Invest New Drugs (2007) 25:565–570
`DOI 10.1007/s10637-007-9068-1
`
`PHASE II STUDIES
`
`Phase II study of KOS-862 in patients with metastatic androgen
`independent prostate cancer previously treated with docetaxel
`
`Tomasz M. Beer & Celestia S. Higano & Mansoor Saleh &
`Robert Dreicer & Gary Hudes & Joel Picus &
`Mark Rarick & Louis Fehrenbacher & Alison L. Hannah
`
`Received: 9 May 2007 / Accepted: 5 June 2007 / Published online: 7 July 2007
`# Springer Science + Business Media, LLC 2007
`
`Summary Based on the pre-clinical spectrum of activity in
`taxane-resistant cell lines, we evaluated KOS-862 (epothilone
`D; 12,13-desoxyepothilone B) as second-line chemotherapy
`in androgen-independent prostate cancer.
`Thirty-eight men with metastatic androgen-independent
`prostate cancer and evidence of progression following
`docetaxel-based chemotherapy were treated with KOS-862,
`100 mg/m2 (maximum of 240 mg) i.v. weekly for 3 weeks,
`repeated every 4 weeks. The primary objective for this study
`was to determine the antitumor activity, measured by PSA
`decline by more then 50% confirmed 4 weeks later.
`Two patients (5.3%, 90% CI 1–16%) met criteria for
`confirmed PSA decline. While both of these patients had
`previously been treated with docetaxel, neither had confirmed
`docetaxel-refractory disease. None of the 24 patients with
`measurable disease had a confirmed partial response. Seventy-
`three percent of patients had an adverse event leading to dose
`delay, reduction, or treatment discontinuation. Neurological
`
`toxicity and fatigue predominated. Seventeen patients
`(44.7%) had treatment related grade 3 neurological adverse
`events including peripheral sensory neuropathy (n=4,
`10.5%), ataxia (n=3, 7.9%), peripheral motor neuropathy
`(n=1, 2.6%), involuntary muscle contractions (n=1, 2.6%)
`and neuropathic pain (n=1, 2.6%). One subject (2.6%) had a
`grade 4 treatment peripheral motor neuropathy.
`Further study of this dose and schedule of KOS-862 in
`this patient population cannot be recommended due to both
`lack of activity and excessive toxicity.
`
`Keywords Prostate cancer . Docetaxel
`
`Background
`
`Chemotherapy has recently been recognized as useful in the
`management of advanced prostate cancer that is unrespon-
`
`T. M. Beer
`Oregon Health & Science University Cancer Institute,
`Portland, OR, USA
`
`J. Picus
`Washington University School of Medicine,
`St. Louis, MO, USA
`
`C. S. Higano
`University of Washington School of Medicine,
`Seattle, WA, USA
`
`M. Saleh
`Georgia Cancer Specialists,
`Marietta, GA, USA
`
`R. Dreicer
`Cleveland Clinic,
`Cleveland, OH, USA
`
`G. Hudes
`Fox Chase Cancer Center,
`Philadelphia, PA, USA
`
`M. Rarick
`Northwest Kaiser Permanente,
`Portland, OR, USA
`
`L. Fehrenbacher
`Permanente Medical Group,
`Vallejo, CA, USA
`
`A. L. Hannah
`Kosan Biosciences, Inc., Hayward, CA, USA
`
`T. M. Beer (*)
`Department of Medicine, Oregon Health & Science University,
`3303 SW Bond Ave, CH14R, Portland, OR 97239, USA
`e-mail: beert@ohsu.edu
`
`AVENTIS EXHIBIT 2187
`Mylan v. Aventis IPR2016-00712
`
`

`
`566
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`Invest New Drugs (2007) 25:565–570
`
`sive to hormonal manipulation. After mitoxantrone with
`prednisone was established as a palliative regimen, [1]
`docetaxel with prednisone was shown to improve survival,
`as well as pain control and quality of life over mitoxantrone
`plus prednisone [2]. This advance was modest, however,
`since survival improvement was relatively brief and the
`median time to disease progression was approximately six
`months. There remains an urgent need for new agents to
`treat patients who have already been treated with docetaxel.
`KOS-862 (epothilone D; 12,13-desoxyepothilone B) is a
`cytotoxic macrolide capable of causing mitotic arrest by
`stabilizing tubulin polymerization. KOS-862 has demon-
`strated in vitro cytotoxic activity in a panel of human cell
`lines, equipotent to that of paclitaxel. KOS-862 is more
`potent than paclitaxel in p-glycoprotein overexpressing cell
`lines that demonstrate multiple drug resistant activity [3].
`KOS-862 has also been shown to be active in the androgen-
`independent PC-3 human prostate cancer cells with IC50 of
`0.0128 μM [4]. In vivo, KOS-862 has shown significant
`antitumor activity in a range of xenograft models, including
`those that are resistant to paclitaxel [3].
`The dose limiting toxicity for KOS-862 in phase I
`studies has been neurologic including both central and
`peripheral neurologic toxicity. Approximately 75% of
`patients enrolled in phase I studies experienced at least
`one neurologic toxicity. Based on the pre-clinical spectrum
`of antitumor activity, particularly activity in taxane-resistant
`cell lines, we evaluated KOS-862 as second-line chemo-
`therapy in androgen-independent prostate cancer.
`
`Methods
`
`Patients
`
`Eligible patients had histologically confirmed adenocarcino-
`ma of the prostate with radiographically documented metas-
`tases and evidence of progression on standard androgen
`deprivation therapy and following treatment with a docetaxel-
`containing regimen. Progression was defined as either PSA
`progression defined by consensus criteria, [5] or objective
`disease progression. One of the PSA values or the imaging
`studies showing objective progression must have been at
`least 4 weeks after flutamide discontinuation or 6 weeks
`after bicalutamide or nilutamide discontinuation. Patients
`could be enrolled if their disease progressed at any time
`following docetaxel-based chemotherapy. Patients who met
`progression criteria and had previously received docetaxel-
`containing chemotherapy for metastatic prostate cancer were
`eligible. Other inclusion criteria were: ECOG performance
`status ≤ 2, age ≥ 18 years,
`testosterone ≤ 50 ng/dl,
`hemoglobin ≥ 8 g/dl, neutrophil count ≥ 1.5×109/l, platelet
`count ≥ 75×109/l, serum creatinine ≤ 2.0 mg/dl, serum
`
`bilirubin ≤ 1.8 mg/dl, aspartate aminotransferase (AST)
`≤ 2.5 × upper limit of normal (ULN) (≤ 5×ULN in case of
`hepatic metastasis), and serum prostate specific antigen
`(PSA) ≥ 5 ng/ml. All adverse events caused by prior
`chemotherapy, surgery or radiotherapy must have resolved
`to NCI-CTCAE grade ≤ 1, and a minimum of 3 weeks must
`have passed since the last receipt of chemotherapy, radio-
`therapy, surgery, or any investigational agent (8 weeks for
`radiopharmaceuticals).
`Patients were excluded from the study if they had any
`pre-existing neuropathy of CTCAE grade ≥ 2, or if they had
`a documented hypersensitivity reaction CTCAE grade ≥ 3
`to prior
`therapy containing Cremophor. Patients were
`ineligible if they had treatment with a second-line chemo-
`therapy regimen for metastatic disease, however prior
`adjuvant, neoadjuvant, or radiosensitization chemotherapy
`did not affect eligibility. Patients were also excluded for
`known CNS metastases, leptomeningeal metastases requir-
`ing steroids, a known personal or
`family history of
`congenital long QT syndrome, or any medical conditions
`that, in the investigator’s opinion, would impose excessive
`risk to the patient were also excluded from the study. The
`study was approved by Institutional Review Boards at all
`participating institutions and written informed consent was
`obtained from all patients before any study-specific
`procedures were performed.
`
`Objectives
`
`The primary objective for this study was to determine the
`antitumor activity of KOS-862, measured by PSA decline,
`[5] in patients with hormone resistant prostate cancer whose
`disease had progressed following docetaxel-based chemo-
`therapy for metastatic disease. The secondary objectives
`included: safety, objective response rate in patients with
`measurable disease, time to tumor progression, time to PSA
`progression, duration of PSA and tumor response, and
`overall survival.
`Additional pre-specified exploratory analysis were: the
`PSA decline rate in docetaxel-refractory patients (those
`progressing while receiving, or within 60 days of receiving,
`docetaxel-based therapy) vs. docetaxel-relapsed patients
`(progression > 60 days after the last dose of docetaxel-based
`therapy) and measured PSA velocity during the first 3 months
`of therapy as described by SWOG 9916 investigators [6].
`
`Treatment
`
`Patients were treated with KOS-862, 100 mg/m2 (maximum
`body surface area of 2.4 m2) administered by intravenous
`infusion over 90 min weekly for 3 weeks, repeated every
`4 weeks until progression or unacceptable toxicity. All
`patients were pre-medicated with antihistamines (H1 and
`
`

`
`Invest New Drugs (2007) 25:565–570
`
`Table 1 Patient demographic
`and baseline characteristics
`
`Characteristic
`
`Age (mean), years
`Median (Range)
`Age Group [n, (%)]
`<65 years
`≥65 years
`ECOG Performance Status [n, (%)]
`0
`1
`2
`PSA (ng/ml)a
`Median (Range)
`Testosterone (ng/dl)
`Median (Range)
`Alkaline Phosphatase (u/l)
`Median (Range)
`Serum LDH (u/l)
`Median (Range)
`Hemoglobin, g/dl
`Median (range)
`Time Since Original Diagnosis (years)
`Median (range)
`Time Since Progression (years)
`Median (range)
`Prior Radiotherapy for Malignancy [n, (%)]
`Yes
`No
`Radiopharmaceuticals [n, (%)]
`Yes
`No
`No. of prior hormonal therapies for prostate cancer [n, (%)]
`1
`2
`3
`≥4
`No. of prior chemotherapy regimens for prostate cancer b[n, (%)]
`1
`2
`Prior chemotherapy experience docetaxela [n, (%)]
`Docetaxel refractory
`Docetaxel relapsed
`
`a At Screening (within 14 days
`prior to start of treatment)
`b Any stage of disease
`
`567
`
`N=38
`
`69.2
`69.0 (56, 87)
`
`10 (26.3)
`28 (73.7)
`
`11 (28.9)
`21 (55.3)
`6 (15.8)
`
`103.2 (2.4, 2825)
`
`16.0 (0.0, 38.0)
`
`98.5 (40, 1016)
`
`222.5 (127, 2011)
`
`11.5 (9.3, 15.4)
`
`6.2 ( 1, 16)
`
`0.4 ( 0, 14)
`
`28 (73.7)
`10 (26.3)
`
`1
`37 (97.4)
`
`3 (7.8)
`12 (31.6)
`11 (28.9)
`12 (31.6)
`
`32 (84.2)
`6 (15.8)
`
`8 (21.1)
`30 (78.9)
`
`H2 blockers) and corticosteroids (methylprednisolone 40–
`80 mg IV or dexamethasone 10–20 mg IV) 30–60 min prior
`to the infusion of KOS-862.
`
`Monitoring
`
`Baseline evaluation included a physical examination, three
`electrocardiograms (done at
`least 5 min apart),
`toxicity
`evaluation, a neurological assessment and mini-mental
`status exam (MMSE), vital signs, complete blood count
`(CBC) with differential, prothrombin time and partial
`thromboplastin time (PT/PTT), serum chemistry, PSA,
`testosterone, urinalysis, bone scan and tumor measurements
`by computed tomography.
`
`The physical examination, toxicity evaluation, neurolog-
`ical assessment, CBC with differential, PT/PTT, serum
`chemistry, PSA, and urinalysis were repeated prior to each
`4-week treatment cycle. Tumor measurements and bone
`scans (if positive at baseline) were repeated every 8 weeks.
`
`Statistical considerations
`
`This study was a single-arm, open-label clinical trial, and
`was conducted at multiple centers throughout the United
`States. A response rate (proportion with at
`least 50%
`decline in serum PSA) of at least 25% was considered
`worthy of further study (alternative hypothesis), whereas a
`response rate of only 10% or less (null hypothesis) was
`
`

`
`568
`
`Invest New Drugs (2007) 25:565–570
`
`considered uninteresting. The sample size calculation was
`based on the Simon two-stage optimal design [7] with the
`aforementioned null hypothesis and alternative hypotheses,
`and selected two-sided type I error (α) = 0.10 and type II
`error (β) = 0.10. A maximum sample size of 50 evaluable
`patients was required, with a first-stage accrual of 21
`patients. Accrual beyond stage one was permitted until
`evaluation of stage one patients was completed. Three or
`more PSA responses in stage one were required for the trial
`to accrue stage two fully, after which 8 or more confirmed
`PSA responses in 50 evaluable patients were required for
`KOS-862 to be considered worthy of further study in
`prostate cancer.
`
`Results
`
`Patient characteristics
`
`The trial was stopped prematurely due to insufficient
`activity after 39 men were enrolled between January and
`October 2005. One patient withdrew prior to receiving any
`therapy. The remaining 38 patients are included in the
`intent-to-treat
`(ITT) analysis. Eight patients were not
`evaluable for efficacy analyses for the following reasons:
`received two or
`fewer infusions of KOS-862 without
`documented disease progression or death (n=6, 15.8%),
`did not have a confirmatory PSA level for response/pro-
`gressive disease at a minimum of a 4 week interval (n=4,
`10.5%), or violated clinically significant inclusion/exclusion
`criteria (n=2, 5.2%). Results for the entire ITT (n=38)
`dataset are reported. Pretreatment characteristics are sum-
`marized in Table 1. All patients had progressed following
`
`initial docetaxel-based chemotherapy for metastatic disease.
`Seven patients had active peripheral neuropathy prior to
`study entry (either peripheral motor or sensory neuropathy).
`
`Treatment
`
`Eighty-two treatment cycles were administered. The median
`number of cycles was 2.0 (range 1, 7). Most subjects were
`treated for one cycle (n=10, 26.3%) or two cycles (n=19,
`50%). The median dose intensity was 68.9 mg/m2/week
`(range: 49, 75). The median relative dose intensity was
`91.9% (range: 66, 100). Seventeen patients (44.7%) had a
`dose delay; for 11 patients (28.9%), the delay was due to
`toxicity. Six patients (15.8%) had a dose decrease as a result
`of recalculated BSA (n=3, 7.9%) or toxicity (n=3, 7.9%).
`
`Toxicity
`
`All patients experienced a treatment related adverse event.
`Six patients (15.7%) experienced a serious adverse event
`considered to be related to the study drug. 73% (n=28) of
`patients had an adverse event leading to dose delay, dose
`reduction, or treatment discontinuation. Eighteen patients
`(47%) experienced an adverse event
`that
`led to patient
`discontinuation of study drug.
`The most frequently observed treatment-related adverse
`events that occurred in ≥ 10% of patients, graded by using
`the maximum grade for a patient, are indicated below in
`Table 2.
`As expected from the phase 1 experience, neurological
`toxicity and fatigue predominated. Most neurological
`events were assessed by the investigator as having a
`maximum intensity of grade 1–2. These grade 1–2 events
`
`Table 2 Summary of most frequently experienced treatment related adverse events (>10 %) by MedDRA preferred term (n=38)
`
`Preferred term
`
`Grade 1 (%)
`
`Grade 2 (%)
`
`Grade 3 (%)
`
`Grade 4 (%)
`
`Number patients (%)
`
`Peripheral sensory neuropathy
`Fatigue
`Nausea
`Dizziness
`Diarrhoea
`Dysgeusia
`Anorexia
`Flushing
`Vomiting
`Arthralgia
`Balance disorder
`Hypoaesthesia
`Constipation
`Memory impairment
`Oedema peripheral
`Ataxia
`
`16 ( 42.1)
`5 (13.2)
`11 (28.9)
`9 (23.7)
`8 (21.1)
`5 (13.2)
`3 (7.9)
`7 (18.4)
`6 (15.8)
`5 (13.2)
`4 ( 10.5)
`4 ( 10.5)
`3 (7.9)
`5 (13.2)
`4 ( 10.5)
`0 (0)
`
`11 (28.9)
`7 (18.4)
`4 ( 10.5)
`3 (7.9)
`3 (7.9)
`4 ( 10.5)
`3 (7.9)
`1 (2.6)
`2 (5.3)
`1 (2.6)
`2 (5.3)
`2 (5.3)
`2 (5.3)
`0 (0)
`1 (2.6)
`1 (2.6)
`
`MedDRA Medical Dictionary for Regulatory Activities (Version 7.1)
`
`4 ( 10.5)
`8 (21.1)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`2 (5.3)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`3 (7.9)
`
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`31 (81.6)
`20 (52.6)
`15 (39.5)
`12 (31.6)
`11 (28.9)
`9 (23.7)
`8 (21.1)
`8 (21.1)
`8 (21.1)
`6 (15.8)
`6 (15.8)
`6 (15.8)
`5 (13.2)
`5 (13.2)
`5 (13.2)
`4 (10.4)
`
`

`
`Invest New Drugs (2007) 25:565–570
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`569
`
`included peripheral sensory neuropathy, ataxia, dizziness,
`dysgeusia, balance disorder, hypoaesthesia, memory im-
`pairment, paresthesia, headache, restless leg syndrome and
`disturbance in attention. Seventeen patients (44.7%) had
`treatment related neurological adverse events with a maxi-
`mum intensity of grade 3. These included peripheral sensory
`neuropathy (n=4, 10.5%), ataxia (n=3, 7.9%), peripheral
`motor neuropathy (n=1, 2.6%), involuntary muscle contrac-
`tions (n=1, 2.6%) and neuropathic pain (n=1, 2.6%). One
`subject (2.6%) had a treatment related grade 4 peripheral
`motor neuropathy.
`
`Efficacy
`
`The primary efficacy variable was PSA decline. Only two
`patients (5.3%, 90% CI 1%–16%) met criteria for con-
`firmed PSA decline. Both of these patients were in the
`docetaxel-relapsed group. No patients who were docetaxel-
`refractory had a confirmed PSA decline. No confirmed
`partial responses in patients with measurable disease (n=
`24) were observed.
`The median time to tumor progression, defined as time
`from the first day of treatment to the first documentation of
`progressive disease based upon imaging studies, was
`9.0 weeks (90% CI 7.9–19.4 weeks with 45.8% patients
`censored) in efficacy evaluable patients. Median overall
`survival was 32 weeks.
`
`Other analyses
`
`PSA velocity was measured based on the first 3 months
`of
`therapy [6]. Specifically, mean PSA velocity was
`96.2 ng/ml/mo (Standard deviation 215.4, N=38). PSA
`velocity values varied considerably,
`ranging from
`0.11 ng/ml/mo to 1007.99 ng/ml/mo. These data may prove
`useful for design of future clinical
`trials in this patient
`population.
`
`Discussion
`
`KOS-862 did not have sufficient antitumor activity to
`recommend further evaluation in this patient population.
`Treatment was also associated with frequent severe
`neurotoxicity (45%), particularly toxicity affecting the
`central and peripheral nervous system. The incidence of
`severe neurologic toxicity exceeded that expected from the
`phase I experience and from prior phase 2 single-agent
`trials in metastatic breast [8] and lung cancer [9]. In these
`studies,
`the incidence of grade 3 or higher neurologic
`toxicity was 21% and 22% respectively. The reasons for
`higher than expected severe neurotoxicity in our study are
`not known.
`
`This study does not allow us to confidently comment
`about the viability of microtubules and the mitotic spindle
`as a therapeutic target in docetaxel-treated AIPC patients.
`The high frequency of treatment discontinuation due to
`toxicity may have contributed to the low level of activity
`observed. The median progression-free survival duration
`observed in this study was similar to those reported in both
`arms of the randomized study of prednisone with or without
`satraplatin,
`[10] and in studies of mitoxantrone and
`epothilone B in similar patient populations. We cannot
`determine if a lower dose of KOS-862 that would
`presumably have produced less toxicity would have yielded
`more encouraging results.
`Other approaches to targeting microtubules in this
`patient population, including novel taxanes and epothilone
`class agents are under investigation. Preliminary data from
`studies of other epothilones suggest that this class of agents
`has important activity in prostate cancer. In chemotherapy-
`naïve patients, ixabepilone has been studied in two multi-
`institutional phase II studies. PSA decline rates of 48% [11]
`and 33% [12] were reported and activity in measurable
`disease was seen.
`It is less clear if this class of agents has important activity
`in docetaxel-treated AIPC patients, as the activity levels seen
`in these patient populations to date are of marginal interest.
`Ixabepilone therapy was associated with a 17% PSA decline
`rate in patients whose androgen-independent prostate cancer
`progressed on or within 60 days of docetaxel-based chemo-
`therapy [13]. Treatment with EPO906 was associated with a
`22% PSA decline rate in 37 patients that included both
`chemotherapy-naïve and chemotherapy pre-treated AIPC
`patients [14]. Studies of several members of this class of
`drugs in prostate cancer are ongoing.
`Grade 1 or 2 neurotoxicity was reported in 19% of
`patients and no grade 3 or higher neurotoxicity was noted
`in the preliminary report of EPO906 in advanced prostate
`cancer [14]. Severe neurotoxicity was reported in 17% of
`prostate cancer patients treated with ixabepilone [12]. It is
`possible,
`therefore,
`that
`the frequency and severity of
`neurotoxicity varies across members of this drug class,
`but comparisons of this sort across small phase II studies
`are not reliable and additional studies would be needed to
`definitively comment on this question.
`Overall survival in this challenging population remains
`poor highlighting the need for new therapies and the
`development of new agents capable of treating this lethal
`form of prostate cancer remains a top priority for the field.
`
`References
`
`1. Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore
`MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy
`
`

`
`570
`
`Invest New Drugs (2007) 25:565–570
`
`KC (1996) Chemotherapy with mitoxantrone plus prednisone or
`prednisone alone for symptomatic hormone-resistant prostate
`cancer: a Canadian randomized trial with palliative end points. J
`Clin Oncol 14(6):1756–1764
`2. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN,
`Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA,
`Eisenberger MA (2004) Docetaxel plus prednisone or mitoxan-
`trone plus prednisone for advanced prostate cancer. N Engl J Med
`351(15):1502–1512
`3. Chou TC, O’Connor OA, Tong WP, Guan Y, Zhang ZG, Stachel
`SJ, Lee C, Danishefsky SJ (2001) The synthesis, discovery, and
`development of a highly promising class of microtubule stabili-
`zation agents: curative effects of desoxyepothilones B and F
`against human tumor xenografts in nude mice. Proc Natl Acad Sci
`U S A 98(14):8113–8118
`4. Chou TC, Zhang XG, Harris CR, Kuduk SD, Balog A, Savin KA,
`Bertino JR, Danishefsky SJ (1998) Desoxyepothilone B is
`curative against human tumor xenografts that are refractory to
`paclitaxel. Proc Natl Acad Sci U S A 95(26):15798–15802
`5. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D,
`Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain
`M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor
`O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL,
`Vollmer R, Wilding G (1999) Eligibility and response guidelines for
`phase II clinical trials in androgen-independent prostate cancer:
`recommendations from the Prostate-Specific Antigen Working
`Group. J Clin Oncol 17(11):3461–3467
`6. Petrylak DP, Ankerst DP, Jiang CS, Tangen CM, Hussain MH,
`Lara PN Jr, Jones JA, Taplin ME, Burch PA, Kohli M, Benson
`MC, Small EJ, Raghavan D, Crawford ED (2006) Evaluation of
`prostate-specific antigen declines for surrogacy in patients treated
`on SWOG 99-16. J Natl Cancer Inst 98(8):516–521
`7. Simon R (1989) Optimal two-stage designs for phase II clinical
`trials. Control Clin Trials 10(1):1–10
`8. Buzdar A, Silverman P, Kaufmann P, Waintraub S, Doyle T,
`Kroener J, Robinson P, Zhang A, DeMario M (2005) A phase II
`
`study of KOS-862 (epothilone D) in anthracycline and taxane
`pretreated metastatic breast cancer: updated results. San Antonio
`Breast Cancer Symposium Proceedings: abstract 1087
`9. Yee L, Lynch T, Villalona-Calero M, Rizvi N, Gabrail N, Sandler
`A, Cropp G, Palmer G (2005) A Phase II Study of KOS-862
`(Epothilone D) as Second-Line Therapy in Non-Small Cell Lung
`Cancer. Proceedings of
`the American Society for Clinical
`Oncology: abstract 7127
`10. Petrylak DP, Sartor O, Witjes F, Ferrero J, Berry WR, Koletsky
`A, Falcon S, Nathan FE, Petrone ME, Sternberg C (2007) A
`phase III, randomized, double-blind trial of satraplatin and
`prednisone vs placebo and prednisone for patients with hormone
`refractory prostate cancer (HRPC). Prostate Cancer Symposium
`Proceedings: 144
`11. Galsky MD, Small EJ, Oh WK, Chen I, Smith DC, Colevas AD,
`Martone L, Curley T, Delacruz A, Scher HI, Kelly WK (2005)
`Multi-institutional randomized phase II trial of the epothilone B
`analog ixabepilone (BMS-247550) with or without estramustine
`phosphate in patients with progressive castrate metastatic prostate
`cancer. J Clin Oncol 23(7):1439–1446
`12. Hussain M, Tangen CM, Lara PN Jr, Vaishampayan UN,
`Petrylak DP, Colevas AD, Sakr WA, Crawford ED (2005)
`Ixabepilone (epothilone B analogue BMS-247550) is active in
`chemotherapy-naive patients with hormone-refractory prostate
`cancer: a Southwest Oncology Group trial S0111. J Clin Oncol
`23(34):8724–8729
`13. Lin AM, Rosenberg JE, Weinber VK, Kelly WK, Michaelson
`MD, Hussain M, Wilding G, Gross ME, Small E (2006) Clinical
`outcome of taxane-resistant (TR) hormone refractory prostate
`cancer (HRPC) patients (pts) treated with subsequent chemother-
`apy (ixabepilone (Ix) or mitoxantrone/prednisone (MP). J Clin
`Oncol 24(18S):231s
`14. Hussain A, Dipaola RS, Baron AD, Higano CS, Tchekmediyan
`NS, Miller JA, Rothermel JD (2004) A Phase IIa trial of weekly
`EPO906 in patients with hormone-refractory prostate cancer
`(HPRC). J Clin Oncol 22(14S):397s