Received: 4 September 2010 / Accepted: 17 September 2010 / Published online: 14 October 2010 Ó Springer Science+Business Media, LLC.

Breast Cancer Res Treat (2011) 125:115 120 DOI 10.1007/s10549-010-1187-2 CLINICAL TRIAL Adjuvant dose-dense doxorubicin plus cyclophosphamide followed by dose-dense nab-paclitaxel is safe in women with early-stage breast cancer: a pilot study Nicholas Robert Lea Krekow Chris Stokoe Alicia Clawson Jose Iglesias Joyce O Shaughnessy Received: 4 September 2010 / Accepted: 17 September 2010 / Published online: 14 October 2010 Ó Springer Science+Business Media, LLC. 2010 Abstract Every-2-week (dose-dense) adjuvant doxorubicin (A) plus cyclophosphamide (C) followed by paclitaxel is a safe and effective adjuvant chemotherapy regimen. Every- 3-week nab-paclitaxel is safe and more effective at 50% higher dose than every-3-week paclitaxel in metastatic breast cancer (BC). This study evaluated the safety of adjuvant dose-dense AC followed by dose-dense nab-paclitaxel for early-stage BC. Women with operable, histologically confirmed BC received four cycles of dose-dense A 60 mg/m 2 plus C 600 mg/m 2 with pegfilgrastim, followed by dose-dense 260 mg/m 2 nab-paclitaxel (with pegfilgrastim given as needed). Endpoints were adverse events (AEs), including myelosuppression. Patients with neuropathy were followed until symptom improvement to grade B1. Thirty women received four cycles of dose-dense AC with no unanticipated AEs, one withdrew after AC therapy. Of 29 Presented, in part, at the Primary Therapy of Early Breast Cancer 2009: 11th International Conference, St Gallen, Switzerland, March 11 14, 2009 (Abst 0151). N. Robert (&) US OncologyVirginia Cancer Specialists, 8503 Arlington Blvd, #400, Fairfax, VA, USA e-mail: Nicholas.Robert@usoncology.com L. Krekow J. O Shaughnessy US Oncology/Texas Oncology, Dallas, TX, USA C. Stokoe Texas Oncology/US Oncology, Plano, TX, USA A. Clawson J. Iglesias Abraxis BioScience, Los Angeles, CA, USA J. O Shaughnessy Baylor Sammons Cancer Center, Dallas, TX, USA women who began nab-paclitaxel therapy, 27 received all the four doses (mean cumulative dose, 959 mg/m 2 ); one discontinued nab-paclitaxel after two doses due to unacceptable AEs. Four patients had a grade 3 nab-paclitaxelrelated neuropathy (no grade 4 event). Of 29 patients, 34% received pegfilgrastim during nab-paclitaxel therapy and 31% had a nab-paclitaxel treatment delay, mainly due to hematologic toxicity. Based on the Kaplan Meier probability estimates, the percentage of patients having B1 grade neuropathy at the end of treatment, 2, and 8 months after treatment were 59, 79, and 97%. Administering adjuvant dose-dense AC followed by 260 mg/m 2 dose-dense nabpaclitaxel was feasible in women with early-stage BC, with manageable AEs. Most patients had B1 grade neuropathy 2 months after treatment completion. Keywords Adjuvant Introduction nab-paclitaxel Early-stage breast cancer Clinical trials in node-positive breast cancer, including CALGB 9344, PACS 01, BCIRG 001, and NSABP B-28, demonstrated that the addition of taxanes to anthracyclines improves clinical efficacy in the adjuvant setting [1]. In particular, based on the CALGB 9344 trial, the US Food and Drug Administration approved paclitaxel as an additive after four cycles of doxorubicin (A) plus cyclophosphamide (C) chemotherapy [2]. In the CALGB 9741 trial, every-2- week (dose-dense) regimens of AC therapy, and paclitaxel administered either concurrently or sequentially produced significantly longer durations of disease-free survival (risk ratio = 0.74, P = 0.010) and overall survival (risk ratio = 0.69, P = 0.013, median follow-up = 36 months),

116 Breast Cancer Res Treat (2011) 125:115 120 compared to every-3-week (q3w) administration [3]. Administering dose-dense regimens with the use of pegfilgrastim did not increase toxicity compared with the q3w schedule. In addition, dose-dense, sequential, single-agent chemotherapy (A? paclitaxel? C) was found to be as effective as dose-dense, concurrent AC, followed by paclitaxel (AC? paclitaxel), suggesting that the shortened time interval between treatments was the main contributor to the greater efficacy seen with dose-dense compared with q3w therapy. nab-paclitaxel, a nanoparticle albumin-bound form of paclitaxel (ABRAXANE Ò ; Abraxis BioScience, Los Angeles, CA), was developed to avoid toxicities associated with the cremophor vehicle used in formulating paclitaxel [4 6]. In phase 1 studies, nab-paclitaxel weekly or q3w was tolerated at higher doses than that approved for paclitaxel, even without the use of corticosteroids to prevent hypersensitivity reactions associated with the paclitaxel [7, 8]. Clinical and preclinical studies demonstrated increased antitumor activity of nab-paclitaxel compared with equitoxic doses of paclitaxel [9, 10]. Antitumor activity of nab-paclitaxel (100 or 125 mg/m 2 weekly) was also demonstrated in taxane-refractory patients, with 14 16% response rate, 12 21% stable disease, 3.0 3.5 months of progression-free survival, and 9.1 9.2 months of overall survival [11]. In a phase 3 study, nab-paclitaxel given q3w was safe and more effective than paclitaxel q3w in patients with metastatic breast cancer [5]. nab-paclitaxel produced a higher objective response rate and longer time to tumor progression at 260 mg/m 2 q3w than q3w paclitaxel at 175 mg/m 2 (33% vs. 19% [P = 0.001] and 23.0 weeks vs. 16.9 weeks [P = 0.006]) [5]. Weekly nab-paclitaxel was safe and more effective than q3w nab-paclitaxel or q3w docetaxel [12]. However, no data exist regarding the safety and efficacy of dose-dense nab-paclitaxel. Based on these findings of superior efficacy of nabpaclitaxel compared with every-3-week paclitaxel, the current pilot study was designed to evaluate the safety dose-dense AC therapy followed by dose-dense nab-paclitaxel as adjuvant therapy in patients with early-stage breast cancer. Patients and methods This study was conducted in compliance with Good Clinical Practice, Guidelines of the International Conference on Harmonization, and the Declaration of Helsinki. The protocol and related materials were approved by the US Oncology, Inc., institutional review board (Houston, TX). Written informed consent was required from all the patients before participation. Patients Enrollment was initiated in March 2005 and the last patient completed enrollment on September 8, 2005. This study was conducted in C18- to B70-year-old women with operable, histologically confirmed, high-risk adenocarcinoma of the breast [defined as tumors that were T1-3, N1-2, or node-negative (N0) disease with tumors that are [2 cm, or N0 disease with tumors that are [1 cm and estrogen- and progesterone-receptor negative]. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1 and no evidence of metastatic disease at staging evaluation. HER2 status was not initially determined in this study, but only HER2 negative patients were enrolled after the adjuvant trastuzumab data became available in June 2005 [13]. Study design and assessments This open-label, multicenter, nonrandomized pilot study was designed to evaluate the safety of dose-dense (every-2- week) AC therapy followed by dose-dense nab-paclitaxel therapy in women with high-risk breast cancer. The endpoints were incidence of adverse events (AEs), serious AEs, premature discontinuations of study drug, and need for dose reductions or dose interruptions. Treatment consisted of dose-dense (every-2-week) A 60 mg/m 2 administered intravenously (IV) plus dose-dense C 600 mg/m 2 IV for four cycles, with pegfilgrastim 6 mg administered subcutaneously (SC) the day after each chemotherapy treatment (day 2). Doxorubicin plus cyclophosphamide therapy was followed by dose-dense nabpaclitaxel 260 mg/m 2 IV administered over 30 min for four cycles. Per protocol, pegfilgrastim was given to all the patients during AC therapy. Pegfilgrastim was given during nab-paclitaxel treatment if patients developed febrile neutropenia or if they could not receive nab-paclitaxel on schedule due to an absolute neutrophil count (ANC) of \1 9 10 9 /l on the day treatment was due. Patients did not receive premedication with corticosteroids or antihistamines prophylactically to prevent hypersensitivity reactions prior to nab-paclitaxel administration. All the unresolved AEs, as well as serious AEs observed during the study or that began within 30 days of the last study drug administration or end of study date, whichever was later, were followed by the until resolution or stabilization. Patients who developed peripheral neuropathy Cgrade 2 were followed until improvement of symptoms to grade 1 or 0. Peripheral neuropathy was assessed by the physician using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) version 3.0 at baseline, following completion of AC therapy, each nab-paclitaxel

Breast Cancer Res Treat (2011) 125:115 120 117 treatment, and at the end of study. Additionally, peripheral neuropathy was also assessed using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane) (version 4) Additional Concerns subscale. Complete blood counts (CBSs) and comprehensive metabolic panels (CMPs) were collected at baseline, on days 1 and 8 of every cycle, at the end of study, and at follow-up for AEs. Patients continued study treatment in the absence of disease progression or unacceptable toxicity. A 25% dose reduction was permitted for AC and/or for nab-paclitaxel for grade 3 or 4 AEs, and dose reductions were permanent. Statistical methods The 30-patient sample size was selected to provide preliminary information about the safety of the regimen. All the analyses were performed on the treated population (i.e., enrolled patients who received at least 1 dose of study drug). A formal safety analysis was done for each 10-patient cohort after completion of four cycles of nabpaclitaxel treatment. The incidence of AEs was summarized by NCI CTCAE version 3.0. To investigate the maximal degree of myelosuppression, the NCI CTCAE grade for absolute neutrophil, white blood cell, and platelet counts, and hemoglobin concentration were summarized using the most severe grade for each AC cycle and each nab-paclitaxel cycle of therapy based on clinical laboratory test values. The most severe grade overall was summarized for AC therapy (cycles 1 to 4), nab-paclitaxel therapy (cycles 5 to 8), and the entire regimen. The time from last dose of nab-paclitaxel until improvement of neuropathy to grade 0 or 1 was analyzed using Kaplan Meier methods for patients who received at least 1 dose of nab-paclitaxel. Summary statistics included the number and percentage of patients in each category for discrete variables, and the sample size, mean, median, standard deviation (SD), and range for continuous variables. SAS Ò Version 9.1 (SAS Institute Inc., Cary, North Carolina) was used to produce all data summaries. Results Patients Thirty women enrolled at 11 US Oncology practice sites in the United States and were evaluable for safety. Most of the patients were Caucasian (87%), \65 years of age (97%), and premenopausal (73%, Table 1). All the 30 (100%) patients had breast adenocarcinoma, 77% of whom had stage II disease at primary diagnosis. One patient (3%) had preexisting peripheral neuropathy (grade 1). Safety/tolerability All the 30 (100%) patients received four cycles of AC therapy with pegfilgrastim (Table 2). Twenty-nine (97%) of the 30 patients received treatment with nab-paclitaxel. One (3%) patient chose to discontinue treatment prior to receiving nab-paclitaxel. Of the 29 patients, 27 received four cycles of nab-paclitaxel treatment (Table 2). The mean (± SD) cumulative nab-paclitaxel dose was 959 (±150.1) mg/m 2 (Table 3). Patients received an average (±SD) of 92.5% (±9.33) of the planned protocol dose of nab-paclitaxel. Table 3 summarizes the cumulative dose, dose intensity, and percentage of protocol dose of all the therapeutic agents used in the study. Two patients discontinued treatment after receiving two cycles of nab-paclitaxel. One of the two patients, after receiving the initial full dose of nab-paclitaxel without delay, received a 25%-reduced second dose (195 mg/m 2 ) because of grade 1 edema and grade 2 peripheral neuropathy, and had a 1-week dose delay because her ANC had not recovered to C1 9 10 9 /l 2 weeks after cycle 1. Two weeks later, the patient discontinued treatment at her own Table 1 Demographic and other baseline characteristics Characteristic Age, years Median 48.0 Range 30 69 \65, n (%) 29 (97) C65, n (%) 1 (3) Race, n (%) White (nonhispanic, nonlatino) 25 (83) Black (African heritage) 2 (7) Asian 1 (3) White (Hispanic or Latino) 1 (3) Other 1 (3) Weight (kg) Median 67.5 Range 50 109 Menopausal status, n (%) Premenopausal 22 (73) Postmenopausal 8 (27) Hormone-receptor status, n (%) ER and/or PR positive 20 (67) ER and PR negative 10 (33) AC? nab-paclitaxela (N = 30) AC cyclophosphamide plus doxorubicin, ER estrogen receptor, nab nanoparticle albumin-bound, PR progesterone receptor a AC (doxorubicin 60 mg/m 2 plus cyclophosphamide 600 mg/m 2 IV every 2 weeks for four cycles) followed by nab-paclitaxel (260 mg/m 2 IV every 2 weeks for four cycles)

118 Breast Cancer Res Treat (2011) 125:115 120 Table 2 Treatment exposure N (%) of patients Patients who started AC therapy a 30 (100) Patients who started nab-paclitaxel therapy a 29 (97) b Did not complete four cycles 2 (7) of nab-paclitaxel therapy Received pegfilgrastim during 10 (34) nab-paclitaxel therapy Patients with dose reductions of AC therapy 2 (7) nab-paclitaxel therapy 9 (31) Grade 3 neurotoxicity 3 (10) Grade 2 neurotoxicity 4 (14) Other grade 3 nonhematologic toxicity c 1 (3) Grade 2 ALT 1 (3) Patients with treatment delays due to AC therapy 5 (17) nab-paclitaxel therapy 9 (31) Hematologic toxicity 7 (24) Nonhematologic toxicity 2 (7) AC cyclophosphamide plus doxorubicin, ALT alanine aminotransferase, nab nanoparticle albumin-bound a AC (cyclophosphamide 60 mg/m 2 plus doxorubicin 600 mg/m 2 IV every 2 weeks for four cycles) followed by nab-paclitaxel (260 mg/m 2 IV every 2 weeks for four cycles) b One patient withdrew from the study prior to receiving nabpaclitaxel c Leg pain discretion. The grade 2 peripheral neuropathy completely resolved 5 months later. The second patient who discontinued nab-paclitaxel therapy withdrew following cycle 2 due to unacceptable AEs (urinary incontinence, myalgia, and peripheral neuropathy, all of which were grade 3). Within 1 month of discontinuing therapy, the myalgia resolved completely and the incontinence resolved with sequelae (i.e., improved to grade 2 and then resolved completely by 6 months). The grade 3 peripheral neuropathy improved to grade 2 after 1 month and was considered stabilized 4 months later. None of the patients in this study had an unanticipated AE or an AE that resulted in death. The most frequently reported grade 2 4 AEs in [10% patients are presented in Table 4. During AC therapy, treatment-related grade 3 and 4 AEs (primarily neutropenia) were experienced by four (13%) and eleven (37%) patients, respectively. During nab-paclitaxel therapy, treatment-related grade 3 and 4 AEs (primarily neutropenia and peripheral neuropathy) were experienced by 13 (45%) and 3 (10%) patients, respectively. No episodes of febrile neutropenia or grade 4 peripheral neuropathy occurred during nab-paclitaxel therapy. Two (7%) patients had an AC dose reduction due to grade 3 febrile neutropenia and nine (31%) had a nab-paclitaxel dose reduction, primarily due to peripheral neuropathy [seven (24%) patients] (Table 2). Five (17%) patients had AEs starting during AC treatment that resulted in dose delay and nine (31%) had AEs starting during nab-paclitaxel treatment that resulted in dose delay. In both cases, the majority of the dose delays were due to hematologic toxicity. All the 30 (100%) patients in this study experienced at least one treatment-related nonhematologic AE. The most frequently reported events (all grades, for the entire regimen) were anemia, fatigue, nausea, and peripheral neuropathy (Table 4). In general, patients experienced more fatigue, nausea, alopecia, constipation, vomiting, mucositis/stomatitis, and dyspepsia during AC therapy and more peripheral neuropathy, and arthralgia during nab-paclitaxel therapy. During nab-paclitaxel therapy, ten (34%) patients received pegfilgrastim. Two patients received pegfilgrastim during cycle 5, i.e., the first cycle of nab-paclitaxel therapy, prophylactically for infectious complications during AC therapy. One of these patients continued pegfilgrastim prophylactically for all the 4 nap-paclitaxel cycles. The other patient did not receive pegfilgrastim at cycle 6. Six patients received pegfilgrastim during cycles 6 and 7, and 2 additional patients received pegfilgrastim during cycle 8. Pegfilgrastim administration was given to avoid repeated dose delay in patients whose ANC did not recover adequately for on-time nab-paclitaxel treatment or per investigator discretion to prevent severe neutropenia. Of the 29 patients who received nab-paclitaxel treatment, 27 (90%) experienced peripheral neuropathy. The maximum grade any time on study was 13 grade 1 (45%), 10 grade 2 (34%), 4 grade 3 (14%) peripheral neuropathy, and no grade 4 event was observed (Table 4). The only patient with preexisting grade 1 peripheral neuropathy developed a grade 3 event during nab-paclitaxel treatment. Based on Kaplan Meier probability analyses of the time from last dose of study drug to improvement of neuropathy to grade 1 or 0, the percentage of patients having Bgrade 1 neuropathy at the end of treatment, 2, and 8 months after treatment were 59, 79, and 97%, respectively (Fig. 1). Although this study did not address efficacy, no recurrences of tumor were observed during the follow-up period. Discussion In this study, administration of adjuvant, dose-dense AC therapy with pegfilgrastim followed by dose-dense nabpaclitaxel therapy with pegfilgrastim as needed was

Breast Cancer Res Treat (2011) 125:115 120 119 Table 3 Cumulative dose, dose intensity, and percentage of protocol dose of nab-paclitaxel, doxorubicin, and cyclophosphamide nab nanoparticle albuminbound, SD standard deviations a AC (doxorubicin 60 mg/m 2 plus cyclophosphamide 600 mg/m 2 IV every 2 weeks for four cycles) followed by nab-paclitaxel (260 mg/m 2 IV every 2 weeks for four cycles) feasible and had a manageable safety profile in women with early-stage breast cancer. In this study, over 90% of patients received the planned protocol dose of nab-paclitaxel, demonstrating the feasibility of administering the protocol specified dose. In general, except for neurotoxicity, the observed AEs and cycle delays in this study were comparable to that reported in the dose-dense AC therapy followed by dose-dense paclitaxel with pegfilgrastim in the phase 3 CALGB 9741 trial, even without the use of prophylactic pegfilgrastim during nab-paclitaxel therapy [3]. The incidence of treatment-related AEs and need for treatment discontinuation were similar to those reported for this patient population in CALGB 9741, and indicate no safety concerns for nab-paclitaxel therapy even without nab-paclitaxel a (N = 29) Doxorubicin a (N = 30) Cyclophosphamide a (N = 30) Planned cumulative dose (mg/m 2 ) 1040 240 2400 Cumulative dose during study (mg/m 2 ) Average 959.3 238.5 2385.0 SD 150.10 6.04 60.39 Median 1040.0 240.0 2400.0 Range 455 1040 210 240 2100 2400 Dose intensity (mg/m 2 /week) Average 120.3 29.5 295.0 SD 12.13 1.32 13.15 Median 127.7 30.0 300.0 Range 95 132 26 31 263 311 Protocol dose (%) Average 92.5 98.4 98.4 SD 9.33 4.38 4.38 Median 98.3 100.0 100.0 Range 73 102 88 104 88 104 Table 4 Incidence of most common treatment-related adverse events (reported for [10% patients who had grade 2 4 events) Adverse events, n (%) AC cycles 1 4 (N = 30) nab-paclitaxel cycles 5 7 (N = 29) Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4 Leukopenia a 6 (20) 2 (7) 3 (10) 0 10 (34) 12 (41) 4 (14) 1 (3) Anemia a 19 (63) 9 (30) 0 0 18 (62) 9 (31) 1 (3) 0 Neutropenia a 0 0 1 (3) 2 (7) 7 (24) 9 (31) 3 (10) 3 (10) Febrile neutropenia a 0 0 2 0 0 0 0 0 Fatigue 19 (63) 9 (30) 0 0 5 (17) 5 (17) 0 0 Peripheral neuropathy 0 0 0 0 13 (45) 10 (34) 4 (14) 0 Arthralgia 1 (3) 1 (3) 0 0 8 (28) 11 (38) 1 (3) 0 Nausea 20 (67) 8 (27) 0 0 1 (3) 0 0 0 Myalgia 1 (3) 1 (3) 0 0 3 (10) 4 (14) 2 (7) 0 Excluding alopecia AC cyclophosphamide plus doxorubicin, nab nanoparticle albumin-bound a Based on clinical laboratory test values; all the other values were based on adverse event reports prophylactic pegfilgrastim and premedication with corticosteroids and antihistamines to reduce the risk of hypersensitivity reactions. One-third of the patients received pegfilgrastim because their ANC did not recover to C1 9 10 9 /l by day 1 of next cycle (in 2 weeks). While all the patients received pegfilgrastim during AC therapy, two developed febrile neutropenia, but no febrile neutropenia was observed during nab-paclitaxel therapy without prophylactic pegfilgrastim. Most of the seven (24%) patients who had a nab-paclitaxel dose delay because of hematologic toxicity received pegfilgrastim for the remaining cycles. On the other hand, two-thirds of the patients did not require pegfilgrastim during the four cycles of nab-paclitaxel therapy.

120 Breast Cancer Res Treat (2011) 125:115 120 Fig. 1 Probability of time to resolution/reduction of peripheral neuropathy to grade 0 or 1 after the last dose of nab-paclitaxel Although grade 2 and 3 peripheral neuropathy was common during dose-dense nab-paclitaxel treatment (48% of patients), it was generally transient and improved significantly or resolved in most patients. Neuropathy in this study improved rapidly, with almost all the patients (97%) having grade 1 or complete resolution by 8 months after the last dose, confirming the reversibility of nab-paclitaxelinduced peripheral neuropathy. These results were consistent with observations in a previous phase 2 study where neuropathy occurred in 21, 9, and 22%, of patients receiving nab-paclitaxel 300 mg/m 2 every 3 week, 100 mg/m 2 weekly, and 150 mg/m 2 weekly, respectively, and was observed to improve rapidly with median time to improvement of 21 days [12]. These safety data provide evidence that four cycles of adjuvant dose-dense nab-paclitaxel 260 mg/m 2 without the routine use of pegfilgrastim following dose-dense AC can be safely administered to patients with early-stage breast cancer. Acknowledgments This study was sponsored by Abraxis BioScience, Los Angeles, California. Medical writing assistance was provided by Anita Nagypál Schmid, PhD, Abraxis BioScience. Conflict of interest Alicia Clawson and Jose Iglesias, MD, are employees and stockholders of Abraxis BioScience. Joyce O Shaughnessy, MD, is on Abraxis Speakers Bureau. The other authors have no conflict of interest to disclose. References 1. Campone M, Fumoleau P, Bourbouloux E, Kerbrat P, Roche H (2005) Taxanes in adjuvant breast cancer setting: which standard in Europe? Crit Rev Oncol Hematol 55:167 175 2. Hayes DF, Thor A, Dressler L, Weaver D, Broadwater G, Goldstein L et al. (2006) HER2 predicts benefit from adjuvant paclitaxel after AC in node-positive breast cancer: CALGB 9344. In: 2006 American Society of Clinical Oncology, Atlanta, June 2 6. J Clin Oncol 24:18s: Abstr#510 3. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ et al (2003) Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431 1439 4. Gradishar WJ (2006) Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother 7:1041 1053 5. Gradishar WJ, Tjulandin S, Davidson N, Shan H, Desai N, Bhar P et al (2005) Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794 7803 6. Henderson IC, Bhatia V (2007) Nab-paclitaxel for breast cancer: a new formulation with an improved safety profile and greater efficacy. Expert Rev Anticancer Ther 7:919 943 7. Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E et al (2002) Phase I and pharmacokinetic study of ABI- 007, a cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 8:1038 1044 8. Nyman DW, Campbell KJ, Hersh E, Long K, Richardson K, Trieu V et al (2005) Phase I and pharmacokinetics trial of ABI- 007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J Clin Oncol 23:7785 7793 9. Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A et al (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of Cremophor-free, albuminbound paclitaxel, ABI-007, compared with Cremophor-based paclitaxel. Clin Cancer Res 12:1317 1324 10. Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC et al (2005) Multicenter phase II trial of ABI-007, an albuminbound paclitaxel, in women with metastatic breast cancer. J Clin Oncol 23:6019 6026 11. Blum JL, Savin MA, Edelman G, Pippen JE, Robert NJ, Geister BV et al (2007) Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 7:850 856 12. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A et al (2009) Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 27:3611 3619 13. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659 1672