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`original article
`
`Annals of Oncology 19: 1547–1552, 2008
`doi:10.1093/annonc/mdn171
`Published online 23 April 2008
`
`A multicenter phase II study of XRP6258 administered
`as a 1-h i.v. infusion every 3 weeks in taxane-resistant
`metastatic breast cancer patients
`X. Pivot1*, P. Koralewski2, J. L. Hidalgo3, A. Chan4, A. Goncxalves5, G. Schwartsmann6,
`S. Assadourian7 & J. P. Lotz8
`1Department of Medical Oncology, University Hospital Jean Minjoz, Besancxon; Institut National de la Sante´ et de la Recherche Me´dicale, Unit 645, Besancxon, France;
`2Rydygier Memorial Hospital, 31-826 Krakow, os. Zlotej Jesieni 1, Poland; 3Clinical Oncology Institution and Research, Mendoza, Argentina; 4Department of Medical
`Oncology, Mount Hospital, Perth, Australia; 5Department of Medical Oncology, Institut Paoli Calmettes, UMR599 Inserm, Universite´ de la Me´diterrane´e Marseille,
`France; 6Department of Medical Oncology, Federal Univ, Porto Alegre, Brazil; 7Department of Oncology development, Sanofi-Aventis, Antony; 8Department of Medical
`Oncology, Hopital Tenon, Paris, France
`
`Received 14 February 2008; revised 19 March 2008; accepted 20 March 2008
`
`Background: XRP6258 is a novel taxoid with a low affinity for P-glycoprotein. This multicenter phase II study
`assessed the activity of XRP6258 in the treatment of taxane-resistant metastatic breast cancer (MBC).
`Patients and methods: XRP6258 was administered as a 1-h i.v. infusion every 3 weeks at 20 mg/m2 (then, in the
`absence of severe toxicity, at 25 mg/m2 from cycle 2). The primary end point was the objective response rate (ORR)
`assessed according to response evaluation criteria in solid tumours (RECIST) guidelines.
`Results: Seventy-one patients were enrolled. The median relative dose intensity was 0.98. The ORR was 14%
`(two complete, eight partial responses). Eighteen patients (25%) had stable disease of >3 months duration. At
`a median follow-up of 20.0 months, the median time to progression was 2.7 months, and the median overall survival
`12.3 months. The most common grade 3/4 adverse events (AEs) were neutropenia (73%) and leucopenia (55%), with
`a low febrile neutropenia rate (3%) and infrequent grade 3/4, treatment-related, non-hematological AEs (<5% patients
`for any AE). Two deaths were reported, one related to study drug and one to unknown cause.
`Conclusions: XRP6258 was active and well tolerated in this group of MBC patients with taxane-resistant disease.
`These results support the further clinical development of this agent.
`Key words: chemotherapy, metastatic breast cancer, resistance, taxane, taxoid, XRP6258
`
`introduction
`
`While breast cancer is generally not overtly metastatic at
`presentation (6% cases), 30% of women with early stage
`lesions eventually develop advanced disease [1]. Metastatic
`breast cancer (MBC) remains essentially incurable, with
`median survival in the range of 2–4 years [2]. In this clinical
`situation, systemic therapies are palliative, aiming primarily at
`controlling disease symptoms, improving survival and
`preserving quality of life [3]. Regimens containing
`anthracyclines and taxanes as first-line treatment in MBC
`have demonstrated their potential to prolong patient survival
`[1, 4, 5]. When disease progression occurs after the completion
`of first-line treatment, additional lines of chemotherapy may
`be administered, with the capecitabine–docetaxel combination
`being an important treatment option for women with
`anthracycline-pretreated MBC [6, 7], However, if metastatic
`disease becomes resistant to anthracycline and/or taxanes,
`
`*Correspondence to: Prof. X. Pivot, Service d’Oncologie Me´ dicale, Centre Hospitalier
`Universitaire de Besancxon, 25030 BESANCON cedex, France.
`Tel: +33-3-81-66-88-58; Fax: +33-2-81-66-88-58; E-mail: Xavier.pivot@univ-fcomte.fr
`
`effective treatment options are limited. With the growing use
`of anthracycline/taxane-containing regimens in adjuvant
`therapy, there remains an unmet clinical need for effective
`compounds to treat patients with MBC developing or having
`developed resistance to taxanes.
`For this reason, a program of medicinal chemistry was
`undertaken to identify new taxoid compounds with a broader
`spectrum of activity than the marketed taxanes, paclitaxel
`and docetaxel. XRP6258 and larotaxel (XRP9881) are new
`taxoids efficient in stabilizing microtubules against
`cold-induced depolymerization, the mechanism of action
`which is unique to the taxane class [8]. While the commercially
`available taxanes are substrates for P-glycoprotein, encoded
`by the multidrug resistance gene ABCB1, XRP6258 and
`larotaxel were selected for their low affinity for this drug efflux
`pump [9, 10]. This optimization suggested that both could
`be clinically effective in tumors expressing a multidrug
`resistance phenotype as a consequence of high-level expression
`of P-glycoprotein. Preclinical studies demonstrated that
`XRP6258 was cytotoxic for cell lines with acquired resistance to
`doxorubicin, vincristine, vinblastine, paclitaxel or docetaxel
`
`ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
`
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`[11]. Similarly, both agents showed an in vivo spectrum of
`antitumor efficacy on most docetaxel-sensitive, -refractory
`or -resistant models, such as B16/TXT melanoma [9, 11].
`Interestingly, both compounds showed the ability to cross the
`blood–brain barrier, a characteristic which may be
`a consequence of their low affinity for P-glycoprotein [12, 13].
`Weekly and every 3-week schedules of administration of
`XRP6258 were tested in phase I trials [14, 15]. In one study,
`XRP6258 was given on a weekly schedule as a 1-h i.v. infusion
`on days 1, 8, 15 and 22 every 5 weeks. For the weekly regimen,
`the recommended dose was 10 mg/m2 and the dose-limiting
`toxicity was diarrhea. Two studies have been carried out with
`XRP6258 administered as a 1-h i.v. infusion every 3 weeks.
`For this regimen, the maximum tolerated dose (MTD) was
`reached at the 30 mg/m2 dose level, at which dose-limiting
`adverse events (AEs) such as febrile neutropenia and grade 4
`neutropenia >5 days occurred. The recommended dose for
`phase II and III studies was 20 mg/m2.
`Originally, a three-arm study was initiated which was
`designed to compare the relative efficacy and safety of the
`two new taxoids, XRP6258 and larotaxel. However, due to
`low recruitment during the first 6 months, the protocol was
`amended to a single-arm phase II study exploring the
`activity of XRP6258 given every 3 weeks in patients with
`taxane-resistant MBC, as summarized in Figure 1.
`Consequently, only the data from this arm are reported.
`
`patients and methods
`
`This open-label phase II study was conducted in 39 study centers in Europe,
`Northern America and Southern America from August 2002 to January
`2005 (cut-off date). The protocol complied with recommendations of
`the 18th World Health Congress (Helsinki, 1964) and all relevant
`amendments and was approved by the ethics committee of each
`participating institution. All patients gave their written informed consent.
`
`main eligibility criteria
`Eligibility criteria included the following: age ‡18 years, with histologically
`confirmed human epidermal growth factor receptor 2 (HER2)-negative
`(or HER2-positive previously failing trastuzumab) metastatic breast
`adenocarcinoma, Eastern Cooperative Oncology Group performance status
`(PS) zero to two and adequate hematological (granulocytes ‡2 · 109/l,
`platelet count ‡100 · 109/l), renal [creatinine £upper limit of normal
`(ULN) or creatinine clearance ‡60 ml/min] and liver (total bilirubin £ULN,
`
`Annals of Oncology
`
`serum aspartate aminotransferase/alanine aminotransferase and alkaline
`phosphatase £2.5 · ULN) functions. Patients were required to have at
`least one measurable lesion according to RECIST guidelines [16].
`Resistance to previous taxane-containing chemotherapy was required.
`This resistance was defined as: for advanced disease; progressive disease
`(PD) as the best overall response after first- or second-line treatment; or,
`PD within 4 months following discontinuation of first- or second-line
`treatment after an initial objective response or disease stabilization; or,
`stable disease (SD) as the best overall response if first- or second-line
`treatment with a taxane-containing regimen had been administered for
`at least 3 months; or, for patients who had received an adjuvant or
`neo-adjuvant taxane-containing regimen, a disease-free interval (DFI)
`£12 months from the end of treatment.
`Patients were excluded if they had concurrent cancer, received more
`than two lines of chemotherapy for metastatic disease, hypercalcemia,
`grade 2 or 3 neuropathy, brain or leptomeningeal symptomatic
`involvement or uncontrolled significant comorbid conditions.
`
`treatment assignment and schedule
`Patients in the analyzed experimental arm received XRP6258 at 20 mg/m2,
`given as a 1-h i.v. infusion on day 1 every 3 weeks. Intrapatient dose
`escalation to 25 mg/m2 was permitted in patients who did not
`experience a significant AE during cycle 1. Patients received i.v.
`antihistaminic anti-H1 premedication 30 min before study drug
`administration. No prophylactic antiemetic drugs were allowed at the
`first cycle. In case of nausea/vomiting, patients could receive preventive
`antiemetic treatment in compliance with the conventional antiemetic
`protocol of the center, for subsequent cycles. In the event of
`a treatment-related severe AE occurring during any cycle, a 20%–25%
`dose reduction and treatment delay for the individual drug was required
`on the basis of predefined criteria. Treatment was continued until disease
`progression, the occurrence of an unacceptable AE or the withdrawal of
`patient consent.
`
`evaluations before and during therapy
`Before registration, a complete medical history was taken and a physical
`examination was carried out, which included a complete blood count,
`blood chemistry analyses and tumor assessments.
`Tumor measurements were made every 6 weeks by chest, abdominal
`and brain computed tomography scans or magnetic resonance imaging.
`Responses had to be confirmed by two evaluations taken at least 4 weeks
`apart. Complete blood counts were routinely carried out weekly or
`every day if grade 4 neutropenia occurred (until recovery to grade 3) or
`in the case of fever. Patients were regularly assessed for potential AEs
`and disease-related signs and symptoms. Follow-up including physical
`examination, tumor assessments and survival data were collected every
`
`Figure 1. Randomization schedule.
`
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`6 weeks for the first 3 months and then every 3 months until the subject’s
`death or until the study cut-off date.
`
`Table 1. Patient and cancer characteristics
`
`data analysis
`Following low recruitment during the first 6 months, the protocol was
`amended on 21 January 2003. The study consequently became
`a multicenter, multinational, open-label, single-arm, stratified phase II
`study in patients with taxane-resistant MBC treated with XRP6258
`administered every 3 weeks. Two strata were defined according to the
`number of lines of taxane-containing treatment previously administered
`(stratum 1: resistance to an adjuvant/neo-adjuvant or first-line
`taxane-based regimen for advanced disease versus stratum 2: resistance
`to a second-line, taxane-based regimen for advanced disease). For each
`of the strata, a two-stage modified Fleming design was used where accrual
`was to be stopped if no response was observed after the first 20 per-protocol
`patients. Within each stratum, if at least one response was observed,
`20 additional per-protocol patients were accrued. If at least five responses
`were observed in the final set of 40 per-protocol patients per stratum, the
`null hypothesis—that the true response rate was £5%—was rejected.
`Overall, at a significance level of 10%, the procedure had a power of 98%.
`The primary end point was defined as the objective response rate (ORR),
`according to RECIST guidelines, achieved by XRP6258 administered
`every 3 weeks. Secondary efficacy end points were duration of response,
`time to progression (TTP) and overall survival (OS). They were analyzed
`using the Kaplan–Meier method [17]. Efficacy was assessed on the treated
`(all enrolled patients) and the per-protocol population (comprising
`patients who were eligible for the study and evaluable for response).
`Duration of response was measured for patients who had complete
`response (CR) or partial response (PR) as best overall response and
`calculated as the time from first documentation of CR or PR (whichever
`status was recorded first) until the first documented progression or
`death due to any cause. TTP was defined as the time from first infusion
`to first documented progression or death due to any cause. OS was
`calculated from the time of first infusion to death, whatever the cause.
`Where appropriate, 95% confidence intervals (95% CIs) were calculated
`following the Clopper–Pearson exact method [18].
`The safety population included all treated patients. AEs/signs and
`symptoms of disease observed by the investigator or reported by the patients
`were recorded and graded according to the National Cancer
`Institute—Common Toxicity Criteria version 2 whenever possible, otherwise
`the Medical Dictionary for Regulatory Activities version 6 was used.
`
`results
`
`patients
`
`Included patients
`
`Age, years
`Median (minumum–maximum)
`ECOG performance status, N (%)
`0
`1
`2
`Missing
`Hormonal status ER and/or PgR, N (%)
`Positive
`Unknown
`HER2 receptors, N (%)
`Positive
`Not done
`Disease-free interval, monthsa
`Median (minimum–maximum)
`Number of organs involved
`1
`2
`3
`4 or more
`Main organs involved, N (%)
`Any visceral
`Liver
`Lymph nodes
`Bone
`Lung
`Breast
`Connective soft tissue
`Skin
`Brain
`Prior chemotherapy exposure
`Adjuvant
`Advanced
`One lineb
`Two lines
`Three lines
`Prior anthracycline exposure, N (%)
`Last taxane exposure, N (%)
`Docetaxel
`Paclitaxel
`More than one line of taxane
`
`N = 71
`
`53 (35–77)
`
`30 (42)
`33 (46)
`7 (10)
`1 (1)
`
`37 (52)
`6 (8)
`
`19 (27)
`15 (21)
`
`33.3 (1.58–214.01)
`
`15 (21)
`26 (37)
`14 (20)
`16 (23)
`
`53 (75)
`42 (59)
`33 (46)
`31 (44)
`22 (31)
`16 (23)
`11 (15)
`8 (11)
`7 (10)
`
`1 (1)
`70 (99)
`49 (69)
`19 (27)
`2 (3)
`54 (76)
`71 (100)
`46 (65)
`25 (35)
`7 (10)
`
`Of 71 enrolled and treated patients, four were ineligible for
`the study: two were considered not to be resistant to taxanes,
`one did not have a histologically confirmed initial breast cancer
`and one had only one target lesion, in a previously irradiated
`area. Forty-seven eligible patients were accrued in stratum 1
`and 20 in stratum 2. Six patients were not assessable for
`response due to the administration of concurrent treatments or
`early discontinuation due to AE or death. The per-protocol
`population therefore comprised 61 patients. Patient and disease
`characteristics are summarized in Table 1.
`The median age was 53 years and 89% of patients were PS
`zero to one. All patients had previously received chemotherapy:
`1% as adjuvant and 69% and 27% given as first- and
`second-line for metastatic disease, respectively. A total of
`seven patients had detectable metastatic disease at
`presentation and the median DFI for the remaining patients
`
`aFor 64 patients with nonmetastatic disease at presentation.
`bIncluding patients with adjuvant chemotherapy with a DFI < 12 months.
`ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR,
`progesterone receptor; HER2, human epidermal growth factor receptor 2;
`DFI, disease-free interval.
`
`was 33.3 months. Hormonal receptor status was positive in
`52% of tumors and HER2-positive status was scored in 27%
`of tumors (Table 1). The majority (75%) of patients had
`visceral metastatic disease, and 79% had multiple organ
`involvement (two or more).
`
`exposure to study medication
`
`In total, 345 cycles of XRP6258 were administered, with
`a median of four cycles (range 1–25 cycles). The median relative
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`dose intensity was 0.98 (range 0.60–1.14). At least one cycle
`delay of >3 days was observed in 32% of patients and in 14% of
`cycles, half of those delays being related to technical or personal
`reasons. At least one dose reduction was required in 10% of
`patients and in 2% of cycles. The most frequent reasons for
`treatment discontinuation were PD (75%), no further benefit
`expected (13%) and AE (6%).
`
`safety
`
`Treatment emergent grades 3–5 hematological and
`non-hematological AEs possibly related to study medication
`are listed by patient and cycle in Table 2. Neutropenia was the
`most common grade 3/4 hematological AE occurring in 73%
`of patients and 43% of evaluable cycles. Treatment-related
`febrile neutropenia or neutropenic infections were observed
`in 3% and 4% of patients and in <1% of cycles, respectively.
`Grade 3/4 anemia and thrombocytopenia were rare. Dose
`escalation up to 25 mg/m2 from cycle 2, in selected patients, on
`the basis of their good tolerance in cycle 1, was feasible in 20
`patients (28%) with no evident increase in the overall incidence
`of subsequent AEs in this group.
`Treatment emergent grades 3–5 non-hematological AEs
`probably or possibly related to study treatment were also rare,
`
`with the most common including: hypersensitivity (4%),
`fatigue (3%) and hemorrhagic cystitis (3%). No severe AE
`occurred for nausea, vomiting, neuropathy sensory, myalgia
`and fluid retention. The most frequent non-hematological AEs
`at any grade, occurring in >15% of patients, were fatigue
`(35%), nausea (32%), diarrhea (30%), vomiting (18%),
`myalgia (17%), neuropathy sensory (17%) and anorexia (15%).
`At cut-off, 52 patients had died, with 50 of those deaths
`considered to be related to disease progression. Two patients
`died within 30 days of the last on-study treatment: one patient
`on day 9 of cycle 1, due to shock with respiratory failure,
`deemed possibly related to study treatment, and one patient
`on day 21 of cycle 1, of an unknown cause. A total of four
`patients were withdrawn from the study due to AEs: three
`patients for grades 1–2 alteration of liver function tests at
`cycle 1 for one patient and cycle 6 for two patients and one
`for grade 4 allergic reaction at cycle 2.
`
`efficacy
`
`The investigator-determined ORR was 14% (95% CI 7% to
`24%) in the treated patient population (Table 3). Interestingly,
`two patients achieved a complete response. The median
`response duration was 7.6 months (range 2.6+ to 18.7+).
`
`Table 2. Grades 3–5 hematological and non-hematological toxic effects possibly or probably related to study treatment
`
`NCI CTC term, N (%)
`
`Patients, N = 71
`
`Hematological
`Neutropeniaa
`Leukopeniab
`Anemiab
`Thrombocytopeniab
`Neutropenic complications
`All grade 4 neutropenia
`Lasting >5 days
`Febrile neutropenia
`Neutropenic infection
`Non-hematological
`Hypersensitivity reaction
`Infection (neutropenic)
`Fatigue
`Hemorrhagic cystitis
`Diarrhea
`Headache
`Peripheral edema
`Infection without neutropenia
`Arrhythmia supraventricular
`Cyanosis
`Dyspnea
`Incontinence
`Injection site reaction
`Irregular menses
`Pleural effusion
`Thromboembolism
`
`All grades
`67 (94)
`69 (97)
`64 (90)
`7 (10)
`
`All grades
`4 (6)
`3 (4)
`25 (35)
`2 (3)
`21 (30)
`7 (10)
`6 (8)
`3 (4)
`1 (1)
`1 (1)c
`1 (1)c
`1 (1)
`1 (1)
`1 (1)
`1 (1)
`1 (1)
`
`aN = 325 evaluable cycles.
`bN = 326 evaluable cycles.
`cDeath (grade 5).
`NCI CTC, National Cancer Institute Common Toxicity Criteria.
`
`Grade 3/4
`52 (73)
`39 (55)
`2 (3)
`3 (4)
`N = 71
`35 (49)
`19 (27)
`2 (3)
`3 (4)
`Grades 3–5
`3 (4)
`3 (4)
`2 (3)
`2 (3)
`1 (1)
`1 (1)
`1 (1)
`1 (1)
`1 (1)
`1 (1)c
`1 (1)c
`1 (1)
`1 (1)
`1 (1)
`1 (1)
`1 (1)
`
`Cycles, N = 345
`
`All grades
`254 (78)
`248 (76)
`243 (75)
`13 (4)
`
`All grades
`5 (1)
`3 (1)
`68 (20)
`5 (1)
`66 (19)
`16 (5)
`16 (5)
`4 (1)
`1 (0.3)
`1 (0.3)c
`1 (0.3)c
`1 (0.3)
`2 (0.6)
`7 (2)
`2 (0.6)
`1 (0.3)
`
`Grade 3/4
`141 (43)
`95 (29)
`4 (1)
`3 (1)
`N = 325
`67 (21)
`26 (8)
`2 (0.6)
`3 (1)
`Grades 3–5
`3 (1)
`3 (1)
`3 (1)
`3 (1)
`1 (0.3)
`1 (0.3)
`1 (0.3)
`1 (0.3)
`1 (0.3)
`1 (0.3)c
`1 (0.3)c
`1 (0.3)
`2 (0.6)
`7 (2)
`2 (0.6)
`1 (0.3)
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`Table 3. Best overall response rate (modified ITT and per-protocol populations)
`
`original article
`
`Response, N (%)a
`Overall response rate
`Complete response
`Partial response
`No change/stable disease
`Progressive disease
`Response duration, median (minimum–maximum)
`TTP, median (95% CI)
`OS, median (95% CI)
`
`Treated population (N = 71)
`
`Per-protocol population (N = 61)
`
`10 (14)
`2 (3)
`8 (11)
`27 (38)
`29 (41)
`7.6 mo (2.6 6 18.7+)
`2.7 months (1.45–4.07)
`12.3 months (9.49–15.05)
`
`8 (13)
`2 (3)
`6 (10)
`27 (44)
`26 (43)
`7.6 mo (2.6 6 18.7+)
`2.8 months (1.45–4.07)
`–
`
`aResponse/disease stabilization confirmed by analyses at least 1 month apart.
`TTP, time to progression; OS, overall survival; CI, confidence interval.
`
`In addition to the objective responses, 27 patients (38%) had
`SD with a median duration of 4.2 months (95% CI 3.71–5.42),
`including 18 (25%) with tumor stabilization >3 months
`(from 3.4 to 14.6 months). Eight of these patients had
`experienced PD as the best overall response to the last
`taxane treatment. The median TTP was 2.7 months (95%
`CI 1.45–4.07). At a median follow-up of 20.0 months, the
`median OS was 12.3 months (95% CI 9.49–15.05). Although
`numbers were small, no marked difference in response rate was
`apparent for stratum 1 versus stratum 2 (ORR per-protocol
`population: 14% versus 12%, respectively).
`
`discussion
`
`Increasingly, taxane- and anthracycline-containing regimens
`are being used as adjuvant treatments and remain the most
`efficient systemic treatments and consequently the most
`commonly used worldwide in the treatment of MBC. After
`failure of these agents, and particularly in the case of resistance
`of the tumor to taxanes, the prognosis remains poor. Apart
`from capecitabine [6, 19], active agents that could be used in
`subsequent treatment lines are lacking.
`XRP6258 appears to be active in docetaxel- or
`paclitaxel-resistant breast cancer, even when the most
`stringent criterion of resistance (PD on therapy) was used. The
`ORR was 14% (95% CI 7% to 24%) in the treated population.
`In addition, 18 patients (25%) had SD lasting for >3 months
`(range 3.4–14.6 months). Long-lasting SD may be an indicator
`of activity, especially in heavily pretreated patients, who did
`not respond or had responses of short duration to the previous
`line of chemotherapy. The 14% ORR reported is comparable
`to that described by Dieras et al. [20] for larotaxel in a similar
`population. This larotaxel phase II study was conducted in
`130 patients with MBC and was designed to assess the efficacy
`of larotaxel administered every 3 weeks at 90 mg/m2 in
`populations of patients with taxane-resistant and nonresistant
`disease. The different response rates in these groups
`(taxane-resistant, 20% versus nonresistant, 42%) highlighted
`the need to establish a clinical definition of taxane resistance
`comparable to the model reported for anthracycline breast
`cancer resistance.
`Several drugs have recently been reported to be potentially
`effective in the treatment of breast cancer patients following the
`
`failure of anthracycline- or taxane-based treatment. These
`include fluoropyrimidines such as capecitabine [21] and
`combinations including 5-fluorouracil (5-FU) plus oxaliplatin
`[22] and 5-FU plus eniluracil [23], but also gemcitabine [24]
`and vinorelbine [25]. The definitions of taxane resistance
`across these studies were different and often not restrictive.
`Only capecitabine was extensively assessed in stringently
`defined taxane-resistant patients (PD while on therapy).
`Although no responses were observed with gemcitabine,
`response rates between 10% and 26% were observed for the
`other agents/combinations (20% for capecitabine), which are
`comparable to the 14% rate observed for XRP6258 in this
`study. Median TTP and median OS times achieved with
`XRP6258 were also similar to those achieved in these earlier
`studies. Finally, the semisynthetic epothilone, ixabepilone,
`has recently been reported to have achieved response rates
`of 12% in two separate phase II studies in patients with
`taxane-resistant MBC [26–28], albeit against a background
`of difficult-to-manage neurotoxicity.
`The safety profile of XRP6258 was very favorable when
`compared with the known safety profile of the marketed
`taxanes or other compounds under development. No severe
`AE occurred for nausea, vomiting, neuropathy sensory,
`myalgia or fluid retention. The most frequent grade 3/4
`non-hematological AEs were allergic reaction (4%), fatigue
`(3%) and diarrhea (1%). The hematological AE profile was also
`favorable, with rare grade 3/4 anemia and thrombocytopenia.
`Only grade 3/4 neutropenia was common, occurring in
`73% of patients and 43% of cycles. Treatment-related febrile
`neutropenia occurred rarely. Therefore, the biological
`mechanism of cytotoxicity coupled with the evidence of
`activity in taxane-resistant MBC patients and the tolerability
`of this agent justify further clinical testing.
`
`acknowledgements
`
`We would like to thank the patients who enrolled on this trial
`and the medical staff who contributed to their care.
`
`conflict of interest
`
`SA is salaried employee of Sanofi Aventis
`
`Volume 19 | No. 9 | September 2008
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`doi:10.1093/annonc/mdn171 | 1551
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`Downloaded from
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`http://annonc.oxfordjournals.org/
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` at University of Washington on June 9, 2015
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`original article
`
`references
`
`1. O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast
`cancer. Oncologist 2005; 10 (Suppl 3): 20–29.
`2. Chung CT, Carlson RW. Goals and objectives in the management of metastatic
`breast cancer. Oncologist 2003; 8: 514–520.
`3. Dufresne A, Pivot X, Tournigand C et al. Impact of chemotherapy beyond the first
`line in patients with metastatic breast cancer. Breast Cancer Res Treat 2008;
`107(2): 275–279.
`4. Fossati R, Confalonieri C, Torri V et al. Cytotoxic and hormonal treatment for
`metastatic breast cancer: a systematic review of published randomized trials
`involving 31,510 women. J Clin Oncol 1998; 16: 3439–3460.
`5. Bontenbal M, Creemers GJ, Braun HJ et al. Phase II to III study comparing
`doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide
`as first-line chemotherapy in patients with metastatic breast cancer: results of
`a Dutch Community Setting Trial for the Clinical Trial Group of the
`Comprehensive Cancer Centre. J Clin Oncol 2005; 23: 7081–7088.
`6. O’Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine
`plus docetaxel combination therapy in anthracycline-pretreated patients with
`advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:
`2812–2823.
`7. Smith CD, Mooberry SL, Zhang X, Helt AM. A sensitive assay for taxol and other
`microtubule-stabilizing agent. Cancer Lett 1994; 79: 213–219.
`8. Pivot X, Asmar L, Buzdar A et al. An unified definition of clinical anthracycline
`resistance breast cancer. Br J Cancer 2000; 82: 529–534.
`9. Gelmon KA, Latreille J, Tolcher A et al. Phase I dose-finding study of a new
`taxane, RPR 109881A, administered as a one-hour intravenous infusion days 1
`and 8 to patients with advanced solid tumors. J Clin Oncol 2000; 18:
`4098–4108.
`10. Aller AW, Kraus LA, Bissery M-C. In vitro activity of TXD258 in
`chemotherapeutic resistant tumor cell lines. Proc Am Assoc Cancer Res
`2000; 41: 303 (Abstr 1923).
`11. Bissery M-C, Bouchard H, Riou JF et al. Preclinical evaluation of TXD258, a new
`taxoid. Proc Am Assoc Cancer Ress 2000; 41: 214 (Abstr 1364).
`12. Archimbaud Y, Gires P, Pellerin R et al. Pharmocokinetics of a new taxoid
`14C-TXD258, in blood, plasma and brain of mouse, rat and dog. Proc Am
`Assoc Cancer Res 2000; 41: 215 (Abstr 1375).
`13. Kurata T, Shimada Y, Tamura T et al. Phase I and pharmacokinetic study of
`a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients
`with advanced solid tumors. J Clin Oncol 2000; 18: 3164–3171.
`14. sanofi-aventis; data on file.
`
`Annals of Oncology
`
`15. Goetz AD, Denis LJ, Rowinsky EK et al. Phase I and pharmacokinetic study of
`RPR116258A, a novel taxane derivative, administered intravenously over 1 hour
`every 3 weeks. Proc Am Soc Clin Oncol 2001: 20 (Abstr 419).
`16. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the
`response to treatment in solid tumors. European Organization for Research and
`Treatment of Cancer, National Cancer Institute of the United States, National
`Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216.
`17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations.
`J Am Stat Assoc 1958; 53: 457–481.
`18. Clopper CJ, Pearson E. The use of confidence intervals or fiducial limits
`illustrated in cases of the binomial. Biometrika 1934; 26: 404–413.
`19. O’Shaughnessy JA. The evolving role of capecitabine in breast cancer. Clin
`Breast Cancer 2003(Suppl 1): 4–S20–S25.
`20. Dieras V, Valero V, Limentani S et al. Multicenter, non-randomized phase II study
`with RPR109881 in taxane-exposed metastatic breast cancer (MBC) patients
`(pts): final results 2005: 23 Journal of Clinical Oncology ASCO Annual Meeting
`Proceedings (Post meeting edition)(Abstr 565).
`21. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine
`in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17:
`485–493.
`22. Zelek L, Cottu P, Tubiana-Hulin M et al. Phase II study of oxaliplatin and
`fluorouracil in taxane- and anthracycline-pretreated breast cancer patients.
`J Clin Oncol 2002; 20: 2551–2558.
`23. Rivera E, Sutton L, Colwell B et al. Multicenter phase II study of a 28-day
`regimen of orally administered eniluracil and fluorouracil in the treatment of
`patients with anthracycline- and taxane-resistant advanced breast cancer. J Clin
`Oncol 2002; 20: 987–993.
`24. Smorenburg CH, Bontenbal M, Seynaeve C et al. Phase II study of weekly
`gemcitabine in patients with metastatic breast cancer relapsing or failing both an
`anthracycline and a taxane. Breast Cancer Res Treat 2001; 66: 83–87.
`25. Toi M, Saeki T, Aogi K et al. Late phase II clinical study of vinorelbine
`monotherapy in advanced or recurrent breast cancer previously treated with
`anthracyclines and taxanes. Jpn J Clin Oncol 2005; 35: 310–315.
`26. Perez EA, Lerzo G, Pivot X et al. Efficacy and safety of ixabepilone (BMS-247550)
`in a phase II study of patients with advanced breast cancer resistant to an
`anthracycline, a taxane, and capecitabine. J Clin Oncol 2007; 25: 3407–3414.
`27. Thomas E, Tabernero J, Fornier M et al. Phase II clinical trial of ixabepilone
`(BMS-247550), an epothilone B analog, in patients with taxane-resistant
`metastatic breast cancer. J Clin Oncol 2007; 25: 3399–3406.
`28. Pivot X, Dufresne A, Villanueva C. Efficacy and safety of ixabepilone, a novel
`epothilone analogue. Clin Breast Cancer 2007; 7: 543–549.
`
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`Volume 19 | No. 9 | September 2008