
`No. pts
`Median age (range)
`Median Gleason score at diagnosis (range)
`Median ng/ml baseline PSA (range)
`No. soft tissue lesion(s)
`No. prior palliative radiotherapy
`No. secondary hormonal therapies
`No. chemotherapy
`No. opioid analgesics prior to enrolling
`Eastern Cooperative Oncology Group performance status:
`0
`1
`2
`Median U/l lactate dehydrogenase (range)
`Median IU/l alkaline phosphatase (range)
`Median gm/dl glucose (range)
`Median gm/dl hemoglobin (range)
`Median 1,000/mm3 platelets (range)
`
`36
`(51–79)
`70
`(3–9)
`8
`74.35 (1.7–1,458)
`10
`6
`23
`8
`7
`
`12
`23
`1
`198.5
`130.5
`116.5
`12.7
`239.5
`
`(122–397)
`(69–924)
`(80–273)
`(8.7–15.3)
`(101–401)
`
`KT/H/AL
`
`36
`(51–85)
`72
`(4–9)
`8
`78.1 (5.5–1,562)
`8
`7
`21
`7
`9
`
`7
`25
`4
`(137–525)
`196
`134.5 (71–4,000)
`113
`(83–255)
`13.05
`(9–15.4)
`223
`(132–408)
`
`DEF-ABIRA-0000095
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`MYLAN PHARMS. INC. EXHIBIT 1108 PAGE 2
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`

`

`792
`
`PROSTATE CANCER, KETOCONAZOLE AND ALENDRONATE
`
`FIG. 1. Kaplan-Meier graph shows PFS in KT/H and KT/H/AL groups (median 3.8 and 4.6 months, respectively)
`
`mental drugs were evaluable for toxicity and disease re-
`sponse. Overall survival and progression-free survival (PFS)
`duration were calculated from the on-study date until the
`date of death, progression or last followup, as appropriate.
`Response duration was calculated from the date of response
`until the date of progression or last followup. The probability
`of survival, progression-free survival or continued response
`was determined by the Kaplan-Meier method. The statistical
`significance of the difference between a pair of Kaplan-Meier
`curves was determined by the Mantel-Haenszel method. The
`statistical significance of the difference between the 2 ran-
`domized groups with respect to various laboratory parame-
`ters was determined by the Wilcoxon rank sum test. All
`p values are 2-sided.
`
`RESULTS
`Patient data. A total of 72 patients were accrued (36 pa-
`tients per arm) with a median potential followup of 23.9
`
`months. Table 1 lists demographic data. At study entry pa-
`tient characteristics were similar in the 2 treatment groups
`(table 1). The majority of patients received second line hor-
`monal therapy prior to this study and 15 received prior
`chemotherapy.
`Clinical activity. The proportion of patients with a 50% or
`greater decrease in PSA was similar between the 2 groups,
`namely 17 of 36 (47%) in the KT/H arm and 18 of 36 (50%) in
`the combination group. A total of 18 patients had measurable
`disease on CT. No individual had a partial response by CT
`criteria, although several patients had some decrease in meas-
`urable disease (50% or less decrease). All patients had evalu-
`able disease by bone scan. None of the patients had a nor-
`malization of bone scan. There was no significant difference
`in PFS between the 2 treatment arms (fig. 1). Median PFS in
`the KT/H and KT/H/AL groups was 3.8 and 4.6 months,
`respectively (p ⫽ 0.27). However, there was a trend toward a
`prolonged response duration by adding AL. Figure 2 shows
`
`FIG. 2. Kaplan-Meier graph demonstrates response duration in KT/H and KT/H/AL groups (median 6.3 and 8.9 months, respectively)
`
`DEF-ABIRA-0000096
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`MYLAN PHARMS. INC. EXHIBIT 1108 PAGE 3
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`

`

`PROSTATE CANCER, KETOCONAZOLE AND ALENDRONATE
`
`793
`
`that the median duration of response was 6.3 months in the
`KT/H group and 8.9 months in the KT/H/AL group
`(p ⫽ 0.125). At the time of analysis 14 of 16 responders in the
`KT/H group and 13 of 17 in the combined group had pro-
`gressed. A total of 43 patients are currently alive and the
`median survival duration was 24.7 months (fig. 3, A). There
`was no statistically significant difference in overall survival
`between the 2 treatment arms. However, median overall
`survival in KT/H/AL group was 19.0 months and it has not
`been achieved in the KT/H group (p ⫽ 0.074, fig. 3, B).
`Toxicity. All patients who received any treatment were
`evaluated for toxic effects. Overall toxicities were mild and
`there was no significant difference between the 2 arms (table
`2). Of the patients 28 (39%) had grades 1 and 2 nausea and/or
`emesis, and 40 (56%) had fatigue, including 3 with grade 3
`symptoms. Seven patients (10%) had grade 1 or 2 and 1 had
`grade 3 reversible liver function test abnormalities. Grade 1
`skin toxicity, including dryness, dry lips, mild loss of body
`
`hair and skin stickiness (19 patients) was observed in 69% of
`patients. Eight patients experienced grade 3 toxicities. The
`incidence of grade 3 toxicity was only slightly higher for
`KT/H/AL (5 patients) compared with the KT/H arm (3 pa-
`tients). One patient in the combination arm had a duodenal
`ulcer with upper gastrointestinal bleeding. There were no
`grade 4 or 5 events. A total of 11 patients (15%) had hyper-
`glycemia at least once during therapy but only 2 required
`treatment. Three patients experienced a mild increase in
`creatinine, which returned to normal after conservative man-
`agements.
`Pharmacokinetics. Pharmacokinetic analysis was per-
`formed in 21 patients who received a single initial dose of 400
`mg KT on day 1. Figure 4 shows the plasma concentration-
`time profile. Ten hours after administration KT concentra-
`tions were usually low or below the limit of quantitation (62.5
`ng/ml). A 1 compartment model with absorption delay fit the
`data well (r2 ⫽ 0.97). The elimination half-life was 1.9 hours
`
`FIG. 3. Kaplan-Meier graph shows overall survival. A, in all patients median survival was 24.7 months. B, in KT/H and KT/H/AL groups
`median survival was 19 months and not achieved, respectively.
`
`DEF-ABIRA-0000097
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`

`794
`
`PROSTATE CANCER, KETOCONAZOLE AND ALENDRONATE
`
`TABLE 2. Most frequent treatment related adverse events
`No. KT/H/AL (%)
`Grades 1–2
`Grade 3
`
`No. KT/H (%)
`Grades 1–2
`
`Grade 3
`
`No. pts
`Whole body:
`Fatigue
`Edema
`Hot flash
`Headache
`Tearing
`Digestive system:
`Nausea/vomiting
`Dyspepsia
`Diarrhea
`Constipation
`Taste disturbance
`Duodenal ulcer with gastrointestinal bleeding
`Nervous system:
`Dizziness
`Blurred vision
`Skin:
`Dry skin/lips
`Rash
`Metabolic ⫹ other laboratory abnormalities:
`Hyperglycemia
`Increased serum glutamic-pyruvic transaminase
`Increased serum glutamic-oxaloacetic transaminase
`Increased creatinine
`
`36
`
`2 (6)
`
`1 (3)
`
`2 (6)
`
`16 (44)
`10 (28)
`2 (6)
`6 (17)
`2 (6)
`
`12 (33)
`9 (25)
`9 (25)
`9 (25)
`3 (8)
`
`7 (19)
`2 (6)
`
`24 (67)
`3 (8)
`
`4 (11)
`3 (8)
`4 (11)
`2 (6)
`
`36
`
`1 (3)
`
`1 (3)
`1 (3)
`1 (3)
`
`21 (58)
`5 (14)
`5 (14)
`3 (8)
`4 (11)
`
`16 (44)
`5 (14)
`7 (19)
`7 (19)
`8 (22)
`
`2 (6)
`3 (8)
`
`26 (72)
`5 (14)
`
`4 (11)
`3 (8)
`3 (8)
`1 (3)
`
`FIG. 4. Mean KT plasma concentration-time profile data ⫾ SD on 21 patients
`
`(table 3). KT clearance was 22.6 l per hour, similar to that
`obtained with compartmental analysis (22.0 l per hour). The
`mean concentration at steady state ⫾ SD of KT alone and KT
`plus AL was 6.0 ⫾ 3.0 and 6.5 ⫾ 3.7 ␮g/ml, respectively.
`There was no significant difference between the 2 groups
`(unpaired t test p ⬎0.05). Of 36 patients who received AL 34
`achieved a steady-state urine concentration. Patients had a
`mean urine concentration of 488 ng/ml (range 8 to 2,555),
`which was within that anticipated for this dose.
`Changes in bone resorption. A total of 66 patients were
`evaluable for changes in NTx. There were 34 patients in the
`K alone group with a mean decrease of 3.39 nM BCE/l (range
`
`⫺74.9 to 75.1) and 32 in the KT/AL group with a mean
`decrease of 25.97 nM BCE/l (range ⫺52.1 to 571.7). Overall
`there was a mean decrease of 29.37 ⫾ 73.78 nM BCE/l and
`the difference was not statistically significant between the 2
`groups (p ⫽ 0.11).
`Changes in the levels of circulating angiogenic growth fac-
`tor. We analyzed VEGF, bFGF, MMP-2 and MMP-9 levels at
`baseline and during treatment as potential indicators of the
`biological activity of alendronate. Plasma circulating VEGF
`and bFGF levels were evaluated in 10 patients with a PSA
`response and in 10 without a response per group. The rela-
`tionship between changes in PSA (classified as a PSA re-
`
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`PROSTATE CANCER, KETOCONAZOLE AND ALENDRONATE
`
`0–10
`
`0–Infinity
`
`795
`
`Absorption
`Time
`Delay (hrs)
`
`Ka
`(hr⫺1)
`
`TABLE 3. Ketoconazole pharmacokinetic parameters in 21 patients receiving single oral dose of 400 mg
`Max Plasma
`Apparent Plasma
`AUC (␮g hr/ml)
`Concentration
`Clearance/Fraction
`(␮g/ml)
`Absorbed (l/hr)
`
`Max Time
`(hr)
`
`Distribution
`Vol/F (l)
`
`Half-Time
`(hrs)
`
`20.10
`18.54
`8.86
`
`23.11
`21.92
`11.65
`
`4.25
`4.01
`2.05
`
`3.1
`4.0
`1.1
`
`Noncompartment:
`Mean
`Median
`SD
`Compartment:
`Mean
`Median
`SD
`
`22.6
`18.2
`13.8
`
`22.0
`18.1
`13.5
`
`72.6
`64.1
`44.2
`
`54.0
`49.0
`31.6
`
`2.3
`2.2
`0.7
`
`1.9
`1.6
`1.1
`
`1.27
`0.52
`2.20
`
`0.87
`0.90
`0.45
`
`sponse or not), and changes in VEGF and bFGF with time
`were analyzed by the Wilcoxon rank sum test. There was no
`clear association between VEGF level changes and PSA re-
`sponses in the KT alone arm (p ⫽ 0.39) or in the combination
`arm (p ⫽ 0.96). Likewise there was no clear association
`between changes in bFGF and the PSA response in the KT
`alone or KT/AL treatment arm (p ⫽ 0.54 and 0.20, respec-
`tively). There were no significant changes in MMP-2 or
`MMP-9 levels before, and approximately 2 and 4 months
`after treatment in either group. In addition, an association
`between changes in MMP-2 or MMP-9 and PSA responses
`could not be identified in either treatment arm (data not
`shown).
`
`DISCUSSION
`Many patients with advanced prostate carcinoma have
`skeletal metastases, which are responsible for significant
`morbidity. Although most of these metastases are osteoscle-
`rotic, it has been shown that the abnormal osteoblastic for-
`mation is preceded by osteoclastic activation, which appears
`to be associated with bone pain. Compounds that inhibit
`osteoclasts may slow the progression of metastatic bone dis-
`ease. This provides the rationale for using bisphosphonates
`in AIPC. There have been 4 trials of bisphosphonates in
`patients with prostate cancer. One trial compared clodronate
`with placebo in addition to mitoxantrone and prednisone in
`208 patients with symptomatic bone metastases and it failed
`to show a difference in the proportions of patients with skel-
`etal related events.19 Smith found no difference in symptom-
`atic response with or without etidronate in patients with
`AIPC.20 The Zoledronic Acid Prostate Cancer Study Group
`found that the rate of skeletal related events in this patient
`population was significantly decreased by zoledronic acid
`(643 subjects).6 Another study demonstrated that clodronate
`delayed the time to symptomatic bone metastases (311 sub-
`jects).21 Based on these data the clinical use of bisphospho-
`nates in patients with AIPC has increased dramatically.
`Several trials have shown ketoconazole activity in AIPC
`(with a PSA decrease in 30% to 80% of patients).10, 11, 21–23
`The response proportion observed in our study (47%) is sim-
`ilar to those previously reported. The addition of AL to KT
`did not change the response rate (50%). Interestingly the
`median duration of response was superior in the combination
`group, although not significantly so.
`There was no significant difference in overall survival be-
`tween the 2 treatment groups but it favored KT/H and prog-
`nostic factors were evenly distributed. We did not observe
`significant changes in circulating angiogenic markers.
`Whether this reflects a true lack of effect of AL on angiogen-
`esis or rather the fact that such effects are only occurring at
`the cellular level could not be discerned from this study.
`Combination therapy was well tolerated in the majority of
`patients. Dry skin, gastrointestinal discomfort, edema and
`fatigue were the most common complaints noted. Whereas
`toxicities were frequent, they were easily managed by basic
`conservative treatment. There were no grade 4 toxicities and,
`
`although they were uncommon, grade 3 toxicities responded
`to conservative management and dose reduction in the ma-
`jority of cases.
`There was no significant difference of KT levels between
`the KT/H and KT/H/AL groups. The AL urinary concentra-
`tion was within the range expected based on the dose admin-
`istered. Patients had a mean decrease in NTx of 29.37 nM
`BCE/l. Previous study has shown that NTx can be used to
`determine the presence of bone resorption in patients under-
`going hormone ablation.24 It is also used as a marker for bone
`lesions.25⫺27
`
`CONCLUSIONS
`Briefly, this study showed no differences in terms of re-
`sponse rate, progression-free survival or overall survival be-
`tween KT alone and KT plus AL in patients with AIPC.
`However, the addition of AL to KT may increase the response
`duration with an acceptable safety profile compared with KT
`treatment. It remains unclear if this is meaningful clinically
`and if more potent bisphosphonates would have more anti-
`cancer activity.
`Drs. John Wright, Howard Parnes, Michael Hamilton,
`Kevin Knopf and Alice Chen provided clinical assistance, and
`Delmar Henry provided data management assistance. Re-
`search nurses Jane Carter, Catherine Parker, Valerie Dyer
`and Miranda Raggio contributed to this trial. Ritchie L.
`Longoria performed n-telopeptide analysis, Siiri Forbes per-
`formed MMP and VEGF/bFGF analyses, and Andrew Trella
`and Ando Yuichi performed pharmacokinetic analysis. Phar-
`macist David Kohler contributed to this trial.
`
`REFERENCES
`1. Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E. and
`Thun, M. J.: Cancer statistics, 2003. CA Cancer J Clin, 53: 5,
`2003
`2. Petrylak, D. P., Tangen, C., Hussain, M., Lara, P. N., Jones, J.,
`Talpin, M. E. et al: SWOG 99–16: randomized phase III trial
`of docetaxel/estramustine versus mitoxantrone/prednisone in
`men with androgen-independent prostate cancer. Proc Am Soc
`Clin Oncol, abstract 3, 2004
`3. Goodin, S., Rao, K. V. and DiPaola, R. S.: State-of-the-art treat-
`ment of metastatic hormone-refractory prostate cancer. Oncol-
`ogist, 7: 360, 2002
`4. Conte, P. F., Latreille, J., Mauriac, L., Calabresi, F., Santos, R.,
`Campos, D. et al: Delay in progression of bone metastases in
`breast cancer patients treated with intravenous pamidronate:
`results from a multinational randomized controlled trial.
`J Clin Oncol, 14: 2552, 1996
`5. Berenson, J. R., Rosen, L. S., Howell, A., Porter, L., Coleman,
`R. E., Morley, W. et al: Zoledronic acid reduces skeletal-related
`events in patients with osteolytic metastases. Cancer, 91:
`1191, 2001
`6. Saad, F., Gleason, D. M., Murray, R., Tchekmedyian, S., Venner,
`P., Lacombe, L. et al: A randomized, placebo-controlled trial of
`zoledronic acid in patients with hormone-refractory metastatic
`prostate carcinoma. J Natl Cancer Inst, 94: 1458, 2002
`7. Berenson, J. R., Lichtenstein, A., Porter, L., Dimopoulos, M. A.,
`
`DEF-ABIRA-0000099
`
`MYLAN PHARMS. INC. EXHIBIT 1108 PAGE 6
`
`

`

`796
`
`PROSTATE CANCER, KETOCONAZOLE AND ALENDRONATE
`
`Bordoni, R., George, S. et al: Long-term pamidronate treat-
`ment of advanced multiple myeloma patients reduces skeletal
`events. Myeloma Aredia Study Group. J Clin Oncol, 16: 593,
`1998
`8. Stearns, M. E.: Alendronate blocks TGF-beta1 stimulated colla-
`gen 1 degradation by human prostate PC-3 ML cells. Clin Exp
`Metastasis, 16: 332, 1998
`9. Stearns, M. E. and Wang, M.: Effects of alendronate and taxol on
`PC-3 ML cell bone metastases in SCID mice. Invasion Metas-
`tasis, 16: 116, 1996
`10. OH, W. K.: Secondary hormonal therapies in the treatment of
`prostate cancer. Urology, suppl., 60: 87, 2002
`11. Bare, R. L. and Torti, F. M.: Endocrine therapy of prostate
`cancer. Cancer Treat Res, 94: 69, 1998
`12. Blagosklonny, M. V., Dixon, S. C. and Figg, W. D.: Efficacy of
`microtubule-active drugs followed by ketoconazole in human
`metastatic prostate cancer cell lines. J Urol, 163: 1022, 2000
`13. Steinberg, S. M. and Venzon, D. J.: Early selection in a random-
`ized phase II clinical trial. Stat Med, 21: 1711, 2002
`14. Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J.,
`Kaplan, R. S., Rubinstein, L. et al: New guidelines to evaluate
`the response to treatment in solid tumors. European Organi-
`zation for Research and Treatment of Cancer, National Cancer
`Institute of the United States, National Cancer Institute of
`Canada. J Natl Cancer Inst, 92: 205, 2000
`15. Bubley, G. J., Carducci, M., Dahut, W., Dawson, N., Daliani, D.,
`Eisenberger, M. et al: Eligibility and response guidelines for
`phase II clinical trials in androgen-independent prostate can-
`cer: recommendations from the Prostate-Specific Antigen
`Working Group. J Clin Oncol, 17: 3461, 1999
`16. Sparidans, R. W., den Hartigh, J., Cremers, S., Beijnen, J. H.
`and Vermeij, P.: Semi-automatic liquid chromatographic anal-
`ysis of pamidronate in urine after derivatization with
`1-naphthylisocthiocynate. J Chromatogr B Biomed Sci Appl,
`730: 95, 1999
`17. Figg, W. D., Dahut, W., Duray, P., Hamilton, M., Tompkins, A.,
`Steinberg, S. M. et al: A randomized phase II trial of thalido-
`mide, an angiogenesis inhibitor, in patients with androgen-
`independent prostate cancer. Clin Cancer Res, 7: 1888, 2001
`18. Clemens, J. D., Herrick, M. V., Singer, F. R. and Eyre, D. R.:
`Evidence that serum NTx (collagen-type I N-telopeptides) can
`act as an immunochemical marker of bone resorption. Clin
`
`Chem, 43: 2058, 1997
`19. Ernst, D. S., Tannock, I. F., Venner, P. M., Winquist, E. W.,
`Reyno, L., Walker, H. et al: Randomized placebo controlled
`trial of mitoxantrone/prednisone and clodronate versus mitox-
`antrone/prednisone alone in patients with hormone refractory
`prostate cancer (HRPC) and pain: National Cancer Institute of
`Canada Clinical Trials Group study. Proc Am Soc Clin Oncol,
`21: 177a, 2002
`20. Smith, J. A., Jr.: Palliation of painful bone metastases from
`prostate cancer using sodium etidronate: results of a random-
`ized, prospective, double-blind, placebo-controlled study.
`J Urol, 141: 85, 1989
`21. Dearnaley, D. P. and Sydes, M. R. on behalf of the MRC PR05
`Collaborators: Preliminary evidence that oral clodronate de-
`lays symptomatic progression of bone metastases from pros-
`tate cancer: first results of the MRC Pr05 trial. Proc Am Soc
`Clin Oncol, 20: 174a, 2001
`22. Trump, D. L., Havlin, K. H., Messing, E. M., Cummings, K. B.,
`Lange, P. H. and Jordan, V. C.: High-dose ketoconazole in
`advanced hormone-refractory prostate cancer: endocrinologic
`and clinical effects. J Clin Oncol, 7: 1093, 1989
`23. Small, E. J., Halabi, S., Dawson, N. A., Stadler, W. M., Rini, B. I.,
`Picus, J. et al: Antiandrogen withdrawal alone or in combina-
`tion with ketoconazole in androgen-independent prostate can-
`cer patients: a phase III trial (CALGB 9583). J Clin Oncol, 22:
`1025, 2004
`24. Michaelson, M. D., Marujo, R. M. and Smith, M. R.: Contribution
`of androgen deprivation therapy to elevated osteoclast activity
`in men with metastatic prostate cancer. Clin Cancer Res, 10:
`2705, 2004
`25. Koizumi, M., Takahashi, S. and Ogata, E.: Comparison of serum
`bone resorption markers in the diagnosis of skeletal metasta-
`sis. Anticancer Res, 23: 4095, 2003
`26. de la Piedra, C., Castro-Errecaborde, N. A., Traba, M. L.,
`Mendez-Davila, C., Garcia-Moreno, C., Rodriguez de Acuna, L.
`R. et al: Bone remodeling markers in the detection of bone
`metastases in prostate cancer. Clin Chim Acta, 331: 45, 2003
`27. Fukumitsu, N., Uchiyama, M., Mori, Y., Yanada, S., Hatano, T.,
`Igarashi, H. et al: Correlation of urine type I collagen-cross-
`linked N telopeptide levels with bone scintigraphic results in
`prostate cancer patients. Metabolism, 51: 814, 2002
`
`DEF-ABIRA-0000100
`
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