phase i/ii study of ixabepilone plus capecitabine in anthracycline–pretreated/resistant and...

IntroductionBreast cancer remains a leading cause of mortality in women

worldwide.1 Approved originally for the treatment of metastat-ic breast cancer (MBC) and still frequently used in this setting,

anthracyclines and taxanes are also now commonly used in the adjuvant treatment of early-stage breast cancer. Consequently, the vast majority of patients with MBC have been treated with these agents early in the disease course.2 Unfortunately, despite advances in breast cancer treatments, many patients ultimately experience relapse. Tumor resistance to neoplastic agents, including anthracyclines and taxanes, remains a clini-cal challenge in the adjuvant and metastatic settings.3,4 Once metastases are detected, overall survival (OS) is approximately 2 years.2,4,5 Patients whose tumors progress after anthracy-cline and taxane treatment have limited treatment options, including single agents such as capecitabine.4

Capecitabine, the oral prodrug of 5-fluorouracil (5-FU), is active in MBC and is currently the only single agent specifi-cally approved for patients whose tumors fail to respond to

Abstract Purpose: The aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline–pre-treated/resistant and taxane-resistant metastatic breast cancer (MBC). Patients and Methods: A total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21-day cycle). Results: No dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutro-penia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption. Conclusion: Ixabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline–pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.

Clinical Breast Cancer, Vol. 8, No. 3, 234-241, 2008; DOI: 10.3816/CBC.2008.n.026Keywords: Epothilones, Maximum tolerated dose, Microtubule inhibitors

Electronic forwarding or copying is a violation of US and International Copyright Laws.Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

1Dana-Farber Cancer Institute, Boston, MA2Weill Cornell Breast Center, New York, NY3West Cancer Clinic, Memphis, TN4Fred Hutchinson Cancer Research Center, Seattle, WA5Merck & Co, Somerset, NJ6Bristol-Myers Squibb, Research and Development7Kaiser Permanente, Oakland, CA Submitted: Nov 6, 2007; Revised: Jan 29, 2008; Accepted: Mar 12, 2008 Address for correspondence: Craig Bunnell, MD, MPH, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115 Fax: 617-632-1930; e-mail: [email protected]

original contribution

Phase I/II Study of Ixabepilone plus Capecitabine in Anthracycline–Pretreated/Resistant and Taxane-Resistant Metastatic Breast CancerCraig Bunnell,1 Linda Vahdat,2 Lee Schwartzberg,3 Julie Gralow,4 Judith Klimovsky,5 Valerie Poulart,6 Ronald Peck,6 Eva Thomas7

234 • Clinical Breast Cancer June 2008

Clinical Breast Cancer June 2008 • 235

anthracyclines and taxanes. However, a large proportion of patients do not have responses to capecitabine or eventually develop tumor resistance after responding.6-8 Thus, there is a need for new antineoplastic agents and combinations that are active in MBC.

The epothilones are a novel class of antineoplastic agents that stabilize microtubule dynamics and induce cell cycle arrest, leading to cellular apoptosis.9 Ixabepilone, the first drug in this class, is a semisynthetic analogue of the natu-ral drug epothilone B. Unlike many antineoplastic agents, including taxanes and anthracyclines, ixabepilone has low susceptibility to multiple mechanisms of drug resistance, including overexpression of drug efflux transporters and overexpression of resistant β-tubulin isotype III.10-11 In preclinical models, ixabepilone has shown antitumor activity against a broad spectrum of tumor types, including taxane-sensitive and taxane-resistant tumors.12-16 In phase II trials, single-agent ixabepilone has shown clinical activity against MBCs, including tumors resistant to multiple agents, with objective response rates (ORRs) ranging between 12% and 57%17-21 and an acceptable safety profile. The most common toxicities observed in these trials were myelosuppression and peripheral sensory neuropathy.

Ixabepilone has demonstrated synergy with capecitabine in preclinical models.22 The activity of single-agent ixabepi-lone in patients with anthracycline–pretreated/resistant and taxane-resistant MBC, the preclinical synergy of ixabepilone with capecitabine, their complementary modes of action, and the minimally overlapping safety profiles of these 2 agents make this a rational combination to evaluate. We conducted an open-label phase I/II study to define a dose and explore the safety and efficacy of the combination of ixabepilone plus capecitabine in patients with MBC that had progressed after treatment with an anthracycline and a taxane.

Patients and MethodsEligibility

Eligible patients were aged ≥ 18 years with histologically confirmed locally advanced or MBC previously treated with an anthracycline and a taxane. Measurable disease was not required for the phase I (dose-escalation) portion of the study but was required for the phase 2 (response evaluation) por-tion. Additional eligibility criteria included adequate bone marrow, hepatic, and renal function; an Eastern Cooperative Oncology Group performance status of 0/1; life expectancy ≥ 3 months; and an interval of ≥ 3 weeks since the end of pre-vious treatment. Up to 3 previous chemotherapy regimens for MBC were allowed.

Exclusion criteria included previous exposure to epothi-lones, concurrent hormonal or biologic (eg, trastuzumab or lapatinib) therapies, other concurrent investigational treat-ments for MBC, and grade ≥ 2 motor/sensory neuropathy. Previous exposure to 5-FU or capecitabine was allowed following a protocol amendment to increase the population eligible for the phase II portion of the study. Baseline evalu-ation included history and physical examination, laboratory

studies, radiographic tumor measurements, chest radiogra-phy, and electrocardiography.

Study DesignThe study consisted of a dose-escalation phase

(phase I) and a tumor response rate evaluation phase (phase II; Figure 1). Patients were pretreated with oral his-tamine 1- and 2-receptor antagonists before each infusion of ixabepilone to prevent hypersensitivity reaction (HSR). Patients who experienced grade ≥ 2 HSR by National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 2.0, were premedicated with corticosteroids before subsequent ixabepilone administration.

Dose Escalation (Phase I). Two treatment schedules were evaluated in the phase I portion of the trial. For schedule A, ixabepilone was administered as a 3-hour intravenous infu-sion once every 3 weeks, and capecitabine was administered orally twice daily on days 1-14 of a 21-day cycle. The dose of ixabepilone was fixed at 40 mg/m2, and the total dose of capecitabine was increased in the absence of dose-limiting toxicity (DLT) from 1650 mg/m2 daily in the first cohort of 6 patients to 2000 mg/m2 daily in subsequent cohorts. For schedule B, ixabepilone was administered as a 1-hour infu-sion on days 1-3 every 3 weeks, and capecitabine was admin-istered twice daily on days 1-14 of a 21-day cycle. Ixabepilone dosing was initiated at 8 mg/m2 daily, and capecitabine dos-ing was initiated at 1650 mg/m2 daily.

Schedule B was discontinued at the 10-mg/m2 daily ixabe-pilone level in favor of ixabepilone administration (40 mg/m2) once every 3 weeks after data from concomitant phase I/II trials established administration of ixabepilone on day 1 of a 21-day cycle as the schedule of choice.19-21,23-25 Dose-limit-ing toxicity was defined as any treatment-related toxicity requiring permanent discontinuation in ≥ 2 patients during the first 2 treatment cycles at a specific dose. The maximum tolerated dose (MTD) was defined as ixabepilone 40 mg/m2 plus capecitabine 2000 mg/m2 daily for schedule A.

Tumor Response (Phase II). The study was amended to expand the schedule A 40/2000 mg/m2 dose cohort to include an additional 15-30 patients. Sample size was further increased by amendment to accrue 50 response-evaluable patients for the phase II portion of the study. Treatment was continued until disease progression or unacceptable toxicity occurred.

The study was performed in accordance with the prin-ciples of the Helsinki Declaration, the principles of Good Clinical Practice, the institutional review board/independ-ent ethics committee at each study site, and all applicable regulatory requirements. All patients gave written informed consent before enrollment.

Safety Assessment (Phases I and II). Safety was continu-ously monitored in all patients who received study medi-cation in phases I and II. Assessments included physical examination, history, and serum chemistries at the start of

each cycle and weekly complete blood counts with differen-tial counts. Adverse events (AEs), including plantar-palmar erythrodysesthesia (PPE), were coded by Medical Dictionary for Regulatory Activities (MedDRA) system organ classes, graded using NCI-CTC, and summarized by worst CTC grade. Patient deaths on study or within 30 days after the last dose of study medication were recorded.

The doses of one or both drugs were reduced for grade > 2 nonhematologic toxicities (except alopecia or fatigue). Both drugs were reduced for grade 4 neutropenia lasting > 5 days, febrile neutropenia, or grade ≥ 3 thrombocytopenia. Capecitabine dose was reduced for grade ≥ 3 diarrhea, stomati-tis, or PPE. Ixabepilone dose was reduced for grade 2 neuropa-thy lasting ≥ 7 days or grade 3 neuropathy of any duration. Patients were removed from the study if treatment had to be delayed for > 14 days, if they required > 2 dose reductions, or if they experienced any grade 4 nonhematologic toxicity.

Response Assessment (Phase II). Tumor response was assessed after every 2 cycles in patients who received the recommended phase II dose of ixabepilone (40 mg/m2) and capecitabine (2000 mg/m2) and who were evaluable for response (ie, with measurable disease at baseline). Physical examination, radiography, and computed tomography scans (or other imaging studies as appropriate) were used to evaluate tumor size and extent according to Response Evaluation Criteria in Solid Tumors.26 The primary effi-

cacy endpoint was ORR, defined as the number of patients with complete response (CR) plus the number of patients with partial response (PR) divided by the total number of response-evaluable patients. Secondary efficacy endpoints were time to response, duration of response, and progres-sion-free survival (PFS; defined as the time from the first day of treatment until the date of documented disease progression or death).

Statistical AnalysisPoint estimates and 95% confidence intervals (CIs) were

calculated for response rates.27 Discrete variables were sum-marized using descriptive statistics and continuous variables using summary statistics for nonmissing data. Time-to-event variables were analyzed using the Kaplan-Meier method and expressed as estimated medians with 95% CI, and time-to-response data were summarized using univariate statistics.

ResultsPatients

The study was conducted at 5 US centers between January 2002 and February 2005. A total of 106 patients were enrolled, 74 in the phase II dose-escalation portion. As shown in Table 1, 72 patients received treatment with ixa-bepilone/capecitabine at 4 dose levels in phase I: 40/1650 mg/m2 (n = 30) and 40/2000 mg/m2 (n = 30) on schedule A; 8/1650 mg/m2 (n = 6) and 10/1650 mg/m2 (n = 6) on schedule B. No DLTs (treatment-related toxicities within

Treatment SchemaFigure 1

Escalate if no DLT

Amendment 2

Amendment 2 Amendment 3

Ixabepilone 8 mg/m2

Capecitabine 1650 mg

Escalate if no DLT

Ixabepilone 10 mg/m2


Phase I Phase II

Schedule A

Ixabepilone3-hour I.V. on day 1

every 3 weeksCapecitabine

daily on days 1-14

Schedule B

Ixabepilone1-hour I.V. on day 1-3

every 3 weeksCapecitabine

daily on days 1-14

Enrollment

Closed to enrollment because less convenient than schedule Aand data from phase II ixabepilone program in MBC support schedule A administration





Expand to30 patients

Expand to30 patients

Expand to achieve50 response-evaluable patients

Dose Cohorts and Dose-Limiting Toxicities in Phase I (Dose Escalation)Table 1

A: Ixabepilone 3-Hour I.V. on Day 1; Capecitabine Twice Daily on Days 1-14

B: Ixabepilone 1-Hour I.V. on Days 1-3; Capecitabine Twice Daily on Days 1-14

Schedule (21-Day Cycle)

40/1650 mg/m2

40/2000 mg/m2

8/1650 mg/m2

10/1650 mg/m2

Ixabepilone/Capecitabine Dose Cohorts

1/30

2/30

0/6

0/6

Patients with DLT

Grade 3 chest pain

Grade 3 PPE

Grade 3 PPE

–

–

DLT*

*By NCI-CTC.

Ixabepilone plus Capecitabine in MBC


Craig Bunnell et al


the first 2 cycles leading to permanent discontinuation) were observed at the 8/1650 mg/m2 and 10/1650 mg/m2 dose levels of schedule B. Dose-limiting toxicities (grade 3 PPE) occurred in 2 of 30 patients in the 40/2000 mg/m2 cohort, identifying this as the MTD. A phase II trial in MBC with ixabepilone dosed at 8-10 mg/m2 on days 1-3 of a 21-day cycle (schedule B) demonstrated no CRs or PRs in 12 evaluable patients.25 Ten patients had stable disease for ≥ 6 weeks. Because of the greater convenience of administering ixabe-pilone according to schedule A and data from ixabepilone phase II studies that supported the safety and efficacy of 40 mg/m2 administered once in a 21-day cycle,19-21,28,29 the enrollment of patients on schedule B was discontinued.

The 40/2000 mg/m2 dose level (the MTD of the phase I portion) had an acceptable safety profile in the expansion phase of the study and was therefore chosen as the recom-mended phase II dose. An additional 32 patients with meas-urable disease and patients with response-evaluable disease from the phase I/II portions were pooled to create the data-

set analyzed for the phase II portion of the study.

Dose Cohorts and DLTs in Phase I (Dose Escalation)Table 2A

Ethnicity

White

Black

Asian/Pacific Islander

Hispanic

Other

Sex

Female

Male

Median Age, Years (Range)

ECOG PS

0

1

2

Menopausal Status

Premenopausal

Postmenopausal

Unknown/ not reported

Characteristic

58 (81)

6 (8)

1 (1)

6 (8)

1 (1)

71 (99)

1 (1)

50 (26-71)

30 (42)

41 (57)

1 (1)†

36 (50)

28 (39)

8 (11)

Dose-Escalation(Phase I) Cohorts

Number ofTreated Patients

(%; n = 72)

53 (86)

3 (5)

2 (3)

3 (5)

1 (2)

62 (100)

0

51.5 (26-73)

30 (48)

32 (52)

0

33 (53)

24 (39)

5 (8)

Response-Assessment(Phase II) Cohorts*(40/2000 mg/m2)

Number ofTreated Patients

(%; n = 62)

Percentages are rounded and might not add up to 100%.*Includes 30 patients from the phase I and 32 patients from the phase II portions of the study.†A single patient with an ECOG PS of 2 (protocol violation) was included in the analysis.Abbreviations: ECOG = Eastern Cooperative Oncology Group; PS = performance status

Dose Cohorts and DLTs in Phase I (Dose Escalation)Table 2B

CharacteristicNumber of

Treated Patients(%; n = 72)

Number ofResponse-EvaluablePatients (%; n = 50)

Percentages are rounded and might not add up to 100%.*Sequential regimens in the neoadjuvant/adjuvant setting(s) were counted as 2 regimens.†Three patients (6%) received > 2 regimens in the neoadjuvant/adjuvant setting(s).‡HER2 positive by fluorescence in situ hybridization or 3+ by immunohistochemistry.Abbreviations: NA = not applicable

1 Target Lesion

Site of Target Lesion

Soft tissue

Visceral (lung)

Visceral (liver)

Number of Previous Regimens in the Neoadjuvant/Adjuvant Setting

0

1

2

Number of Previous Regimens in the Metastatic Setting

0

1

2

Number of Previous Taxane-Containing Regimens

1

2

Number of Previous Anthracycline-Containing Regimens

0

1

2

Number of Taxane/Anthracycline–Pretreated Patients

ER Status

Positive

Negative

Not reported

PgR Status

Positive

Borderline

Negative

Not reported

HER2 Status‡

Positive

Negative

Unknown

Not reported

Other

ER/PgR/HER2–Negative

Yes

No

72 (100)

NA

NA

NA

11 (15)

41 (57)

20 (28)*

20 (28)

21 (29)

31 (43)

55 (76)

17 (24)

0

67 (93)

5 (7)

72 (100)

26 (36)

44 (61)

2 (3)

20 (28)

1 (1)

48 (67)

3 (4)

12 (17)

56 (78)

1 (1)

2 (3)

1 (1)

32 (44)

40 (56)

50 (100)

21 (42)

9 (18)

27 (54)

6 (12)

23 (46)

21 (42)*†

18 (36)

10 (20)

22 (44)

35 (70)

15 (30)

1 (2)

44 (88)

5 (10)

49 (98)

22 (44)

28 (56)

0

18 (36)

1 (2)

31 (62)

0

7 (14)

40 (80)

0

2 (4)

1 (2)

22 (44)

28 (56)

Patient CharacteristicsA total of 72 patients were treated in the dose-escalation

(phase I) cohorts, and 62 patients received the recommended phase II dose of ixabepilone (40/2000 mg/m2), 30 in phase I and 32 in phase II. Nearly all patients had MBC that had pro-gressed after failure of anthracyclines and taxanes and had extensive tumor metastases at baseline (Table 2). Seventy percent of patients who had previously received a taxane and 50% who had received an anthracycline in the meta-static setting had experienced progression ≤ 4 months after the last dose; 66% of patients who had previously received a taxane and 44% who had received an anthracycline in the adjuvant setting had experienced progression ≤ 12 months after the last dose. Between 14% and 17% of patients had

disease that overexpressed the HER2, and 44% had estrogen receptor (ER)/progesterone receptor (PgR)/HER2–negative (triple-negative) breast cancer.

Safety and Tolerability Response Assessment Cohort (Phase I/II). All 62 patients

who received the ixabepilone/capecitabine dose of 40/2000 mg/m2 (30 from phase I and 32 from phase II) were included in the safety analysis. This dose was well tolerated, with most treatment-related AEs being manageable and mild to moderate in severity (Table 3). The most common grade 3/4 treatment-related AEs reported in ≥ 10% of patients (across all treatment cycles) were fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (13%), diarrhea (10%), and vomiting (10%). Four patients (6%) experienced mild (grade 1/2) HSR. Nineteen patients (67%) in the 40/1650 mg/m2 cohort experienced grade 1/2 PPE (no grade 3/4 PPE reported). For patients on schedule B, 3 of 6 patients (50%) in the 8/1650 mg/m2 cohort experienced grade 2 PPE. In the 10/1650 mg/m2 cohort, 3 patients (50%) experienced grade 2 PPE, and 1 patient (17%) experienced grade 3 PPE.

Leukopenia and neutropenia were common and were managed primarily with dose reduction or treatment inter-ruption. Among the 61 patients for whom ≥ 1 on-treatment value was available, grade 3 neutropenia occurred in 26 patients (43%), and grade 4 neutropenia occurred in 16 patients (26%). Febrile neutropenia, febrile infection, neutro-penic infection, and septic shock were reported in 1 patient (2%) each. In the 40/2000 mg/m2 response assessment cohort, 1 patient died of septic shock, which was judged to be treat-ment related. This patient had been heavily pretreated with doxorubicin, docetaxel, and paclitaxel in the neoadjuvant set-ting and gemcitabine in the metastatic setting.

Treatment-related peripheral neuropathy was primarily sensory, cumulative, and reversible. Treatment-related periph-eral sensory neuropathy in the 40/2000 mg/m2 cohort was grade 1 in 15 patients (24%), grade 2 in 19 patients (31%), and grade 3 in 12 patients (19%). Treatment-related grade 3 peripheral motor neuropathy occurred in 1 patient (2%). The

Treatment-Related Adverse Events Occurring in 10% ofPatients: Response Assessment Cohort (40/2000 mg/m2)

Table 3

Gastrointestinal Disorders

Nausea

Diarrhea

Constipation

Vomiting

Stomatitis

Fatigue

Pyrexia

Increased lacrimation

Metabolism and Nutrition Disorders

Anorexia

Dehydration

Musculoskeletal/ConnectiveTissue Disorders

Myalgia

Arthralgia

Nervous System Disorders

Respiratory, Thoracic, and Mediastinal Disorders

Dyspnea

Skin and Subcutaneous Tissue Disorders

PPE

Alopecia

Rash

Nail disorder

Hematologic*†

Neutropenia

Leukopenia

Adverse EventAll Grades

Number of Patients (%; n = 62)

46 (74)

32 (52)

29 (47)

29 (47)

28 (45)

49 (79)

14 (23)

20 (32)

7 (11)

7 (11)

37 (60)

15 (24)

50 (81)

10 (16)

39 (63)

39 (63)

18 (29)

11 (18)

54 (89)

57 (93)

Grade 4

0

0

0

0

1 (2)

2 (3)

0

0

0

0

1 (2)

0

0

0

0

0

0

0

16 (26)

7 (12)

Grade 3

10 (16)

6 (10)

4 (7)

6 (10)

2 (3)

19 (31)

1 (2)

0

2 (3)

3 (5)

13 (21)

1 (2)

12 (19)

1 (2)

21 (34)

0

1 (2)

0

26 (43)

26 (43)

*Hematologic events determined by clinical laboratory evaluation.†n = 61.

Best Tumor Response: Response Assessment Cohort(40/2000 mg/m2)

Table 4

Complete

Partial

Objective Response Rate

Stable Disease

Progressive Disease

Discontinuation Due to Toxicity

No Tumor Reassessments†

Response

1 (2)

14 (28)

15 (30)

16 (32)

14 (28)

4 (8)

1 (2)

Number of Patients(%; n = 50*)

*Of 62 patients treated with the 40/2000 mg/m2 dose regimen, 50 had measurable disease at baseline and could be evaluated for response.†For reasons other than toxicity-related discontinuation, progressive disease, or early death.



Craig Bunnell et al


median time to onset of severe peripheral neuropathy was 12 weeks (4 treatment cycles). Most patients with peripheral neu-ropathy were able to receive additional treatment cycles after dose reduction. Seven patients (11%) discontinued treatment because of peripheral sensory neuropathy–related events, including 5 patients (8%) with paresthesia (2 [3%] with grade 2; 3 [5%] with grade 3), 1 patient (2%) with grade 2 neuro-pathic pain, and 1 patient with grade 3 peripheral neuropathy. Reversibility of grade ≥ 2 neuropathy was assessed in a sup-plemental analysis. Neuropathy resolved to baseline or grade 1 in 30 of 32 patients (94%), with a median time to resolution of 2.6 weeks (95% CI, 1.1-6.9 weeks). Of the 2 remaining patients, 1 received subsequent neurotoxic therapy poststudy, and neuropathy did not resolve; the status of the other patient was unknown. For patients on schedule B, paresthesia was grade 2 in 1 (17%) and grade 3 in 2 (33%) of 6 patients in the in the 8/1650 mg/m2 cohort. Of six patients treated in the 10/1650 mg/m2 cohort, 2 (33%) experienced grade 2 paresthe-sia, and 1 (17%) experienced grade 3 paresthesia.

Treatment ResponseAmong 30 patients in the 40/1650 mg/m2 ixabepilone/

capecitabine dose-escalation cohort, 19 had measurable dis-ease, and 9 had a PR, yielding an overall ORR of 47% (95% CI, 43%-71%). One patient of 6 in the 10/1650 mg/m2 cohort had a PR, and no objective responses were observed in the 8/1650 mg/m2 cohort.

The combination of ixabepilone plus capecitabine at the 40/2000 mg/m2 dose level had substantial antitumor activity in patients with MBC previously treated with an anthracy-cline and a taxane. Of the 62 patients (from phase I and II) in the response assessment cohort, 50 were response evalu-able. Best tumor responses are shown in Table 4. One patient achieved a CR, and 14 had a PR (ORR, 30%; 95% CI, 18%-45%). The 15 responding patients included 13 with visceral metastatic lesions involving the lung and/or liver at baseline. Median time to response was 6 weeks (range, 5-14 weeks). Median duration of response was 6.9 months (95% CI, 4.3-9.7 months); response lasted for ≥ 9 months in 5 patients and for 16 months in 1 patient. Median PFS was 3.8 months (95% CI, 2.7-5.6 months). There were 22 response-evaluable patients with triple-negative tumors in the 40/2000 mg/m2 dose cohort. This subgroup had an ORR of 23% (95% CI, 7.8%-45.4%), with 5 of 22 patients having a PR.

DiscussionThis phase I/II trial, the first to assess the combination

of ixabepilone plus capecitabine in heavily pretreated MBC, reports clinical activity and an acceptable safety profile for this regimen. The combination of ixabepilone and capecitab-ine was an effective and well-tolerated regimen, due in part to the minimally overlapping toxicities and differing mecha-nisms of action of these agents. Cytopenias (neutropenia and leukopenia) were more frequent with combination therapy. These were managed primarily with dose reduction or treat-ment interruption and supportive care.

Treatment-related neuropathy was primarily sensory and cumulative in nature, with an average time to onset of significant neuropathy of 4 cycles. The incidence of grade 3 neuropathy (19%) was within the range reported for taxanes (2%-32%),30-33 and all patients had received previous taxane therapy. No treatment-related grade 4 neurologic AEs were observed. In addition, a proportion of patients had neuro-logic symptoms at baseline, including grade 1 paresthesia (23%) and hypoesthesia (5%), and 2% had grade 1 periph-eral neuropathy. Importantly, however, treatment-related neuropathy in this study was generally manageable through dose reduction or delay and, ultimately, resolved to grade ≤ 1 in 94% of patients within a median of 2.6 weeks.

Tumor resistance and relapse after treatment with agents such as anthracyclines and taxanes remains a major bar-rier to effective treatment of patients with MBC, and this challenge is likely to increase with the trend to use these drugs early in disease. The 30% ORR observed at the 40/2000 mg/m2 daily dose regimen (schedule A) exceeds response rates reported for either single-agent drug in this breast cancer setting. The dose of capecitabine used in this patient cohort is lower than the FDA-approved dose of 2500 mg/m2 daily. However, retrospective analyses of clini-cal trials have demonstrated that dosing of capecitabine at 2000 mg/m2 daily on days 1-14 of a 21-day cycle improves tolerability without diminishing efficacy.34

This trial also examined alternative doses of ixabepilone (8-10 mg/m2 daily) and capecitabine (1650 mg/m2 daily) administered for 3 consecutive days every 3 weeks (schedule B). Although lower rates of grade 3/4 peripheral neuropa-thy were observed with schedule B dosing, consistent with published studies in MBC that used ixabepilone (6 mg/m2 daily) for 5 consecutive days every 3 weeks,17,18 schedule B was not pursued any further in view of the convenience and demonstrated efficacy of schedule A.

In this study, clinical efficacy and an acceptable safety pro-file were observed in a heavily pretreated patient population, the majority of whom had disease that had progressed rapid-ly after anthracycline and taxane treatment. A large propor-tion of this difficult-to-treat patient population had visceral metastases at study entry. Responses with ixabepilone plus capecitabine compare favorably with those of single-agent capecitabine in similar patient populations, namely those with MBC previously treated with an anthracycline and a taxane. Objective response rates with capecitabine ranged from 20% to 28% in several phase II studies6,35,36 and was 9% in the comparator arm of a phase III trial.37

Responses with ixabepilone plus capecitabine also com-pared favorably with those of trials evaluating combina-tion regimens in less resistant MBC patient populations. One phase III trial evaluated capecitabine in combination with docetaxel in anthracycline-pretreated patients with advanced breast cancer.38 An ORR of 42% was reported; however, the combination regimen also produced a higher incidence of grade 3 AEs, including gastrointestinal side effects and PPE (71% of patients) compared with docetaxel

alone (49% of patients). A second phase III trial evaluated capecitabine plus the anti–vascular endothelial growth fac-tor monoclonal antibody bevacizumab versus capecitab-ine alone in anthracycline/taxane–pretreated patients with MBC.37 A significant increase in ORR was observed for the combination regimen versus capecitabine alone (19.8% vs. 9%); however, no significant differences in PFS and OS were observed between the 2 treatment arms. Bevacizumab has also been evaluated in combination with paclitaxel in a phase III trial in treatment-naive patients with MBC.39 Although improved ORR (36.9% vs. 21.2%) and PFS (11.8 months vs. 5.9 months) were reported for the combination regimen, no benefit in OS was observed compared with paclitaxel alone. Ixabepilone is currently being evaluated in combination with bevacizumab versus paclitaxel plus bevacizumab in treat-ment-naive locally recurrent/metastatic disease.40

Of note, objective responses to treatment with ixabepilone plus capecitabine were experienced in the subgroup of patients with triple-negative disease, which historically has been associ-ated with poor prognosis.41 A study of ixabepilone in the neo-adjuvant setting also reported encouraging responses among this patient subgroup.29 Results reported in this phase I/II study are consistent with the ORR (17%) in a phase II study of ixabepilone in patients with highly refractory MBC in whom anthracyclines, taxanes, and capecitabine had failed.21

ConclusionBased on the safety and efficacy observed in this phase

I/II trial, ixabepilone 40 mg/m2 once every 3 weeks plus capecitabine 2000 mg/m2 daily on days 1-14 of a 21-day cycle is recommended for further clinical evaluation. This regimen was used for a recently completed phase III study in patients with MBC pretreated/resistant to anthracyclines and resistant to taxanes. The study demonstrated signifi-cantly improved efficacy of the combination regimen ver-sus capecitabine alone with a manageable safety profile.42 Based on efficacy data in phase II/III trials, ixabepilone was recently approved by the US FDA in combination with capecitabine for treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is con-traindicated and as single-agent therapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

References 1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence,

mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006; 24:2137-50.

2. Valero V, Hortobagyi GN. Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer? J Clin Oncol 2003; 21:959-62.

3. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005; 205:275-92.

4. Bernard-Marty C, Cardoso F, Piccart MJ. Facts and controversies in systemic treatment of metastatic breast cancer. Oncologist 2004;

9:617-32. 5. Hortobagyi G. Treatment of breast cancer. N Engl J Med 1998;

339:974-84. 6. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of

capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17:485-93.

7. Blum JL, Dees C, Chacko A, et al. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2001; 24:4384-90.

8. Talbot DC, Moiseyenko V, Van Belle S, et al. Randomised, phase II trial comparing oral capecitabine (Xeloda®) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 2002; 86:1367-72.

9. Bollag DM, McQueney PA, Zhu J, et al. Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res 1995; 55:2325-33.

10. Wartmann M, Altmann K. The biology and medicinal chemistry of epothilones. Curr Med Chem Anti Cancer Agents 2002; 2:123-48.

11. Altmann KH. Epothilone B and its analogs - a new family of antican-cer agents. Mini Rev Med Chem 2003; 3:149-58.

12. Fojo AT, Menefee ME, Poruchynsky M, et al. A translational study of ixabepilone (BMS-247550) in renal cell cancer (RCC): assessment of its activity and demonstration of target engagement in tumor cells. J Clin Oncol 2005; 23:388s (Abstract 4541).

13. Galsky MD, Small EJ, Oh WK, et al. Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer. J Clin Oncol 2005; 23:1439-46.

14. O’Connor O, Straus D, Moskowitz C, et al. Targeting the microtubule apparatus in indolent and mantle cell lymphoma with the novel epothilone analog BMS 247550 induces major and durable remissions in very drug resistant disease. J Clin Oncol 2005; 23(16 suppl):577s (Abstract 6569).

15. Vansteenkiste JF, Breton JL, Sandler A, et al. A randomized phase II study of epothilone analog BMS-247550 in patients (pts) with non-small cell lung cancer (NSCLC) who have failed first-line platinum-based chemotherapy. Proc Am Soc Clin Oncol 2003; 22:626 (Abstract 2519).

16. Whitehead RP, McCoy S, Rivkin SE, et al. A phase II trial of epothi-lone B analogue BMS-247550 (NSC #710428) ixabepilone, in patients with advanced pancreas cancer: a Southwest Oncology Group study. Invest New Drugs 2006; 24:515-20.

17. Low JA, Wedam SB, Lee JJ, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol 2005; 23:2726-34.

18. Denduluri N, Low JA, Lee JJ, et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previ-ously untreated with taxanes. J Clin Oncol 2007; 25:3421-7.

19. Roché H, Yelle L, Cognetti F, et al. Phase II clinical trial of ixabepi-lone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 2007; 25:3415-20.

20. Thomas E, Tabernero J, Fornier M, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 2007; 25:3399-406.

21. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol 2007; 25:3407-14.

22. Lee H, Xu L, Wu S, et al. Predictive biomarker discovery and valida-tion for the targeted chemotherapeutic ixabepilone. J Clin Oncol 2006; 24(18 suppl):123s (Abstract 3011).

23. Zhuang SH, Agrawal M, Edgerly M, et al. A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intra-venously on a daily schedule for 3 days. Cancer 2005; 103:1932-8.

24. Aghajanian C, Burris HA, Jones S, et al. Phase I study of the novel epothilone analog ixabepilone (BMS-247550) in patients with advanced solid tumors and lymphomas. J Clin Oncol 2007; 25:1082-8.

25. Denduluri N, Lee JJ, Walshe J, et al. Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks in metastatic breast cancer. Cancer 2007; 25:63-7.

26. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-16.

27. Clopper C, Pearson ES. The use of confidence or fiducial limits illus-trated in the case of the binomial. Biometrika 1934; 26:404-13.

28. Conte P, Thomas E, Martin M, et al. Phase II study of ixabepilone in patients (pts) with taxane-resistant metastatic breast cancer (MBC): final report. J Clin Oncol 2006; 24:18s (Abstract 10505).

29. Roché H, Perez E, Llombart-Cussac A, et al. Ixabepilone, an epothi-lone B analog, is effective in ER, PR, HER-2 negative (triple negative) patients: data from neoadjuvant and metastatic breast cancer trials. Ann Oncol 2006; 17(9 suppl):S93-113.



Craig Bunnell et al


30. Nabholtz JM, Gelmon K, Bontenbal M, et al. Multicenter, random-ized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 1996; 14:1858-67.

31. Winer EP, Berry DA, Woolf S, et al. Failure of higher-dose pacli-taxel to improve outcome in patients with metastatic breast can-cer: cancer and leukemia group B trial 9342. J Clin Oncol 2004; 22:2061-8.

32. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005; 23:5542-51.

33. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005; 23:7794-803.

34. Bernard-Marty C, Cardoso F, Piccart MJ. Facts and controversies in systemic treatment of metastatic breast cancer. Oncologist 2004; 9:617-32.

35. Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40:536-42.

36. Wist E, Sommer HH, Ostenstad B, et al. Oral capecitabine in anthra-

cycline- and taxane-pretreated advanced/metastatic breast cancer. Acta Oncol 2004; 43:186-9.

37. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23:792-9.

38. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812-23.

39. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666-76.

40. A trial of 2 schedules of ixabepilone plus bevacizumab and paclitaxel plus bevacizumab for breast cancer. Available at: http://clinicaltrials.gov/show/NCT00370552. Accessed: January 21, 2008.

41. Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 2006; 24:5652-7.

42. Thomas EA, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007; 25:5210-7.

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