556
`
`Activity of Second-Line Chemotherapy in
`Docetaxel-Refractory Hormone-Refractory
`Prostate Cancer Patients
`RandomizedPhase2StudyofIxabepiloneorMitoxantroneandPrednisone
`
`1
`
`Jonathan E. Rosenberg, MD
`2
`Vivian K. Weinberg, PhD
`3
`W. Kevin Kelly, DO
`Dror Michaelson, MD, PhD
`5
`Maha H. Hussain, MD
`6
`George Wilding, MD
`7
`Mitchell Gross, MD, PhD
`Douglass Hutcheon, BS
`1
`Eric J. Small, MD
`
`4
`
`1
`
`1 Department of Medicine, University of California
`at San Francisco, Comprehensive Cancer Center,
`San Francisco, California.
`2 University of San Francisco, Comprehensive
`Cancer Center, Biostatistics Core, San Francisco,
`California.
`3 Department of Medicine, Memorial Sloan-Ket-
`tering Cancer Center, New York, New York.
`4 Department of Medicine, Harvard Cancer Cen-
`ter, Boston, Massachusetts.
`5 Department of Medicine, University of Michigan
`Comprehensive Cancer Center, Ann Arbor, Michigan.
`
`6 Department of Medicine, University of Wisconsin
`Comprehensive Cancer Center, Madison, Wisconsin.
`
`7 Department of Medicine, Cedars-Sinai Compre-
`hensive Cancer Institute, Los Angeles, California.
`
`Supported by the Cancer Treatment and Evalua-
`tion Program, National Cancer Institute, Prostate
`Cancer Foundation, and Bristol-Myers Squibb,
`Inc. J. E. Rosenberg is supported in part by
`Department of Defense Physician Research Train-
`ing Award W81XWH-05-01-0403.
`
`J. E. Rosenberg has received research funding
`from Bristol-Myers Squibb.
`
`the American Society of
`Presented in part at
`Clinical Oncology Multidisciplinary Prostate Can-
`cer Symposium, February 17–19, 2005, Orlando,
`Florida; and the American Society of Clinical On-
`cology Multidisciplinary Prostate Cancer Sympo-
`sium, February 24–26, 2006.
`
`BACKGROUND. This randomized, noncomparative, multicenter, clinical trial evalu-
`ated ixabepilone or mitoxantrone/prednisone (MP) as second-line chemotherapy
`
`for taxane-refractory, hormone-refractory, prostate cancer (HRPC).
`METHODS. Patients with HRPC that progressed during or within 60 days of cessa-
`tion of taxane chemotherapy were randomly selected with equal probability to
`ixabepilone 35 mg/m2 intravenously every 3 weeks, or mitoxantrone 14 mg/m2
`intravenously every 3 weeks and prednisone 5 mg orally twice daily. Treatment
`
`continued until progression or toxicity; crossover was allowed.
`RESULTS. Forty-one patients were accrued to each arm of the study. The median
`number of cycles administered for each arm was 3. Median survival from protocol
`
`entry was 10.4 months with ixabepilone and 9.8 months with MP. Prostate-specific
`antigen (PSA) declines of 50% were observed in 17% of ixabepilone (95% CI, 7-32)
`and 20% of second-line MP patients (95% CI, 9-35). Partial responses were observed
`
`in 1 of 24 ixabepilone and in 2 of 21 MP patients with evaluable measurable disease.
`
`Median duration of second-line ixabepilone and MP treatment was 2.2 months and
`2.3 months, respectively. For third-line crossover treatment, PSA declines of 50%
`were observed in 3 of 27 ixabepilone-treated and 4 of 15 MP-treated patients. Prior
`
`taxane response was associated with an increased likelihood of second-line ixabepi-
`
`lone or MP response. Low baseline lactate dehydrogenase and absence of visceral
`
`metastases independently predicted improved survival. The most common grade
`
`3/4 toxicity associated with second-line treatment was neutropenia (54% of ixabe-
`
`pilone patients and 63% of MP patients).
`CONCLUSIONS. Ixabepilone and MP had modest activity as second-line chemotherapy
`for docetaxel-refractory HRPC. The median survival for the entire cohort treated in this
`study was 9.8 months. Cancer 2007;110:556–63. Ó 2007 American Cancer Society.
`
`KEYWORDS: prostate cancer, taxane, hormone, refractory,
`trone, prednisone, second-line therapy.
`
`ixabepilone, mitoxan-
`
`C hemotherapy for taxane-refractory, hormone-refractory, prostate
`
`cancer (HRPC) is effective at prolonging survival and palliating
`symptoms. Two large phase 3 studies demonstrated that first-line
`docetaxel chemotherapy is associated with an improvement in me-
`dian survival compared with mitoxantrone/prednisone (MP).1,2
`
`Address for reprints: Jonathan E. Rosenberg, MD,
`University of California at San Francisco, Division
`of Hematology/Oncology, 1600 Divisadero Street,
`Box 1711, San Francisco, CA 94115; Fax: (415)
`353-7779; E-mail: jrosenbe@medicine.ucsf.edu
`
`Received December 21, 2006; revision received
`March 29, 2007; accepted April 2, 2007.
`
`ª 2007 American Cancer Society
`DOI 10.1002/cncr.22811
`Published online 18 June 2007 in Wiley InterScience (www.interscience.wiley.com).
`
`MYLAN - EXHIBIT 1027
`
`

`
`Nearly all HRPC patients eventually progress during
`or after taxane-based treatment. Many patients have a
`good performance status and wish additional treat-
`ment. No standard chemotherapy exists for second-
`line treatment of patients with HRPC after progression
`on taxane-based therapies, although the community
`de facto standard has become MP.
`The natural history of
`taxane-refractory (TR)
`HRPC has not been prospectively defined. Although
`second-line chemotherapy trials have been reported
`in HRPC, these trials are difficult to interpret because
`of heterogeneity of patient populations. Most impor-
`tantly,
`those trials did not restrict enrollment
`to
`overtly TR-HRPC.
`Resistance to taxanes appears mediated by tubu-
`lin mutation and multidrug resistant (MDR) gene overex-
`pression. The epothilones are a new class of nontaxane
`tubulin polymerization agents whose cytotoxic activity
`has been linked to stabilization of microtubules, bypass-
`ing known taxane-resistant mechanisms.3,4 Ixabepilone
`(Bristol-Myers Squibb, New York, NY) is a semisynthetic
`analog of epothilone B that blocks the mitotic phase of
`the cell cycle. It is a highly potent cytotoxin, and preclini-
`cal data demonstrate noncross-resistance with taxanes.
`Ixabepilone has demonstrated antitumor activity as first-
`line chemotherapy in patients with metastatic HRPC.5,6
`The preclinical data indicating noncross-resist-
`ance of ixabepilone with taxanes, the front-line activ-
`ity of
`ixabepilone in HRPC, and the lack of
`prospective data regarding MP as second-line chemo-
`therapy provided the rationale for a randomized, non-
`comparative, phase 2 study in TR-HRPC. This study
`randomly assigned patients with TR-HRPC to either
`single-agent ixabepilone or the perceived community
`standard, MP.
`
`MATERIALS AND METHODS
`Study Design
`This study was a multicenter, randomized, noncom-
`parative phase 2 study. Patients were randomly
`assigned with equal probability to either MP or ixa-
`bepilone. The primary endpoint was the frequency of
`50% PSA declines with each second-line regimen.
`Secondary endpoints included safety, response dura-
`tion, time to progressive disease, third-line (post-
`crossover) activity of each regimen, and overall
`survival.
`
`Eligibility Criteria
`All patients had histologically confirmed metastatic
`prostate cancer. Patients were required to have pro-
`gressive disease despite castrate testosterone levels
`and at least 2 cycles of taxane-based chemotherapy,
`
`Second-line chemotherapy for HRPC/Rosenberg et al.
`
`557
`
`with disease progression documented during or
`within 60 days of completing taxane-based chemo-
`therapy. For patients with measurable disease, pro-
`gression was defined by RECIST criteria.7 For
`patients without measurable disease, a positive bone
`scan and elevated PSA greater than 5 ng/mL were
`required. PSA evidence for progressive prostate can-
`cer was defined by Consensus Criteria.8
`All patients were required to have an Eastern Co-
`operative Oncology Group (ECOG) performance sta-
`tus of 0-2 and grade 1 neuropathy (Common
`Toxicity Criteria, version 2.0). Hormonal
`therapy
`other than luteinizing hormone-releasing hormone
`(LHRH) agonists was not allowed within 4 weeks of
`trial enrollment (6 weeks for bicalutamide or niluta-
`mide). Treatment with a corticosteroid as part of
`first-line chemotherapy was discontinued over 10–14
`days before enrollment. Any radiation therapy or ra-
`diopharmaceutical treatment must have been com-
`pleted more than 4 weeks and 8 weeks before
`enrollment, respectively. All patients were required to
`have a cardiac ejection fraction greater than the
`institutional
`lower limit of normal. Patients were
`excluded
`for
`significant
`cardiovascular disease
`including congestive heart failure (New York Heart
`Association [NYHA] class III or IV), active angina
`pectoris, or myocardial infarction within 6 months
`before enrollment. Patients with known active brain
`metastases were
`excluded. Required laboratory
`values included testosterone \50 ng/dL; creatinine
`\1.5 3 upper limits of normal (ULN) or calculated
`creatinine clearance [40 mL/min; alanine amino-
`transferase (ALT) and aspartate transaminase (AST)
`\3 3 ULN;
`granulocytes [1500/mm3;
`platelets
`100,000/mm3; total bilirubin \1.5 3 ULN; and,
`if
`no measurable disease, a PSA 5 ng/mL.
`This clinical trial was sponsored by the Cancer
`Therapy Evaluation Program of the National Cancer
`Institute and approved by the review boards of each
`participating institution. All patients provided written
`informed consent.
`
`Randomization and Treatment Plan
`Eligible patients were randomly selected by the coor-
`dinating center statistician with equal probability to
`receive either ixabepilone or MP. Allocation to a
`treatment arm was concealed until the patient was
`enrolled. Patients were stratified by performance
`score (0 vs 1-2) and study site, and they were ran-
`domly assigned from within each stratum. Treatment
`assignment was balanced after every 4 patients
`within each stratum.
`Ixabepilone 35 mg/m2 was administered intrave-
`nously over 3 hours every 21 days. Patients were
`
`

`
`558
`
`CANCER August 1, 2007 / Volume 110 / Number 3
`
`premedicated with H1- and H2-blockers before ixa-
`bepilone infusion to prevent hypersensitivity reac-
`tions related to Cremophor EL diluent (BASF Group,
`Ludwigshafen, Germany) Corticosteroids were used
`with subsequent cycles for prior grade 2-4 hyper-
`sensitivity reactions to ixabepilone. Mitoxantrone
`14 mg/m2 was administered intravenously every 21
`days with prednisone 5 mg orally twice daily. Treat-
`ment for all patients was continued until disease
`progression or unacceptable toxicity occurred. Mye-
`loid growth factors were administered according to
`American Society for Clinical Oncology (ASCO)
`guidelines.9 Patients underwent imaging with chest
`s-ray, bone scan, and computed tomography (CT) or
`magnetic resonance imaging (MRI) of the abdomen
`and pelvis at baseline and after every 3 cycles.
`Electrocardiogram and multiple gated-acquisition
`(MUGA) scan or echocardiogram were obtained at
`baseline and repeated every 3 cycles for MP patients.
`Imaging studies were obtained at the time of cross-
`over.
`
`Dose Modifications
`Dose modifications were made according to maximal
`toxicity. Doses were reduced for Day 1 neutrophil
`count \1500/m3 or platelet count \100,000/m3,
`grade 3 nonhematologic toxicity, grade 4 neutrope-
`nia lasting for more than 7 days, grade 4 neutropenia
`and fever, and nadir platelet count \25,000. Ixabepi-
`lone dose was reduced by 5 mg/m2, and mitoxan-
`trone dose was reduced by 2 mg/m2 for each dose
`reduction. Grade 2 neurotoxicity of any duration and
`grade 3 neurotoxicity lasting 7 days required dose
`reduction. Recurrent grade 3 neurotoxicity, grade 3
`neurotoxicity of [7 days duration, or grade 4 neuro-
`toxicity
`required discontinuation of
`treatment.
`Patients were removed from protocol therapy for a
`treatment delay greater than 3 weeks or recurrence
`of the same grade 3 toxicities despite 2 dose reduc-
`tions.
`
`apy for metastatic TR-HRPC patients. The primary
`endpoint was the frequency of PSA declines 50%
`with second-line therapy, confirmed with 2 con-
`secutive measurements. Response to therapy was
`determined for each patient by using PSA declines
`for nonmeasurable disease, and RECIST criteria for
`measurable disease, bone scans, and nontarget
`lesions.7,8 For each treatment arm, a 50% PSA
`decline in at least 25% of patients was considered
`promising and worthy of
`further
`investigation.
`Accrual of 40 patients to each treatment arm was
`sufficient to detect a 25% response proportion com-
`pared with a null hypothesis of 10%. A statistical
`level of significance of 0.04 for a directional test and
`power of 0.82 was assumed to test this hypothesis.
`Secondary endpoints included response duration,
`time to PSA progression, overall survival, frequency
`of toxicity, and frequency of response to third-line
`(crossover) treatment.
`Comparability of the 2 treatment subsets was
`evaluated by using Fisher exact test for categorical
`variables (eg, Gleason score), Student t test for con-
`tinuous variables (eg, lactate dehydrogenase [LDH]),
`and the Mann-Whitney test
`for distributions (eg,
`PSA). The effect of prior taxane response on second-
`line treatment response was analyzed by using the
`Mantel-Haenszel tests of association and homogene-
`ity stratified by the second-line therapy.10 Duration
`of time to progression and overall survival were cal-
`culated from the start of second-line therapy with
`the Kaplan-Meier product-limit method.11 Compari-
`sons of a difference in distributions between subsets
`were performed by using the log-rank test.12 Cox
`proportional hazard model was used to identify inde-
`pendent disease features of overall survival for the
`entire sample.13 Variables predictive of overall sur-
`vival based on the log-rank test were considered in
`building a model. A forward stepwise approach was
`used with the likelihood ratio test to determine sig-
`nificant independent predictors of survival.
`
`Crossover Therapy
`Patients who progressed after at least 2 cycles of pro-
`tocol treatment or who stopped treatment for toxicity
`or other medical reasons were eligible to receive the
`alternate treatment. For patients initially treated with
`MP, prednisone was tapered over 10–14 days before
`starting ixabepilone.
`
`Statistical Considerations
`This was a noncomparative randomized phase 2
`study to assess safety and efficacy of 2 treatment
`regimens, ixabepilone and MP, as second-line ther-
`
`RESULTS
`Patient Characteristics and Disposition
`Between February 2003 and June 2005, 86 patients
`were entered at 6 participating centers. Four patients
`who never
`started protocol
`therapy were not
`included in the analysis, thus 82 patients were evalu-
`able. Forty-one patients were randomly assigned to
`each treatment arm (Fig. 1). Patient baseline charac-
`teristics are detailed in Table 1. Both arms were
`balanced. All patients who received any protocol
`chemotherapy were included in evaluations of
`response and toxicity.
`
`

`
`Second-line chemotherapy for HRPC/Rosenberg et al.
`
`559
`
`FIGURE 1. Patient Disposition. *Received at least 2 cycles of therapy.
`
`TABLE 1
`Baseline Patient Characteristics
`
`2nd Line treatment
`
`Median age, y (range)
`ECOG PS
`0
`1–2
`Prior therapy
`Radiation (RT)
`Prostatectomy (RP)
`RP1RT
`Other
`Median PSA, ng/mL (range)
`Gleason score
`Range
`5–6
`7
`8–10
`Median LDH, IU/L (range)
`Median alkaline phosphatase, U/L (range)
`Median hemoglobin, g/dL (range)
`Mean No. prior taxane chemotherapy cycles (range)
`Prior chemotherapy
`Docetaxel-based
`Docetaxel/estramustine-based
`
`Ixabepilone n = 41
`
`66.5 (51–87)
`
`15 (37%)
`26 (63%)
`
`10 (24%)
`16 (39%)
`2 (5%)
`13 (32%)
`141 (4–17,995)
`n 5 37
`5–10
`14%
`32%
`54%
`266 (103–2291)
`126 (58–1432)
`11.7 (8.8–14.0)
`5.6 (2–25)
`
`18 (45%)
`22 (55%)
`
`MP n = 41
`
`69 (52–84)
`
`15 (37%)
`26 (63%)
`
`7 (17%)
`15 (37%)
`5 (12%)
`14 (34%)
`113 (7–1587)
`n 5 38
`5–10
`11%
`18%
`71%
`273 (101–3065)
`156 (45–664)
`12.2 (8.9–14.7)
`6.8 (2–17)
`
`18 (47%)
`20 (53%)
`
`Second-Line Study Treatment
`A median of 3 cycles of ixabepilone (range, 1 to 22
`cycles) and 3 cycles of MP (range, 1 to 12 cycles)
`were administered as second-line treatment. Thirty-
`two percent of ixabepilone patients and 27% of MP
`patients received at least 5 cycles of therapy. Treat-
`
`ment with ixabepilone was discontinued in 7
`patients for toxicity, 1 for withdrawal of consent, and
`33 patients for disease progression (23 for PSA pro-
`gression, 6 for objective progression, 1 for both PSA
`and objective progression, and 4 for clinical and/or
`symptomatic progression that
`required additional
`
`

`
`560
`
`CANCER August 1, 2007 / Volume 110 / Number 3
`
`TABLE 2
`Response to Second-line Therapy
`
`2nd-Line
`Ixabepilone no. (%)
`
`2nd-Line
`MP no. (%)
`
`Evaluable patients
`Confirmed PSA decline 50%, 95% CI
`Unconfirmed PSA decline 50%
`Objective disease responses
`Measurable disease
`Evaluable patients*
`Partial response (RECIST)
`
`41
`7 (17, 7–32)
`1 (2)
`
`30
`24
`1
`
`* Received at least 2 cycles.
`
`41
`8 (20, 9–35)
`—
`
`23
`21
`2
`
`therapy). Treatment with MP was discontinued in 4
`patients for toxicity and in 36 patients for disease
`progression (28 for PSA progression, 6 for objective
`progression, 2 for both PSA and objective progres-
`sion). One MP patient died on study of unrelated
`causes.
`
`Response
`Of 41 patients treated with second-line ixabepilone, 7
`had a confirmed 50% PSA decline (17%; 95% CI, 7-
`32; Table 2). One additional patient had an uncon-
`firmed 50% PSA decline. The median time to a
`50% PSA decline was 6 weeks (range, 3–14 weeks).
`Twenty-four patients treated with at least 2 cycles of
`second-line ixabepilone had measurable disease,
`and, of these, 1 (4%) patient had an objective partial
`response in addition to a PSA response. The median
`time to PSA progression on ixabepilone was 2.2
`months, and the median duration of response was
`3.8 months (range, 2.8–22.3 months). Three con-
`firmed responders discontinued treatment for toxic-
`ity (motor neuropathy, atrial arrhythmia, and grade 2
`infusion-site reaction), and 4 confirmed responders
`discontinued because of progressive disease.
`Of the 41 patients treated with second-line MP, 8
`had a confirmed 50% PSA decline (20%; 95% CI, 9-
`35; Table 2). For responders, the median time to a
`50% PSA decline was 7 weeks (range, 3–19 weeks).
`Twenty-one patients treated with at least 2 cycles of
`second-line MP had measurable disease, and, of
`these, 2 (10%) patients had an objective partial
`response, 1 of whom also had a PSA response. The
`median time to PSA progression on MP was 2.3
`months, and the median duration of PSA response for
`responders was 5.9 months (range, 2.7–8.2 months).
`Three responders discontinued treatment because of
`toxicity (minor decreases in cardiac ejection fraction
`did not meet criteria for an adverse event according
`to National Cancer Institute’s Common Toxicity Crite-
`
`FIGURE 2. Overall survival.
`
`ria v2.0 in 2 patients; thrombocytopenia occurred in 1
`patient), 4 discontinued for progressive disease, and 1
`died without disease progression.
`An exploratory analysis of the impact of initial
`response to front-line taxane-based therapy on
`response to second-line therapy was performed. Stra-
`tified by second-line treatment, there was a signifi-
`cantly greater
`response to second-line therapy
`among patients who previously responded to taxane
`test: P 5 .0004).10 The
`therapy (Mantel-Haenszel
`association was similar for both second-line treat-
`ment groups (test of homogeneity: P 5 0.87). Among
`patients with a prior PSA response to taxane chemo-
`therapy, 36% (5 of 14; 95% CI, 13-65) responded to
`ixabepilone and 35% (7 of 20; 95% CI, 5-59)
`responded to MP.
`In patients without prior PSA
`response to taxane-chemotherapy, 4% (1 of 26; 95%
`CI, 0-20) of patients responded to ixabepilone, and
`5% (1 of 21; 95% CI, 0-24) responded to MP.
`
`Survival
`Evaluation of survival by treatment is complicated by
`the finding that 56% of patients received the alter-
`nate therapy on crossover. However, the median sur-
`vival for each arm was 10.4 months for ixabepilone
`and 9.8 months for MP. (Fig. 2) The median overall
`survival for the entire study was 9.8 months., and did
`not show differences based on prior taxane response.
`Potential disease features predictive of survival
`from the start of second-line therapy were evaluated
`in patients enrolled on this study in an exploratory
`analysis. When the entire study sample was dichoto-
`mized at the median baseline value, a significantly
`prolonged survival was observed for decreased LDH
`(270 vs [270), decreased alkaline phosphatase
`(130 vs [130) and increased hemoglobin (12
`vs [12)
`(P 5 .007,
`.003, and .01,
`respectively).
`
`

`
`Second-line chemotherapy for HRPC/Rosenberg et al.
`
`561
`
`TABLE 3
`Maximal Grade 3-4 Hematologic Toxicity
`
`TABLE 4
`Maximal Grade 3-4 Treatment-Related Non-Hematologic Toxicity
`
`Ixabepilone
`
`MP
`
`Ixabepilone
`
`MP
`
`2nd-Line,
`n = 41
`
`3rd-Line,
`n = 29
`
`2nd-Line,
`n = 41
`
`3rd-Line,
`n = 16
`
`No. (%)
`
`No. (%)
`
`No. (%)
`
`No. (%)
`
`Grade
`
`2nd-Line,
`n = 41
`
`3
`
`4
`
`3rd-Line,
`n = 30
`
`2nd-Line,
`n = 41
`
`3rd-Line,
`n = 16
`
`4
`
`3
`
`4
`
`4
`
`3
`
`2
`
`1
`
`4
`
`2
`
`1
`
`3
`
`1
`
`1
`1
`
`3
`1
`3
`4
`2
`
`2
`1
`
`1
`
`1
`
`3
`
`1
`1
`1
`
`2
`2
`3
`
`1
`2
`
`1
`2
`
`1
`
`1
`1
`1
`3
`
`1
`
`GI
`Nausea/vomiting
`Anorexia
`Stomatis/pharyngitis
`Diarrhea
`Constipation
`Dehydration
`Hepatic
`Hypotension
`Fatigue
`Muscle weakness
`Renal
`Neurologic
`Motor neuropathy
`Sensory neuropathy
`CNS ischemia
`Syncope
`Lightheadedness
`Mood alteration
`Elevated PT
`Metabolic
`Hypophosphatemia
`Hypoglycemia
`Hyperuricemia
`Hypercalcemia
`Hypokalemia
`Hypersensitivity
`
`1
`
`1
`
`1
`
`1
`1
`
`1
`
`Anemia
`Neutropenia
`Febrile neutropenia
`Thrombocytopenia
`
`4 (10)
`22 (54)
`2 (5)*
`3 (7)
`
`2 (7)
`10 (33)
`2 (7)
`3 (10)
`
`1 (2)
`26 (63)
`4 (10)
`1 (2)
`
`—
`10 (63)
`—
`1 (6)
`
`* 1 patient died of neutropenic sepsis.
`
`The 3 laboratory parameters were highly correlated
`(P < .002 for all pairwise comparisons). Patients with-
`out visceral disease also achieved a significantly longer
`survival (P 5 .02). Categorized LDH (270 vs >270)
`was highly associated with visceral disease (P 5 .005).
`There was no difference in survival due to baseline
`performance score, PSA, or Gleason score. When the
`4 individual parameters significant to predicting sur-
`vival were considered simultaneously by using Cox
`proportional hazard model, a decreased LDH and ab-
`sence of visceral metastases emerged as significant
`independent predictors of prolonged survival (likeli-
`hood ratio test, P 5 .0003, .04, respectively).
`
`Toxicity
`Grade 3 or 4 neutropenia occurred in 54% and 63%
`of patients treated with second-line ixabepilone and
`MP, respectively (Table 3). Febrile neutropenia and
`neutropenic infection occurred in 4 patients treated
`with second-line MP and 3 patients treated with sec-
`ond-line ixabepilone (including 1 patient who died
`from neutropenic sepsis). Treatment-related nonhe-
`matologic toxicities observed in 5% of patients trea-
`ted with second-line ixabepilone included anorexia,
`stomatitis, fatigue, muscle weakness, and prolonged
`prothrombin time (Table 4). Treatment-related non-
`hematologic toxicity observed in 5% of patients
`treated with second-line MP included prolonged pro-
`thrombin times and liver function abnormalities.
`Dose reduction or delay were required in 20 of 41
`(49%) patients treated with second-line ixabepilone
`and 10 of 41 (24%) patients treated with second-line
`MP.
`
`Crossover Therapy
`Sixteen of 41 (39%) patients on second-line ixabepi-
`lone crossed over
`to MP treatment. Of
`the 25
`patients who did not cross over to MP, 8 withdrew
`consent, 2 died, and 14 experienced clinically signifi-
`
`The following grade 3 toxicities occurred with second-line ixabepilone in 1 patient: thrombosis, atrial
`arrhythmia, urinary obstruction, and chest pain.
`
`cant disease progression and/or treatment-related
`toxicity such that they did not cross over. Four of 15
`evaluable patients who received third-line MP
`achieved a confirmed 50% PSA decline (27%; 95%
`CI, 8-55; Table 5). One of 9 (11%) patients with
`measurable disease and at least 2 cycles of therapy
`demonstrated an objective response to third-line MP
`in addition to a PSA response.
`Thirty of 41 (73%) patients on second-line MP
`crossed over
`to ixabepilone therapy. Of
`the 11
`patients who did not cross over to ixabepilone, 2
`withdrew consent, 1 died, 1 was not eligible to con-
`tinue on study because of decreased clinical status,
`and 7 patients experienced clinically significant dis-
`ease progression and/or treatment-related toxicity
`such that they did not cross over. Three of 27 (11%;
`95% CI, 2-29)evaluable patients achieved a confirmed
`50% PSA decline to third-line ixabepilone. One of
`14 (7%) patients with measurable disease and at least
`
`

`
`562
`
`CANCER August 1, 2007 / Volume 110 / Number 3
`
`TABLE 5
`Response to Crossover Therapy
`
`3rd-Line
`MP, n = 16
`
`3rd-Line
`ixabepilone,
`n = 30
`
`PSA responses
`
`No. (%)
`
`No. (%)
`
`Evaluable patients*
`Confirmed PSA decline 50%, 95% CI
`Unconfirmed PSA decline 50%
`Objective disease responses
`Measurable disease
`Evaluable patients*
`Partial response (RECIST)
`
`* Received at least 2 cycles.
`
`15
`4 (27, 8-55)
`—
`
`27
`3 (11, 2-29)
`1 (4)
`
`11
`9
`1
`
`15
`14
`1
`
`2 cycles of therapy demonstrated both an objective
`and a PSA response.
`None of the patients who achieved a PSA response
`to third-line therapy demonstrated a PSA response to
`second-line treatment. None of
`the patients who
`responded to third-line ixabepilone and only 1 patient
`who responded to third-line MP had achieved a previ-
`ous response to front-line taxane chemotherapy.
`
`DISCUSSION
`This study evaluated second-line chemotherapy in
`TR-HRPC patients to address the question of clinical
`cross-resistance between taxanes, epothilones, and
`mitoxantrone, as well as to explore the natural his-
`tory of chemotherapy-refractory HRPC. MP is the de
`facto community standard second-line chemotherapy
`for HRPC in the absence of prospective data in this
`setting. Therefore, determining the activity of sec-
`ond-line MP is important not only to understand the
`usefulness of this regimen as second-line chemother-
`apy but also to define its activity as a control arm for
`future second-line clinical trials. Encouraging precli-
`nical activity in taxane-resistant model systems and
`substantial activity seen in front-line HRPC chemo-
`therapy support the testing of
`ixabepilone in the
`second-line setting.
`The median survival for patients with TR-HRPC
`has not been prospectively evaluated. In the present
`multicenter study, the median survival of all patients
`was 9.8 months from the initiation of second-line
`chemotherapy. As study treatments demonstrated only
`modest activity in this setting, this value provides a
`useful estimate of survival as a baseline for develop-
`ment of future clinical trials in this patient population.
`Treatment of TR-HRPC with MP or ixabepilone
`demonstrated only modest activity. The PSA response
`proportions for MP and ixabepilone were 20% and
`
`17%, respectively. Objective responses were infre-
`quent (10% each arm). Although this study was not
`designed to compare the 2 regimens, the levels of ac-
`tivity in this study appear similar between the 2
`arms. The anticancer activity of ixabepilone as meas-
`ured by PSA declines and objective tumor responses
`contrasts with results of chemotherapy-naive HRPC
`trials with this drug. Although 17% of patients did ex-
`perience PSA responses to ixabepilone in this study,
`this level of activity is not sufficient to justify further
`evaluation of ixabepilone in this dose and schedule
`as single-agent second-line HRPC chemotherapy.
`Although patients were required to have progres-
`sive disease during or shortly after stopping taxane
`chemotherapy, 35% of ixabepilone and 49% of MP
`patients previously experienced a 50% PSA decline
`to first-line taxane therapy. A retrospective analysis
`demonstrated that patients who experienced a PSA
`response to prior therapy were 7-fold to 8-fold more
`likely to respond to either second-line regimen. On
`the basis of these findings, future randomized studies
`should stratify patients for best response to prior
`therapy. In addition, patients who never responded
`to taxane-based therapy are unlikely to respond to
`ixabepilone or MP, and investigational therapy should
`be considered. In an exploratory analysis, elevated
`LDH and the presence of visceral metastases appear
`to be independent prognostic indicators of poor
`overall survival in the second-line setting. These indi-
`cators should be investigated further in future sec-
`ond-line chemotherapy studies.
`The predominant toxicities seen were hemato-
`logic in nature. MP was well tolerated, with only 1
`episode of neutropenic infection. Ixabepilone treat-
`ment resulted in 1 treatment-related death from
`neutropenic sepsis during Cycle 1. Although nonhe-
`matologic toxicities were seen with ixabepilone, none
`were observed with high frequency, and no single
`toxicity predominated. Low rates of neurotoxicity
`seen in this study compared with other trials of ixa-
`bepilone may in part be explained by the require-
`ment that all patients enrolled were required to have
`grade 1 neuropathy after
`taxane chemotherapy.
`This requirement may have selected a population
`less susceptible to neuropathy.
`taxanes
`Previously,
`the noncross-resistance of
`and ixabepilone was reported in a retrospective anal-
`ysis of patients treated on a randomized phase 2 trial
`of first-line ixabepilone with or without estramus-
`tine.14 In that analysis of 49 patients, 51% of patients
`treated with second-line taxane achieved a 50%
`PSA decline. The results of the current study suggest
`there may be a sequence-dependent effect of epothi-
`lone and that taxane therapy that may be responsible
`
`

`
`for the lower level of activity seen with second-line
`ixabepilone.
`In the present study, some patients who experi-
`enced disease progression on either MP or ixabepilone
`and crossed over to the third-line therapy achieved
`third-line PSA responses. In fact, none of the patients
`who responded to their third-line treatment responded
`to their second-line therapy. This implies some non-
`cross-resistance between the 2 regimens.
`Although substantial progress in treating HRPC has
`been achieved with the introduction of effective first-
`line chemotherapy, the identification of new agents with
`high activity in front-line and TR-HRPC patients
`remains a priority. Median survival of patients with TR-
`prostate cancer from the start of second-line chemo-
`therapy remains short. Both novel biologic agents as
`well as novel chemotherapies must continue to be
`investigated to improve survival in this patient popula-
`tion. Stratification by prior treatment response should
`be incorporated into future randomized clinical trials.
`
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