Annals of Oncology Advance Access originally published online on April 1, 2008
Annals of Oncology 2008 19(7):1255-1260; doi:10.1093/annonc/mdn060
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breast cancer |
Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy
1 Department of Medical Oncology, Institut Curie, Paris, France
2 Carolinas Hematology-Oncology Associates, Charlotte, NC, USA
3 Centre Val d'Aurelle, Montpellier
4 Centre René Huguenin, Saint Cloud
5 Centre Catherine de Sienne, Nantes, France
6 Hematology/Oncology, Dartmouth/Hitchcock Medical Center, Lebanon, NH, USA
7 Sanofi-aventis, Bagneux, France
8 MD Anderson Cancer Center, Houston, TX, USA
* Correspondence to: Dr V. Diéras, Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France. Tel: +33-144324675; Fax: +33-144324671; E-mail: veronique.dieras{at}curie.net
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Abstract |
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Background: Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC.
Patients and methods: Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m2 was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated.
Results: One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%).
Conclusions: Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.
Key words: breast cancer, larotaxel, metastatic breast cancer, taxanes, XRP9881
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Approximately 40 000 women die of metastatic breast cancer (MBC) in the United States each year [1]. Despite recent improvements in median overall survival (OS), most patients treated with anthracyclines and taxanes will progress during or after therapy [2–4]. Response rates range from 25% to 60% for first-line chemotherapy and decrease substantially for second- and third-line therapies [1]. There is a clear need for effective therapies for patients with MBC whose disease fails to respond to or progresses after conventional chemotherapy.
One agent with promise in treatment-resistant breast cancer is larotaxel (XRP9881, formerly RPR 109881), a novel semisynthetic taxoid made from 10-deacetyl baccatin III, the major natural taxane extracted from the needles of yew trees. Larotaxel was selected for clinical development on the basis of activity against multidrug-resistant tumors and its ability to cross the blood–brain barrier [5]. Activity has been demonstrated in taxoid-sensitive and taxoid-resistant tumors in preclinical studies [6]. Activity has also been demonstrated in cell lines expressing the multidrug-resistant phenotype and in mdr-expressing murine tumor models [6]. The minimal recognition of larotaxel by P-glycoprotein may account for its ability to penetrate the blood–brain barrier, a feature with potential importance in breast cancer.
From phase I studies, the recommended dose of larotaxel as a single agent in solid tumors was 90 mg/m2, administered i.v. for 1 h every 3 weeks [7–11] with short-lasting neutropenia and neutropenic complications being the main dose-limiting toxic effects. Dose-dependent diarrhea was the most frequently reported nonhematologic toxicity.
We conducted a prospective, multicenter, open-label, nonrandomized, phase II trial in two cohorts of patients to assess the safety and efficacy of larotaxel in women with measurable MBC previously treated with a taxane. The primary end point was the overall response rate (ORR); secondary end points included time to progression (TtP), duration of response, OS, and safety.
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patients and methods |
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patient selection
Eligible patients were women with metastatic breast adenocarcinoma who had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) [12]. All patients were to have received previous chemotherapy with a taxane, discontinued at least 4 weeks before the first infusion of larotaxel. Table 1 describes the criteria used to distinguish patients on the basis of prior taxane response. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status of zero to two, age 18–75 years, and adequate organ function, including neutrophil count >2 x 109 per liter; platelet count >100 x 109 per liter; serum creatinine level within the upper limits of normal (ULN); total bilirubin level within ULN; and L-alanine aminotransferase (ALT) or L-aspartate aminotransferase (AST) and alkaline phosphatase
2.5 x ULN of the institutional norms or ALT/AST 1.5 x ULN and AP 5 x ULN of the institutional norms. Patients had to have discontinued hormone therapy and radiotherapy 4 weeks before registration, with prior radiotherapy to the bone marrow 25%.
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Patients who had received more than one prior regimen for advanced breast cancer or had a history of other prior malignancies, brain or leptomeningeal metastases, or peripheral neuropathy
grade 2 according to the National Cancer Institute’s (NCI) Common Toxicity Criteria (CTC) [13] were excluded. All patients provided written informed consent before participating in the trial. The study was conducted in accordance with the Declaration of Helsinki. The study protocol and consent form were approved by the local ethics committee or institutional review board at each clinical site.
drug administration
Larotaxel 90 mg/m2 was administered every 3 weeks as a 1-h i.v. infusion. Patients with baseline bone marrow involvement received 75 mg/m2 for the first cycle, which could be increased to 90 mg/m2 for subsequent cycles at the investigator's discretion. Premedication consisted of an antihistamine, an H2 receptor antagonist, and a corticosteroid. The use of granulocyte colony-stimulating factor (G-CSF) was allowed in accordance with the clinical practice guidelines of the American Society of Clinical Oncology [14]. Treatment continued until disease progression, unacceptable toxicity, or patient refusal.
The cycle length could be extended by 1 week on the day of planned treatment if the absolute neutrophil count was <1.5 x 109 per liter, platelet count <100 x 109 per liter or nonhematologic (NCI CTC grade 3/4) toxic effects that had not yet recovered to grade 1 (grade 0 for diarrhea). The dose of larotaxel was reduced to 75 mg/m2 after the first cycle for patients who experienced severe drug-related toxic effects. If a severe toxicity was observed after the initial dose reduction, treatment was discontinued.
efficacy assessment
The primary end point was ORR (complete + partial responses) in the per-protocol population, as determined in a blinded fashion by the External Response Review Committee (ERRC) according to RECIST. Secondary efficacy end points included TtP, duration of response (DOR), and OS. Tumor assessments were carried out every two cycles until disease progression or the administration of post-study anticancer therapy.
safety assessment
Hematology parameters were checked weekly or in the case of grade 4 neutropenia, every other day until resolution to grade 3. A complete blood count was also checked at the onset of fever grade 1. Adverse events were graded according to NCI CTC version 2.0 [13]. Febrile neutropenia was defined as grade 4 neutropenia with grade 1 fever, while neutropenic infection required documented infection. Any symptom, illness, or adverse experience that developed or worsened during treatment was considered an adverse event (AE).
statistical methods
A modified two-stage study design was utilized to minimize patient exposure to larotaxel in case of inefficacy [15]. To test the null hypothesis of a response rate 20% and 5% in the nonresistant and resistant groups, respectively, the study called for the initial enrollment of 25 and 20 per-protocol patients. If there were five or fewer responses among the nonresistant patients and none among the resistant patients, the trial was to be terminated. Otherwise, enrollment would proceed to a total of 50 per-protocol patients in the nonresistant group and 40 in the resistant group in stage 2. The sample size was designed with >90% power to detect a difference of 20% in the nonresistant group (ORR 20% versus 40%) and 15% in the resistant group (ORR 5% versus 20%), with a one-sided type I error <5%.
The primary end point of ORR [with 95% confidence interval (CI)] was analyzed in the intent-to-treat (ITT) and per-protocol population on the basis of both ERRC and investigator assessments. The per-protocol population included all eligible patients, assessable for response and free of any major protocol deviations during the study. The ITT population included all patients who received at least one dose of larotaxel.
The 95% CIs for ORR were calculated using the Clopper–Pearson exact method [16]. The Kaplan–Meier method was used to analyze variables of duration and events associated with possible censoring [17]. Statistical analyses were done using the SAS software (version 8.2).
Sanofi-aventis and the academic principal investigators were responsible for development of the protocol.
Data were collected and analyzed by Sanofi-aventis. Decisions related to the content and publication of the manuscript was made by the principal investigator in consultation with the coauthors. All authors had access to the primary data and assume responsibility for the completeness of the data reported.
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results |
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patient characteristics
Criteria for the two-stage study design were met, and the trial continued to full enrollment with 130 patients who received at least one dose of larotaxel (Table 2). In both groups, a majority of patients had received prior docetaxel- and anthracycline-based treatment. The median time between the last taxane-based chemotherapy and the first study drug infusion was 12.8 months (range 2.1–95.2 months) in the nonresistant group and 3.3 months (range 0.6–34.7 months) in the resistant group.
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The per-protocol population comprised 98 patients. In all, 27 of the 130 treated patients were excluded because of major protocol deviations, including failure to obtain a baseline tumor assessment as required (n = 6) and having at baseline a cancer diagnosis or history of a prior therapy not allowed per protocol (n = 12 and 13, respectively). Among these 27 patients, six were not assessable for response. An additional five patients were not assessable for response and therefore were not included in the per-protocol population. Fewer patients in the nonresistant than the resistant group were excluded from the per-protocol population (11% and 36%, respectively).
efficacy
The ORRs in the per-protocol populations were 45% (95% CI 32% to 59%) in the nonresistant group and 23% (95% CI 12% to 39%) in the resistant group (Table 3). In the treated populations, the ORRs were 42% (95% CI 30% to 55%) in the nonresistant group and 19% (95% CI 11% to 31%) in the resistant group. In each group, the number of responses satisfied the study design's requirement to demonstrate substantial clinical activity. The ORRs determined by investigator assessments were similar to those assessed by the ERRC (data not shown).
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Subgroup analyses were conducted to explore efficacy according to the degree of potential taxane sensitivity or insensitivity. Patients were stratified into subgroups using the time between the last taxane treatment and relapse (1–6 months, 6–12 months, 12–24 months, and > 24 months). The ORR estimated in each subgroup ranged between 38% and 50% in the nonresistant group, with overlapping CIs. In the group of taxane-resistant patients who had relapsed or progressed <1 month from their last prior taxane treatment (n = 30), a response rate of 17% (95% CI 6% to 35%) was observed. At a median follow-up of 33 months, the probability of survival at 2 years was 46% and 15% in the nonresistant and resistant groups, respectively. The median DOR in the treated population was 5.3 months (95% CI 4.0 to not evaluable) in the nonresistant group and 5.0 months (95% CI 2.6–7.1 months) in the resistant group. The median TtP in the treated population was 5.4 months (95% CI 4.0–6.8 months) in the nonresistant group and 1.6 months in the resistant group (95% CI 1.4–2.7 months) (Figure 1). In the per-protocol population, the median TtP was 5.8 months (95% CI 4.1–6.9 months) and 1.9 months (95% CI 1.4–3.7 months) in the nonresistant and resistant groups, respectively.
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safety
Seventeen patients (13%) discontinued treatment due to treatment-related adverse events. All patients experienced at least one AE, and hematologic toxicity was common (Table 4). The majority of patients (82%) experienced uncomplicated grade 3/4 neutropenia during the course of treatment. About 12 (9%) developed febrile neutropenia, and 11 (8%) others had neutropenic infections. G-CSF was administered with at least one cycle of therapy in 26% of patients in the nonresistant group and 30% of patients in the resistant group.
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The most common nonhematologic AEs were diarrhea, alopecia, fatigue, nausea, peripheral neuropathy, and myalgia. Grade 1 fluid retention (edema or lymphedema) was reported in 6 (5%) patients, and none experienced weight gain as a consequence. Hypersensitivity reaction (HSR) was reported in 7 (5%) patients, one of whom received incomplete premedication. Most HSR events were grade 1; one grade 2 event and one grade 3 event led to treatment discontinuation for two patients. The most common grade 3/4 AEs were fatigue, diarrhea, dyspnea, peripheral neuropathy, nausea, vomiting, and myalgia.
Three patients died within 30 days of receiving a larotaxel infusion. One patient with a history of chemotherapy-induced neutropenia experienced grade 4 stomatitis, neutropenic infection, and grade 3 diarrhea with dehydration related to the first dose. She died on day 9, secondary to septic shock. The second patient had grade 1 neutropenia at enrollment and received one dose of larotaxel 75 mg/m2. On day 10, she experienced grade 4 dyspnea and abdominal pain and died within 2 h. The investigator suspected an ischemic event related to the study drug. There were no clinical or radiological data to support possible bowel necrosis, embolism, ulcer, peritonitis, or tumor involvement in the abdomen at enrollment; no autopsy was carried out. The third patient received six cycles of larotaxel without dose delay or reduction. She developed meningismus, and malignant cells were documented in the cerebrospinal fluid. She was withdrawn from the study and died 25 days after the last larotaxel infusion.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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In this large, phase II study, larotaxel had good activity in patients with MBC who had previously received taxane-based therapy with a higher ORR (42%) in the nonresistant patient cohort than in the resistant cohort (19%). There were a substantial number of partial responses and disease stabilizations in the nonresistant cohort, with only 20% of patients having progressive disease as their best overall response compared with 50% in the resistant group, indicating greater activity for larotaxel in patients with nontaxane-resistant disease.
These results compare favorably with those achieved with second-line or salvage chemotherapy in previously treated MBC patients in other phase II trials. Docetaxel produced an 18% ORR as third-line therapy after prior anthracycline- and paclitaxel-based regimens [18]. When pegylated liposomal doxorubicin was compared with a comparator arm that included vinorelbine or mitomycin C and vinblastine as either second- or third-line therapy for taxane-refractory metastatic disease, ORRs of 10% and 12% were demonstrated in the pegylated liposomal doxorubicin, and comparator arms, respectively [19]. Capecitabine achieved a 26% ORR in patients with advanced breast cancer who had received two or three prior regimens, with at least one that was taxane based [20]. Ixabepilone, an epothilone compound, in second-, third-, or fourth-line therapy has recently reported an ORR of 12% in two separate trials in patients with taxane-resistant MBC [21, 22]. Finally, nanoparticle albumin-bound paclitaxel demonstrated an ORR of 21% as second-line therapy or more for metastatic disease [23].
The safety profile of larotaxel in this study was similar to that of the taxanes. Fatigue, alopecia, diarrhea, nausea, sensory neuropathy, and myalgia were common; the majority of these events were mild to moderate in severity. Fatigue was the most common grade 3/4 nonhematologic adverse event, in treated patients (15%). Peripheral neuropathy occurred in 62% of patients, and despite many patients reporting neuropathy at baseline, only 7% reached grade 3/4. It is important to note that the incidences of fluid retention (5%) and nail changes (10%) were relatively low compared with historical data for single-agent docetaxel in patients with MBC (59% and 44%, respectively) [24]. In addition, with a simple 1-day premedication regimen, the incidence of HSR was low (5%). Although the incidence of diarrhea was relatively high in this trial, it was generally manageable. Despite a high incidence of grade 3/4 neutropenia, febrile neutropenia was relatively uncommon, and the majority of patients did not receive G-CSF.
In conclusion, in patients with MBC who have received prior taxane therapy, larotaxel showed promising clinical activity and an acceptable safety profile when administered at a dose of 90 mg/m2 every 3 weeks. The taxanes are widely used in the management of early-stage breast cancer, increasing the need for new agents after taxane failure. These encouraging data support the evaluation of larotaxel in combination with other agents in randomized phase III trials in patients with MBC or locally advanced breast cancer previously treated with taxane-based therapy.
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Acknowledgements |
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We extend our thanks to the following to all the patients who participated in this study; the study's principal investigators and their site personnel—France (59): Drs Dieras, Romieu, Tubiana-Hulin, Lortholary, Ferrero, Levy, Bonnetere, and Delozier; United States (43): Drs Valero, Limentani, Kaufman, Bushunow, Modiano, and Thomas; Germany (12): Drs Von Minckwitz, Elermann, Kretzschmar, Morack, Clemens, and Kolbl; Italy (11): Drs Barone, Martoni, Conte, Sorio, and Galligioni; Spain (4): Drs Arumburo, Anton, and Gascon; The Netherlands (1): Dr Erdkamp; the MD Anderson Cancer Center's Department of Scientific Publications; and Sanofi-aventis personnel: Dalila Sellami, Sunil Gupta, Pierre Mancini, Sandrine Anneheim, Stephane Cheradame, Judy Ackerman, and Lynn Ceurvels.
Received for publication December 5, 2007.
Revision received February 11, 2008. Revision received February 12, 2008.
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