Breast Cancer Research and Treatment

, Volume 108, Issue 2, pp 241–250

Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer

Authors

  • Keun Seok Lee
    • Center for Breast Cancer, Research Institute and Hospital, National Cancer Center
    • Korean Cancer Study Group
  • Hyun Cheol Chung
    • Yonsei Cancer Center, Yonsei University College of Medicine
    • Korean Cancer Study Group
  • Seock Ah Im
    • Department of Internal MedicineSeoul National University College of Medicine
    • Korean Cancer Study Group
  • Yeon Hee Park
    • Department of Internal MedicineKorea Cancer Center Hospital
    • Korean Cancer Study Group
  • Chul Soo Kim
    • Comprehensive Cancer Center, Inha University Hospital and College of Medicine
    • Korean Cancer Study Group
  • Sung-Bae Kim
    • Department of Internal MedicineAsan Medical Center, University of Ulsan College of Medicine
    • Korean Cancer Study Group
  • Sun Young Rha
    • Yonsei Cancer Center, Yonsei University College of Medicine
    • Korean Cancer Study Group
  • Min Young Lee
    • Samyang Corporation
    • Center for Breast Cancer, Research Institute and Hospital, National Cancer Center
    • Korean Cancer Study Group
Clinical Trial

DOI: 10.1007/s10549-007-9591-y

Cite this article as:
Lee, K.S., Chung, H.C., Im, S.A. et al. Breast Cancer Res Treat (2008) 108: 241. doi:10.1007/s10549-007-9591-y
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Abstract

Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel. This single arm, multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM in patients with histologically confirmed metastatic breast cancer (MBC). Forty-one women received Genexol-PM by intravenous infusion at 300 mg/m2 over 3 h every 3 weeks without premedication until disease progression or intolerability. A total of 331 chemotherapy cycles were administered, with a median of 8 cycles per patient (range, 1–16). Overall response rate was 58.5% (95% CI: 43.5–72.3) with 5 complete responses and 19 partial responses. Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5–73.7), and two responses were reported in four patients treated in the second-line setting for their metastatic disease. The median time to progression (TTP) for all patients was 9.0 months (range, 1.0–17.0+ months). Grade 3 non-hematologic toxicities included sensory peripheral neuropathy (51.2%), and myalgia (2.4%). Eight patients (19.5%) experienced hypersensitivity reactions, with grade 3 in two patients. Hematologic toxicities were grade 3 and 4 neutropenia (51.2 and 17.1%, respectively), and grade 1 and 2 thrombocytopenia (22.0%). Notably, no febrile neutropenia was observed. Genexol-PM appears a promising new paclitaxel in view of significant efficacies. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted.

Keywords

Breast cancerClinical trialGenexol-PMPhase II

Introduction

Paclitaxel, which exerts its anticancer effects by interfering with microtubule function, is one of the most effective chemotherapeutic agents for the treatment of metastatic breast cancer (MBC) [1]. Due to its hydrophobicity, intravenous administration of paclitaxel requires the use of solubilizing agents such as Cremophor EL (CrEL) [2], which compromise the therapeutic value of paclitaxel in many aspects. CrEL often contributes to hypersensitivity reactions including hypotension or dyspnea with bronchospasm, some of which are major and potentially life-threatening. Minor allergic reactions such as transient rashes and flushing also may occur. Despite pretreatment with corticosteroids and histamine antagonists, minor reactions still occur in 10–44% of all patients, with 1–3% of patients experiencing potentially fatal reactions [35]. CrEL may also act as a potential cofactor for the development of peripheral neuropathy [6]. In addition, CrEL can leach di-(2-ethylhexyl) phthalate (DEHP), a form of plasticizer, from the polyvinylchloride bags and infusion sets used routinely in clinical practice. As DEHP is suspected to be a hepatotoxin, carcinogen, teratogen, and mutagen [7, 8], special infusion sets must be used clinically when administering CrEL-based paclitaxel to circumvent this leaching problem.

Given the drawbacks resulting from the use of CrEL as a solubilizer, new CrEL-free formulations of paclitaxel are of great interest for development in clinical use [9]. One novel formulation of paclitaxel is Genexol-PM (Samyang Co., Seoul, Korea), a form of paclitaxel formulated with sterile, lyophilized polymeric micells that allow intravenous delivery of paclitaxel without CrEL. The polymeric micelle formulation is composed of hundreds of low molecular weight, nontoxic, and biodegradable amphiphilic diblock copolymers which include monomethoxy poly(ethylene glycol)-block-poly(D,L-lactide), and has a great potential in terms of water solubility, in vivo stability, and the nanoscopic size (a diameter of 20–50 nm) of the micellar structure [10, 11].

A phase I study established that Genexol-PM administered at 390 mg/m2 intravenously for 3 h every 3 weeks was the maximum tolerable dose (MTD) in humans. Dose-limiting toxicities were neuropathy, myalgia, and neutropenia. No hypersensitivity reactions were observed in any patients despite the absence of antiallergic premedication. The recommended dosage for phase II studies was 300 mg/m2 [10].

We conducted a phase II trial to explore the efficacy and safety of Genexol-PM at the recommended dose of 300 mg/m2 in patients with MBC. The primary endpoint was tumor response rate. Secondary objectives included the evaluation of toxicity, time to progression (TTP), and overall survival.

Patients and methods

Study design

The study was designed as a two-stage phase II, nonrandomized, single-arm trial, using Genexol-PM at a dose of 300 mg/m2, administered intravenously over a period of 3 h every 3 weeks until disease progression, unacceptable toxicity, or patient withdrawal. Patients were enrolled at the six major hospitals in Korea. The protocol and all related materials were approved by the local institutional review boards. The study was conducted in compliance with the Good Clinical Practice guidelines of the International Conference on Harmonization, and the Declaration of Helsinki. All patients provided informed written consent before participating.

Eligibility of patients

Patients eligible for this study were nonpregnant women having histologically confirmed breast cancer with evidence of metastasis. Prior anthracycline-containing regimens were allowed when patients developed recurrence after ≥6 months from the last dose in an adjuvant setting, or once patients responded to the therapy in a metastatic setting. In case of taxane administration, as in adjuvant or neoadjuvant chemotherapy, patients were eligible for the study when the taxane-free interval was ≥12 months.

Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, expected survival of >3 months, and measurable disease using the Response Criteria in Solid Tumors (RECIST) [12]. They had adequate organ function, as indicated by an absolute neutrophil count ≥1,500/μl, a platelet count ≥100,000/μl, serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminases ≤3 times the ULN, and serum creatinine ≤ULN.

Exclusion criteria included central nervous system metastases, uncontrolled infection, serious psychiatric disorders, heart failure, myocardial infarction within the previous 6 months, a history of epilepsy or use of anticonvulsant medications, and prior malignancies other than nonmelanoma skin cancer or in situ cervical cancer within the previous 5 years.

Treatment and planned dose adjustments

Genexol-PM at a dose of 300 mg/m2 was diluted in 500 ml of 5% dextrose solution and infused intravenously over 3 h on an outpatient basis. Prophylactic medications including antiemetics, steroids, or antihistamines were not routinely recommended by protocol, but permitted after the first treatment cycle at the discretion of the investigator. Specialized IV infusion sets or in-line filtration were not used. Treatment was repeated every 3 weeks until either disease progression or unacceptable toxicity occurred. Toxicities were assessed at baseline and at the conclusion of each cycle of treatment using NCI Common Toxicity Criteria version 2.0 [13]. Dose reductions of 20% of the original dose (from 300 to 240 mg/m2) were required for grade 4 hematologic toxicity, neutropenic fever or sepsis, or grade 3 or 4 nonhematologic toxicity. If any of these adverse events (AEs) recurred after initial resolution, reinitiation of Genexol-PM at a further reduced dose of 190 mg/m2 was recommended for all subsequent cycles.

Evaluation of tumor response

Measurable disease was assessed by imaging using the RECIST criteria [12]. Patients underwent baseline imaging within 4 weeks prior to enrollment, and were scanned with the imaging method used for a given tumor at baseline before every other cycle. All partial and complete responses were confirmed at least 4 weeks later with repeat imaging.

Statistical design and methods

The primary endpoint of the trial was response rate; a 50% response rate was considered to be of interest, and a response rate of <30% was considered unacceptable. The study used a two-stage group sequential design [14], with 90% power to detect a response rate of 50% and <5% chance of continuing the trial if the response was <30% (Fig. 1). In the first stage, we were required to enroll 30 patients. According to the current design, if less than 9 of the first 30 patients showed a response, the study would terminate early with the conclusion that the study drug was not worthy of further investigation. The study would also terminate early if more than 15 of the first 30 patients exhibited responses, indicating that Genexol-PM was worthy of further investigation. If the number of responders was between 9 and 15, the study would go to the second stage, and enrollment would continue until 25 additional patients were added.
https://static-content.springer.com/image/art%3A10.1007%2Fs10549-007-9591-y/MediaObjects/10549_2007_9591_Fig1_HTML.gif
Fig. 1

Two-stage group sequential design of the study. The null hypothesis and the alternative hypothesis were set at H0: P ≤ P0 ( = 0.3) vs. H1: P ≥ P1 (= 0.5). Since 18 of the 30 initial subjects showed responses, the clinical study was terminated at the first stage with the conclusion that Genexol-PM was effective

The response rate was calculated as the percentage of patients who achieved complete or partial responses. TTP was calculated for all patients enrolled, the time from the first day of treatment to the day of evidence of progressive disease, with censoring at the last follow-up (without progression), or removal from the study due to toxicity or patient withdrawal. TTP and survival were summarized by using Kaplan–Meier methods [15]. To test for associations between patient characteristics and response rate, the χ2 or Fisher’s exact test was applied as appropriate. A P < 0.05 level was considered significant. All statistical analyses were performed with SPSS version 14.0 (SPSS, Inc., Chicago, IL).

Results

Patient characteristics

In this multicenter phase II study, 43 patients signed the informed consent form between July 2004 and December 2004. Two patients withdrew the consent before treatment, and 41 patients who received at least one cycle of treatment were included in the analysis. The patients received a median of eight courses (range, 1–16 courses) with a total of 331 cycles of treatment. Response could not be evaluated in two patients, who were lost to follow-up after the first cycle, but included in the analysis on the intent-to-treat basis. The baseline characteristics of the patients are summarized in Table 1.
Table 1

Characteristics of the 41 enrolled patients at baseline

Characteristics

No.

%

Age, years

Median (Range)

48(30–69)

Stage

Stage IV (de novo)

9

22.0

Recurrent

32

78.0

No. of disease sites

1–2

29

70.7

≥3

12

29.3

Liver involvement

Yes

7

17.1

No

34

82.9

Previous chemotherapy

Anthracycline-containing adjuvant chemotherapy

15

36.6

First line anthracycline chemotherapy

4

9.8

ECOG performance status

0

12

29.3

1

29

70.7

ER

Positive

24

58.5

Negative

11

26.8

Unknown

6

14.6

PR

Positive

18

43.9

Negative

17

41.5

Unknown

6

14.6

HER2 immunohistochemistry

0–2+

22

53.7

3+

8

19.5

Unknown

11

26.8

Abbreviations: ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; PR, progesterone receptor

Efficacy

The objective response rate was 58.5% (95% CI: 43.5–72.3), with 5 complete responses and 19 partial responses (Table 2). The median response duration of the 24 responders was 7.2 months (range, 2.4–11.0 months). Thirteen patients (31.7%) achieved a stable disease state for a minimum of 6 weeks. The overall clinical benefit rate, the sum of objective response rate and the proportion of patients (17.1%) who achieved SD for 6 months or more, was 75.6% (95% CI: 60.5–86.4). Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5–73.7), and two of four patients in the second-line setting responded. Clinical and pathologic characteristics including recurrent disease, number of disease sites, liver involvement, chemotherapy settings, anthracycline-pretreatment, taxane-pretreatment, estrogen or progesterone receptor positivity, and HER2 status by immunohistochemistry did not significantly affect the response rate (Table 3). The median TTP for all patients was 9.0 months (range, 1.0–17.0+ months) and the median overall survival was not reached with a median follow-up of 17 months (range, 10+ to 19.8+) (Fig. 2).
Table 2

Response and clinical benefit rates

 

No. (n = 41)

%

95% CI

Overall response (CR + PR)

24

58.5

43.4–72.3

Clinical benefit

31

75.6

60.5–86.4

(CR + PR + SD ≥ 6 months)

   

    CR

5

12.2

 

    PR

19

46.3

 

    SD

13

31.7

 

    PD

2

4.9

 

    NA*

2

4.9

 

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not assessable

* not assessable due to early dropout

Table 3

Response rates according to clinical and pathologic characteristics

 

No.

CR + PR No. (%)

95% CI

P-value

Recurrent disease

    Yes

32

20 (62.5)

45.2–77.1

0.450

    No

9

4 (44.4)

18.8–78.8

No. of disease site

    1–2

29

17 (58.6)

40.7–74.5

0.986

    ≥3

12

7 (58.3)

31.9–80.7

Liver involvement

    Yes

7

5 (71.4)

35.2–92.4

0.679

    No

34

19 (55.9)

39.4–71.1

Chemotherapy for metastatic disease

    First-line

37

22 (59.5)

43.5–73.7

1.000

    Second-line

4

2 (50.0)

15.0–85.0

Anthracycline-pretreated

    Yes

19

11 (57.9)

36.2–76.9

0.938

    No

22

13 (59.1)

38.7–76.8

Taxane-pretreated

    Yes

5

3 (60.0)

22.9–88.4

1.000

    No

36

21 (58.3)

42.2–72.9

ER or PR

    Positive

24

14 (58.3)

38.8–75.6

0.716

    Negative

11

5 (45.5)

21.2–72.0

HER2 immunohistochemistry

    3+

8

6 (75.0)

40.1–93.7

0.407

    0–2+

22

11 (50.0)

30.7–69.3

Abbreviations: CR, complete response; PR, partial response; ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; PR, progesterone receptor

https://static-content.springer.com/image/art%3A10.1007%2Fs10549-007-9591-y/MediaObjects/10549_2007_9591_Fig2_HTML.gif
Fig. 2

Time to progression (a) and overall survival (b)

Adverse events

AEs were evaluated in all 41 enrolled patients. The worst grade of the most common hematologic and nonhematologic AEs for each patient are summarized in Table 4. The most significant findings were neutropenia and sensory peripheral neuropathy (PN). Grade 3 or 4 neutropenia was reported in 28 patients (68.3%). No episodes of febrile neutropenia occurred in any of the 41 enrolled patients. Twenty-one of the 41 patients (51.2%) developed grade 3 sensory PN, which tends to increase with more treatment cycles. The incidence of grade 3 PN was 17.1% prior to the sixth cycle (Fig. 3). On the other hand, nine patients (22.0%) experienced grade 1 motor PN with no episode of grade 2, 3, or 4 motor PN. Other observed grade 3 and 4 AEs were fatigue in four patients (9.8%), and dyspnea in four patients (9.8%).
Table 4

Summary of toxicities/adverse events (n = 41)

Toxicity

Grade 1

Grade 2

Grade 3

Grade 4

No.

%

No.

%

No.

%

No.

%

Hematologic toxicities

    Leucopenia

4

9.8

19

46.3

16

39.0

0

0

    Neutropenia

6

14.6

7

17.1

21

51.2

7

17.1

    Anemia

19

46.3

8

19.5

0

0

0

0

    Thrombocytopenia

7

17.1

2

4.9

0

0

0

0

Non-hematologic toxicities

    Alopecia

2

4.9

34

82.9

4

9.8

0

0

    Anorexia

11

26.8

11

26.8

1

2.4

0

0

    Arthralgia

3

7.3

14

34.1

1

2.4

0

0

    Constipation

7

17.1

6

14.6

1

2.4

0

0

    Diarrhea

16

39.0

6

14.6

0

0

0

0

    Fatigue

12

29.3

6

14.6

4

9.8

0

0

    Hypersensitivity

3

7.3

3

7.3

2

4.9

0

0

    Muscle weakness

0

0

4

9.8

1

2.4

0

0

    Myalgia

1

2.4

34

82.9

1

2.4

0

0

    Nausea

17

41.5

9

22.0

1

2.4

0

0

    Pruritus

8

19.5

14

34.1

1

2.4

0

0

    Rash

3

7.3

29

70.7

0

0

0

0

    Sensory neuropathy

6

14.6

13

31.7

21

51.2

0

0

    Stomatitis

13

31.7

7

17.1

0

0

0

0

    Vomiting

8

19.5

11

26.8

1

2.4

0

0

https://static-content.springer.com/image/art%3A10.1007%2Fs10549-007-9591-y/MediaObjects/10549_2007_9591_Fig3_HTML.gif
Fig. 3

Cumulative incidence of grade 3 sensory peripheral neuropathy (a) and proportion of grades of sensory peripheral neuropathy among patients at the specified cycle (b)

During the study, 8 of 41 patients (19.5%) experienced hypersensitivity reactions. Grade 1, 2, and 3 hypersensitivity reactions were observed in three, three, and two patients, respectively. One patient with grade 2 hypersensitivity discontinued treatment prematurely because of this reaction. Two patients who experienced grade 3 hypersensitivity (transient dyspnea) responded well to corticosteroid and/or antihistamine administration, and subsequent premedication with corticosteroids prevented further hypersensitivity reactions. Predosing corticosteroid or antihistamines were used in 12 patients (29.3%) during the study, with 9 patients (22.0%) receiving corticosteroids and 8 patients (19.5%) receiving antihistamines.

Neutropenia and neuropathy led treatment delays in 8 cycles (2.5% of 331 cycles) and in 15 cycles (4.5% of 331 cycles), respectively. Dose reduction was necessary due to neuropathy in 24 cycles (7.3%). The treatment delays and dose reductions occurred after several courses of therapy had been given. Despite the delays and dose reductions, dose intensities were well maintained with the median and the mean relative dose intensities of 1.0 and 0.87, respectively.

Discussion

Genexol-PM, a Cremophore-free, polymeric micelle formulation of paclitaxel, is a novel taxane developed to avoid problems associated with CrEL-based paclitaxel. This is the first phase II trial using polymeric micellar paclitaxel without CrEL in patients with MBC. In preclinical studies, Genexol-PM showed a threefold higher MTD value, which resulted in significantly higher tumor drug concentrations and reductions in tumor volume than CrEL-based paclitaxel in xenografted animal studies [11]. Genexol-PM also resulted in significantly lower leaching of a plasticizer from infusion sets compared to CrEL-based paclitaxel [16]. In addition to these preclinical reports, a phase I study of Genexol-PM established 390 mg/m2 as the MTD and 300 mg/m2 as the recommended dose [10], approximately two times higher than the MTD of CrEL-based paclitaxel.

In line with the results of preclinical and clinical studies suggesting higher applicable doses of Genexol-PM compared to CrEL-based paclitaxel, this phase II study confirmed significant activity of Genexol-PM at 300 mg/m2 given every 3 weeks in first-line or anthracycline-pretreated patients with MBC. The overall response rate was 58.5%, which can be compared favorably to the response rate of 47.6% produced by ABI-007 (Abraxane; American BioScience Inc., Santa Monica, CA) at 300 mg/m2 on an every 3-week dosing regimen [17]. Genexol-PM also showed favorable efficacies compared with conventional paclitaxel. Conventional CrEL-based paclitaxel showed response rates of 21–54% as a first-line therapy in patients with MBC [1822]. A phase III trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed response rate of 25% in patients with MBC when paclitaxel was administered in comparison with doxorubicin as a first-line therapy [19]. In another large randomized study conducted by the ECOG, first-line paclitaxel in comparison with doxorubicin and the combination of doxorubicin and paclitaxel showed response rate of 34% [20]. As a second-line therapy with CrEL-based paclitaxel, overall response rates of 25–42% have been reported in patients with anthracycline-treated or anthracycline-resistant breast cancer [2326].

Despite a study performed by Cancer and Leukemia Group B (CALGB) did not demonstrate superior activities by higher doses of CrEL-based paclitaxel [18], data from several other phase II studies in MBC suggest a dose-response relationship. The response rates by ABI-007 at 300 mg/m2, ABI-007 at 260 mg/m2, and CrEL-based paclitaxel at 175 mg/m2 were 64.1% [17], 42.3% [27], and 27.0% [27], respectively. The high response rate achieved by Genexol-PM in the current study is likely due to the higher dose of available paclitaxel delivered as well. In addition, the inferior responsiveness by CrEL-based paclitaxel could partly be explained by CrEL-associated entrapment of paclitaxel. By entrapping paclitaxel in micelles, CrEL may limit the bioavailability and antitumor activity of paclitaxel [2, 28]. Hence, higher doses of CrEL-based paclitaxel bring in higher concentrations of CrEL in the body, and as a consequence the failure to improve efficacies as seen in the CALGB study [18]. In contrast, CrEL-free formulations such as Genexol-PM could result in higher response rates with higher doses by circumventing the problems associated with entrapment of paclitaxel and by enhancing tumor distribution of paclitaxel.

It has been suggested that the higher intratumoral paclitaxel concentrations achieved by ABI-007, an albumin-bound paclitaxel, are due to albumin binding to the endothelial gp60 receptor with transcytosis of bound paclitaxel through the caveolar transport system [27, 29]. It is possible that the lack of CrEL per se in this system may play an important role in achieving higher intratumoral concentrations to have resulted in increased tumor responses. Genexol-PM and other CrEL-free paclitaxels invariably showed higher intratumoral drug concentrations than conventional CrEL-based paclitaxel regardless of the vehicles [11, 30, 31].

The main AEs of Genexol-PM were neutropenia and sensory PN. In this study the combined incidence of grade 3 and 4 neutropenia was 68.3%, while this incidence in a phase II trial of ABI-007 was 50.8%. However, the incidence of grade 4 neutropenia was 17.1% in this trial, which is lower than that of 23.8% shown in the ABI-007 trial [17]. No patients were complicated by neutropenic fever in this study. The absence of episode of neutropenic fever can be partly explained by the less profound myelosuppression caused by Genexol-PM.

Sensory and motor PN are the major AEs of taxane and other microtubule-stabilizing agent-based chemotherapy, and their incidence is dependent upon the dose per treatment cycle, the schedule of treatment, and the duration of infusion [6, 32]. In the current study, about half of the patients experienced grade 3 sensory PN. Seven to 33% of patients receiving CrEL-based paclitaxel reportedly experienced grade 3 or 4 sensory PN depending on the administered doses [18]. In trials of ABI-007, grade 3 or 4 PN was observed in 11.1% of patients receiving ABI-007 at 300 mg/m2 every 3 weeks (n = 63) [17], and in 24 of 229 patients (10.5%) receiving ABI-007 at 260 mg/m2 every 3 weeks [27]. The median number of cycles of Genexol-PM administered in the current study was eight, while a median of six or less cycles were administered in trials with ABI-007 [17, 27]. The greater number of treatment cycles might explain the higher incidence of PN in the current study. The incidence of grade 3 PN prior to the sixth cycle was 17.1%, and gradually increased toward the tenth cycle (Fig. 3). However, sensory PN was manageable, resulting in recovery in the majority of patients. Eleven of 21 patients with grade 3 sensory PN recovered promptly within a brief period off therapy, while 6 patients experienced gradual recovery over a few months only after complete cessation of the drug. No information is available for four other patients.

As no hypersensitivity reactions were observed in any patients in a phase I study of Genexol-PM [10], prophylactic corticosteroids were not routinely recommended in this trial. However, 3 of 41 patients (7.3%) experienced definite and 5 patients (12.2%) probable hypersensitivity reactions to Genexol-PM. Most patients recovered promptly after antihistamine and/or corticosteroid dosing and continued the treatment without further development of hypersensitivity on subsequent cycles. Only one patient (with grade 2 hypersensitivity) discontinued treatment prematurely because of hypersensitivity. The occurrence of hypersensitivity reactions with Genexol-PM, a CrEL-free formulation of paclitaxel, suggested that paclitaxel itself caused hypersensitivity reaction. When histamine release was observed with paclitaxel while no histamine was released by CrEL alone, paclitaxel was assumed to be the probable cause of hypersensitivity [33]. The development of hypersensitivity reactions was an unexpected drawback of Genexol-PM. It may be prudent to use small dose of prophylactic corticosteroid and/or antihistamine to prevent hypersensitivity reactions when Genexol-PM is administered at this dose and schedule. Preexisting CrEL-based paclitaxel cause minor hypersensitivity reactions in 10–44% of patients and fatal reactions in 1–3% of patients despite routine prophylaxes with corticosteroids and histamine antagonists [35]. On the other hand, Genexol-PM caused hypersensitivity reactions in 19.5% of patients in the absence of premedications, which then were abrogated by subsequent anti-histamines and/or corticosteroids pretreatment. ABI-007, a CrEL-free paclitaxel, required corticosteroid pretreatment in 6% of patients and corticosteroid therapy at some point in time during the courses in 22% [34]. Therefore, it appears that CrEL-free paclitaxels such as Genexol-PM and ABI-007 are not able to eliminate completely but to minimize corticosteroids use to a significant extent.

The current study used a two-stage group sequential design for sample size calculation (Fig. 1) [14]. Usually, two-stage designs are used in situations when early termination is desirable for ethical reasons when the treatment is ineffective. Unlike conventional two-stage designs including Gehan’s design, Simon’s optimal design, and Simon’s minimax design, the current study could be terminated early if the response rate was either exceptionally low or exceptionally high. Although slightly more complex than usual two-stage designs, the two-stage group sequential design was shown to be both safe for patients and efficient for investigators.

In conclusion, Genexol-PM, a CrEL-free paclitaxel formulated with polymeric micelles, showed significant efficacies in patients with MBC. The relatively high incidence of sensory PN noted in this study was likely related to more treatment cycles administered. Notably, the courses were not complicated by neutropenic fever. Prophylactic corticosteroid and/or antihistamine may be used to prevent hypersensitivity reactions when Genexol-PM is administered at this dose and schedule. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted in MBC.

Acknowledgements

Supported in part by NCC grant 0610240-1, the Korean Health 21 R&D Project Grant, Ministry of Heath & Welfare, Republic of Korea (0412-CR01-0704-0001), and Samyang Co.

Copyright information

© Springer Science+Business Media, LLC 2007