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Originally published as JCO Early Release 10.1200/JCO.2006.08.9102 on July 2 2007 © 2007 American Society of Clinical Oncology. Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Patients With Taxane-Resistant Metastatic Breast Cancer
From The University of Texas M.D. Anderson Cancer Center, Houston, TX; Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona; Servicio Oncologia, Hospital Clinico Universitario, Valencia; Hospital Clinico San Carlos, Prof Martin Lagos S/N, Madrid, Spain; Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Oncology and Hematology, University Hospital, Modena, Italy; Centre Georges-François Leclerc, Dijon, France; Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY; Dana-Farber Cancer Institute, Boston, MA; The Sarah Cannon Cancer Center, Nashville, TN; Institut Paoli-Calmettes, Centre Regional de Lutte Contre le Cancer, Service d'Oncologie Medicale 2, Marseille, France; and Bristol-Myers Squibb, Princeton, NJ Address reprint requests to Eva Thomas, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: est5151{at}yahoo.com
Purpose Ixabepilone (BMS-247550) is an epothilone analog that optimizes the properties of naturally occurring epothilone B. Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing apoptosis. This international phase II trial assessed the activity of ixabepilone in patients with metastatic breast cancer (MBC) that was resistant to taxane therapy. Patients and Methods MBC patients, who had experienced disease progression while receiving or within 4 months of taxane therapy (6 months if adjuvant taxane only), and who had a taxane as their last regimen, received ixabepilone (1- or 3-hour infusion of 50 mg/m2 or 3-hour infusion of 40 mg/m2 every 3 weeks). Results Of 49 patients treated with 40 mg/m2 ixabepilone during 3 hours, 35 (73%) had experienced disease progression within 1 month of their last taxane dose. The response rate was 12% (95% CI, 4.7% to 26.5%). All responses (n = 6) were partial; five of six patients had not responded to prior taxane therapy. In responders, the median response duration was 10.4 months. In 20 patients (41%), stable disease was the best outcome. Median time to progression was 2.2 months (95% CI, 1.4 to 3.2 months); median survival was 7.9 months. For treated patients across all cohorts (intent-to-treat population), the response rate was also 12% (eight of 66). Treatment-related adverse events in the study were manageable and primarily grade 1/2. Treatment-related neuropathy was mostly sensory and mild to moderate. Conclusion Ixabepilone (40 mg/m2 as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity and an acceptable safety profile in patients with taxane-resistant MBC.
Metastatic breast cancer (MBC) is considered incurable; however, an increase in the number of available new drugs and early detection have improved survival during the last 5 years.1 Currently, anthracyclines and taxanes are among the most effective drugs used in the treatment of MBC, but responses vary in efficacy and duration.2 Development of resistance to these agents is common, and the remaining therapeutic options have limited efficacy. The natural epothilones and their analogs are a novel class of microtubule-stabilizing agents derived from the myxobacterium Sorangium cellulosum. The 16-member macrolides bind tubulin and result in apoptosis. Ixabepilone (BMS-247550) is an epothilone B analog that optimizes the antineoplastic properties of the naturally occurring product. It is a potent inducer of microtubule stabilization,3 and has demonstrated efficacy in taxane-sensitive and taxane-resistant tumors in vitro and in vivo.3,4 The efficacy of ixabepilone in resistant tumors may be explained by the fact that ixabepilone has low susceptibility to key mechanisms of tumor resistance, including changes in proportions of tubulin isotypes, tubulin mutations, and overexpression of cell membrane transporters.3,5 Ixabepilone has also shown synergy with other cytotoxic agents.6,7 Previously reported phase I and II studies with ixabepilone, using various doses and schedules, have demonstrated a tolerable safety profile and evidence of objective responses in a range of tumor types.4,8-13 We conducted a phase II international, multicenter, open-label, clinical trial to evaluate the efficacy of ixabepilone in patients with taxane-resistant MBC. Secondary objectives included safety, response duration, time to progression, and overall survival. This report focuses on the efficacy and safety of 40 mg/m2 ixabepilone administered as a 3-hour infusion, and also summarizes the efficacy and safety of 50 mg/m2 ixabepilone administered as a 1- and 3-hour infusion.
Eligibility Eligible female patients were aged  18 years with a life expectancy of 12 weeks and had a diagnosis of histologically or cytologically confirmed MBC (stage IV or recurrent) that was measurable bidimensionally. Prior treatment must have included an anthracycline-based regimen. Patients must have received docetaxel-based or paclitaxel-based chemotherapy as their most recent chemotherapy, and must have experienced disease progression during therapy or within 4 months of their last dose immediately before study enrollment. Adequate hepatic, renal, and hematologic function was required, as was an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients were excluded if they had received more than three prior chemotherapy regimens for metastatic disease or had grade 2 neuropathy (National Cancer Institute Common Toxicity Criteria [CTC] version 2.0) at baseline. Concurrent hormonal therapy or trastuzumab use was not permitted.
Study Design and Treatment Dosing continued every 3 weeks for a maximum of 18 cycles, unless there was evidence of progressive disease (PD; 25% or greater increase in overall sum of the products of diameters of all target lesions in reference to the smallest sum recorded at or following baseline or unequivocal progression of existing non-target lesions overall or presence of new lesions) and/or patients met the discontinuation criteria (physician's decision, patient's request, study drug toxicity, disease progression or relapse, death). Patients with stable disease (SD; failure to observe complete response [CR] or partial response [PR], in the absence of any progressive or new lesions, confirmed on at least two consecutive observations at least 4 weeks apart) or PR (50% of greater decrease in overall sum of the products of diameters of all target lesions in reference to the baseline sum, persistence of one or more nontarget lesions with no new lesions confirmed on at least two consecutive observations at least 4 weeks apart) were treated until disease progression for a maximum of 18 cycles. Patients were assessed every 3 months after treatment discontinuation. Patients who experienced any drug-related toxicities were monitored at least every 4 weeks until all drug-related toxicities were resolved, stabilized, returned to baseline, or were deemed irreversible. Dose reductions were made depending on the treatment tolerability. This study was conducted in accordance with the US Food and Drug Administration, the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and the institutional review board/independent ethics committee.
Response Assessment
Toxicity Assessment
Statistical Design and Methods For the patients enrolled onto the 40 mg/m2 3-hour cohort, analyses consisted of the point estimate for response rate and the adjusted two-sided exact 95% CIs based on the method proposed by Atkinson and Brown.18 For the 50 mg/m2 cohort, the 95% CI for the response rate was assessed using the Clopper-Pearson method.19 Discrete variables were summarized with the number and proportion of patients classified into each category. Estimates of the median duration of response, TTP, and survival, with their associated 95% CIs, were calculated for each cohort using the Kaplan-Meier product-limit method.20 The safety of ixabepilone was assessed through medical review of AEs and laboratory abnormalities in hematology and serum chemistry parameters, classified according to CTC version 2.0 criteria. Continuous variables, such as safety and laboratory data, were summarized using descriptive statistics.
Patients Sixty-six patients were enrolled and treated between May 2001 and April 2004 in 11 study centers (five in the United States, three in Spain, two in France, and one in Italy). At the beginning of the study, ixabepilone was administered as a 50 mg/m2 infusion during 1 hour, subsequently during 3 hours, and then as a 40 mg/m2 infusion during 3 hours every 3 weeks. This report focuses primarily on the clinical activity and safety of ixabepilone administered as a 3-hour infusion at a dose of 40 mg/m2. The baseline demographic and clinical characteristics of the patients in the 40 mg/m2 3-hour cohort are summarized in Table 1. All 49 patients had primary breast surgery for their disease; the majority received prior radiation (78%) and hormonal (55%) therapy. All patients received prior chemotherapy, with the majority (86%) receiving at least two prior chemotherapy regimens. All patients had received at least one prior taxane-containing regimen; 31% received at least two. Ninety-eight percent of patients had a taxane-containing regimen as their most recent in the metastatic setting (26 patients, docetaxel; 22 patients, paclitaxel) and 73% of patients had experienced progression within 1 month of their last dose. Four patients (8%) had received previous trastuzumab treatment.
Before ixabepilone therapy was started, the most frequently reported baseline symptoms in this cohort included alopecia (37%), fatigue (31%), and sensory neuropathy (31%). No patient had baseline sensory neuropathy grade 2. Patients received a median of three cycles (range, one to 15 cycles) and a median cumulative dose of 120 mg/m2 (range, 39.6 to 489.8 mg/m2) of ixabepilone chemotherapy. Thirty-six patients (74%) discontinued treatment because of disease progression or relapse and eight patients (16%) discontinued because of study drug toxicity, five of whom had treatment-related neurotoxicity. Two patients (4%) discontinued at their own request, two patients (4%) discontinued due to death, and one patient (2%) discontinued as a result of physician decision.
Efficacy
The median TTP for all patients receiving ixabepilone 40 mg/m2 during 3 hours every 3 weeks was 2.2 months (95% CI, 1.4 to 3.2 months; Fig 1A). The median survival was 7.9 months (95% CI, 6.1 to 14.5 months; Fig 1B).
Among eight patients treated with ixabepilone 50 mg/m2 during 1 hour, two achieved a PR (duration of responses, 5.5 and 2.9 months, respectively); four patients achieved SD as their best overall response. The median TTP for patients on this regimen was 3.8 months (95% CI, 1.1 to 5.5 months). None of the nine patients receiving ixabepilone 50 mg/m2 during 3 hours achieved a PR, and four (44%) had SD. The median TTP for all patients in this cohort was 1.4 months (95% CI, 1.2 to 3.8 months). For the ITT population, the median TTP was 2.3 months (95% CI, 1.5 to 3.1; Fig 2A). The response rate was 12% (eight of 66 patients; 95% CI, 5.4% to 22.5%; Table 2). All eight patients had PR; the median duration of response was 8.5 months (95% CI, 6.3 to 22.0 months; Fig 2B). SD was the best response in 42% of patients (28 of 66).
Toxicities Treatment-related adverse events (TRAEs) were manageable; the majority were grade 1/2 (55%; Table 4). Among patients on the 40 mg/m2 during 3 hours regimen, 48 patients (98%) reported at least one TRAE, and 21 (43%) reported at least one grade 3/4 TRAE. The most frequent grade 3 TRAEs were fatigue (27%), sensory neuropathy (12%), myalgia (10%), nausea (6%), and vomiting (6%).
Eleven (22%) of the 49 patients had treatment-related serious adverse events (SAEs; defined per protocol as fatal or life threatening, resulting in death or permanent disability, requiring or prolonging patient hospitalization, cancer, congenital anomaly, overdose, resulting in the development of drug dependency or drug abuse or an important medical event). Febrile neutropenia was reported as a treatment-related SAE in three patients (6%; two febrile neutropenia; one infection with neutropenia). Other treatment-related SAEs included vomiting, diarrhea, constipation, anemia, and fever (in two patients each), and nausea, stomatitis/pharyngitis, dysphagia, infection without neutropenia, hypotension (orthostatic hypotension), CNS hemorrhage/bleeding (reported by the investigator as hypovolemic shock secondary to severe diarrhea and vomiting), hemorrhage/bleeding with grade 3/4 thrombocytopenia, sensory neuropathy, neurology-other (gastroparesis, orthostatic hypotension), toxidermia, alkaline phosphatase elevation, and gamma glutamyl transferase elevation (in one patient each). Most treatment-related neuropathy was sensory, and mild to moderate in severity (grade 1 or 2). Sensory neuropathy was grade 1 or 2 in 25 patients (51%) and grade 3 in six patients (12%), three of whom discontinued treatment because of this event. Resolution or improvement to grade 1 was seen in five of the six patients with grade 3 sensory neuropathy (Fig 3). The sixth patient discontinued due to grade 3 sensory neuropathy characterized by paresthesias and hypovolemic shock resulting from severe diarrhea and vomiting after three cycles. This patient's neuropathy did not resolve before her death from PD 2 months later. No patients experienced grade 4 sensory neuropathy. One patient had motor neuropathy (grade 2) and one patient had autonomic neuropathy (grade 2 gastroparesis, orthostatic hypotension). Sensory neuropathy was managed mainly with dose reductions (12 of 49 patients [24%] had their ixabepilone dose reduced because of treatment-related neuropathy).
The most common grade 3/4 hematologic abnormality in this cohort was neutropenia (grade 3, 33%; grade 4, 20%). Only six patients (12%) required growth factor support for neutropenia during treatment. Treatment-related febrile neutropenia occurred in three patients (6%; two febrile neutropenia; one infection with neutropenia). An additional patient had an unrelated SAE of infection with neutropenia after study discontinuation (within 30 days of last dose) and after initiation of follow-up therapy.
PD was cited as the most common reason for discontinuing study treatment (36 of 49 patients; 74%). Eight patients (16%) discontinued because of TRAEs. Five patients (10%) discontinued because of neuropathy after a median of six cycles (range, three to eight cycles); three patients had sensory neuropathy, one patient had sensory and motor neuropathy, and one patient had autonomic neuropathy (three of these patients achieved a PR). The three patients (6%) who discontinued due to sensory neuropathy received three, six, and seven cycles of ixabepilone therapy, respectively. For two of these patients, the sensory neuropathy had lessened to grade Five patients (10%) died during the study or within 30 days of their last dose of ixabepilone; no deaths were judged to be related to ixabepilone therapy. Causes of death were PD (two patients), acute respiratory disease (secondary to pulmonary embolism), pneumonia, and subsequently administered paclitaxel plus vinorelbine toxicity (grade 4 infection with neutropenia [septic shock]; one patient each). Secondary objectives of the study were to evaluate the safety of ixabepilone administered at a dose of 50 mg/m2 1- and 3-hour infusions. Among the eight patients treated with 50 mg/m2 during 1 hour, three patients (38%) developed treatment-related grade 3 sensory neuropathy. Three patients discontinued due to treatment-related sensory neuropathy (two patients with grade 3; one patient with grade 2), one of whom had additional AEs leading to discontinuation. Among the nine patients in this cohort, five (56%) developed febrile neutropenia (one [11%] grade 1; three [33%] grade 2; one [11%] grade 3) and two patients (22%) developed mucositis/stomatitis (one [11%] grade 1; one [11%] grade 2). Two patients (22%) discontinued treatment because of AEs (one arthralgia, one neuropathic pain).
Among the 49 patients enrolled at the dose of 40 mg/m2 during 3 hours in this study, six (12.2%) achieved a PR to ixabepilone; five of these six patients had not responded to prior taxane treatment. One had received paclitaxel and docetaxel, and one had undergone high-dose chemotherapy with peripheral-blood stem-cell transplantation. Overall, 73% of patients had experienced disease progression on their taxane therapy within 1 month of enrollment. The response rate for ixabepilone was similar in the ITT analysis (response rate, 12%). The small number of patients treated in the two 50 mg/m2 cohorts precluded clinically meaningful interpretation of the results for these regimens. The results of this study are consistent with preclinical evidence showing a lack of cross-resistance between ixabepilone and taxanes. In the current study, taxane was to be the most recent therapy and each patient had proven progression while receiving treatment or within 4 months of the last dose. Thus, the patient population had tumors that demonstrated resistance to a microtubule-stabilizing agent. In other studies of single agents in patients with PD during paclitaxel treatment, capecitabine or docetaxel monotherapy yielded response rates of 20% and 18%, respectively.21,22 Although progression while receiving paclitaxel was a requirement for both studies, it was not required to have taxane as the most recent therapy, as it was in this study. Ixabepilone has shown low susceptibility to key mechanisms of chemotherapy resistance, including changes in proportions of tubulin isotypes, tubulin mutations, and cell membrane transporters3,5; this may explain the efficacy of ixabepilone in resistant tumors. Ixabepilone therapy was well tolerated in this study, with manageable adverse effects. Fatigue and sensory neuropathy were the most common adverse effects. Febrile neutropenia occurred in 6% of patients receiving the 40 mg/m2 dose. In contrast to paclitaxel and docetaxel, ixabepilone treatment did not require corticosteroid premedication because hypersensitivity reactions are rare with this drug. Sensory neuropathy was most common in those patients treated with the initial 50 mg/m2 during 1 hour infusion. The subsequent dose and schedule adjustment to 40 mg/m2 during 3 hours reduced both the incidence and severity; only 12% of patients developed grade 3 sensory neuropathy compared with 38% at 50 mg/m2 during 1 hour. The rate of grade 3 neuropathy seen with ixabepilone in this study falls within the published incidence with taxanes (range, 2% to 32%).23-28 It will be important to refine the dosing of ixabepilone further to minimize associated sensory neuropathy. In summary, ixabepilone has demonstrated antitumor activity in patients with MBC resistant to prior taxane therapy for whom few therapeutic options exist. Ixabepilone, for the most part, was well tolerated, with few grade 3 toxicities; it does not require corticosteroid premedication, and the schedule (once every 3 weeks) is convenient for patients. Collectively, these results warrant the continued investigation of this agent. Additional trials are ongoing with ixabepilone, including two phase III randomized studies of ixabepilone administered at 40 mg/m2 during 3 hours plus capecitabine compared with capecitabine alone. Another study is evaluating the efficacy of ixabepilone in patients previously treated with an anthracycline, a taxane, and capecitabine.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Pierre Fumoleau, Bristol-Myers Squibb; Edgardo Rivera, Bristol-Myers Squibb; Valerie Poulart, Bristol-Myers Squibb; Judith Klimovsky, Bristol-Myers Squibb; David Lebwohl, Novartis Leadership: N/A Consultant: Pierfranco Conté, Bristol-Myers Squibb; Pierre Fumoleau, GlaxoSmithKline, Roche, Schering-Plough; Howard A. Burris, Bristol-Myers Squibb; José Baselga, Roche, Amgen, AstraZeneca, Bristol-Myers Squibb, Merck; Miguel Martin, Bristol-Myers Squibb, Sanofi-aventis, Novartis Stock: David Lebwohl, Novartis, Bristol-Myers Squibb Honoraria: Monica Fornier, Bristol-Myers Squibb; Howard A. Burris, Bristol-Myers Squibb; José Baselga, Roche, Merck, GlaxoSmithKline; Miguel Martin, Pfizer, Bristol-Myers Squibb, Pharmamar, Roche Research Funds: Eva Thomas, Bristol-Myers Squibb; Josep Tabernero, Bristol-Myers Squibb; Monica Fornier, Bristol-Myers Squibb; Craig A. Bunnell, Bristol-Meyers Squibb; José Baselga, Bristol-Myers Squibb Testimony: N/A Other: N/A
Conception and design: Pierfranco Conté, José Baselga, David Lebwohl Provision of study materials or patients: Josep Tabernero, Monica Fornier, Pierre Fumoleau, Linda T. Vahdat, Craig A. Bunnell, Howard A. Burris, Patrice Viens, José Baselga, Edgardo Rivera, Valentina Guarneri Collection and assembly of data: Josep Tabernero, Monica Fornier, Ana Lluch, Craig A. Bunnell, Howard A. Burris, Valentina Guarneri, David Lebwohl, Miguel Martin Data analysis and interpretation: Eva Thomas, Josep Tabernero, Linda T. Vahdat, Howard A. Burris, Valerie Poulart, Judith Klimovsky, David Lebwohl Manuscript writing: Eva Thomas, Josep Tabernero, Linda T. Vahdat, Craig A. Bunnell, Miguel Martin Final approval of manuscript: Eva Thomas, Josep Tabernero, Monica Fornier, Pierfranco Conte, Pierre Fumoleau, Linda T. Vahdat, Craig A. Bunnell, Howard A. Burris, Patrice Viens, José Baselga, Edgardo Rivera, Valentina Guarneri, Judith Klimovsky, David Lebwohl, Miguel Martin
The following investigators and institutions participated in this trial (primary investigators are listed first for each institution): Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 70030 (Eva Thomas, Daniel Booser, Massimo Cristofanilli, Francisco Esteva, Gabriel Hortobagyi, Lajos Pusztai, Edgardo Rivera, Melanie Royce, Karin Hahn); Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115 (Craig A. Bunnell, Eric Winer, Irene Kuter, Jerry Younger, Harold Burstein, Lawrence Shulman, Susana Campos, Judy Garber, Rochelle Scheib, Lyndsay Harris, Ursula Matulonis, Leroy Parker, Wendy Chen, Leif Ellisen, Paula Ryan, Steven Come, Nadine Tung, Lowell Schnipper, Virginia Borges, Ann Partidge, Susan Domchek); Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (Monica Fornier, Teresa Gilewski, Larry Norton, Jacqueline Bromberg, Clifford Hudis, Maura Dickler, Pamela Munster, Jeffery Ye, Chau Dang, Mary Ellen Moynahan, Maria Theodoulou, Mark Robson, Mark Moasser, Nancy Sklarin, Gabriella D' Andrea, Diana Lake, Violante Currie, Andrew Seidman, Adriadne Bach); Hospital Clinico San Carlos, Prof Martin Lagos S/N, 2840 Madrid, Spain (Miguel Martin, Antonio Casado); The Sarah Cannon Cancer Center, 250 25th Ave North, Suite 412, Nashville, TN 37203 (Howard Burris, Denise Yardley, John Barton, Victor Gian, F. Anthony Greco, Jeffrey Patton, Anthony Meluch, Mitchell Toomey, Fernando Miranda, Eric Raefsky, Charles McKay, Nancy Peacock, John Hainsworth, Dana Thompson, Michel Kuzar); University Hospital, via del Pozzo 71, 4100 Modena, Italy (Pierfranco Conté, Valentina Guarneri); Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 (Edith Perez, Elizabeth Johnson, Gerardo Colon-Otero, William Maples, Lawrence Solberg, Philip Kuriakose, Cristopher Thomas, Alvaro Moreno-Aspita, Han Tun, Winston Tan, Stephen Myers); New York Presbyterian Hospital/Columbia and Cornell Campuses, 425 East 61st St, Eighth Floor, New York, NY 10021, and 177 Fort Washington Ave, Milstein Hospital 6-435, New York, NY 10032 (Linda Vahdat, Amy Tiersten, Dawn Hershman); University of Alabama at Birmingham Comprehensive Cancer Center, 1824 6th Ave South, Birmingham, AL 35294-3300 (Andres Forero, Albert LoBuglio, John Rinehart, Carla Falkson, Lisle Nabell); Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall D'Hebron 119 to 129 08,035, Barcelona, Spain (Josep Tabernero, Sonia Gonzalez, José Baselga); Servicio Oncologia, Hospital Clinico Universitario, Avda Blasio Ibanez, 17 46,010, Valencia, Spain (Ana Lluch, Jose Manuel Sastre Albiach); Centre Rene Gauducheau, Site Hopitalier Nord de Nantes, Boulevard Jacques Monod, 44805 Saint-Herblain Cedex (Pierre Fumoleau, Emmanuelle Bourbouloux, Valerie Delecroix, Dominique Berton-Rigaud); Institut Paoli Calmettes, Centre Redional de Lutte Contre le Cancer, Service d'Oncologie Medicale 2, 232 bd Sainte Marguerite, 13273 Marseille Cedex 09, France (Patrice Viens, Ach Braud, M. Vittot, Francois Bertucci, Anthony Goncalves, Malika Chaouche, Gwenaelle Gravis, Frederic Viret).
The authors thank Laura Whitaker, the trial protocol manager, for her coordination and management of this trial, and Michelle Utton, PhD, Medicus International, for her editorial assistance.
published online ahead of print at www.jco.org on July 2, 2007. Supported by Bristol-Myers Squibb (editorial). Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
progressing to grade 2 at cycles 2, 3, 4, 5,6, 7, one patient with motor neuropathy; 
progressing to grade 3 at cycles 1, 2, 3, 6, 8; 
progressing to grade 2 at cycles 1, 2, 3, 4; ||resolving at cycle 6 and FO1; ¶resolving at cycles 3 and 5 and at FO1; #resolving at cycle 2 and at FO1 and FO2. F, follow-up; C, cycle.
1 within 1 to 2 months of the end of therapy. 
