Epothilone (Ixabepilone) Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced Breast Cancer - Study Results

Study Type:	Interventional
Study Design:	Randomized, Open Label, Active Control, Parallel Assignment
Conditions:	Cancer Breast Cancer
Interventions:	Drug: Ixabepilone + Capecitabine Drug: Capecitabine

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
PLEASE NOTE: Completed=number of participants completing ≥18 cycles of treatment; not completed=number of subjects coming off study treatment prior to completing at least 18 cycles, with specified reasons for coming off study treatment. Participants continued to be followed for overall survival.

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone in combination with capecitabine (combination group): Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each cycle only, plus oral capecitabine 1000 mg/m2 twice a day (BID) (2000 mg/m2 daily dose) x 14 days, followed by 1 week of rest.
Capecitabine	Capecitabine alone: Capecitabine 1250 mg/m2 BID (2500 mg/m2 daily dose) x 14 days, followed by 1 week of rest.

Participant Flow: Overall Study

	Ixabepilone + Capecitabine	Capecitabine
STARTED	609	612
COMPLETED	15^[1]	15^[2]
NOT COMPLETED	594	597
Adverse Event	12	17
Death	8	18
Disease Progression/Relapse	270	388
Physician Decision	50	61
Lost to Follow-up	1	2
Study Drug Toxicity	179	66
Withdrawal by Subject	55	30
Still On Treatment	2	1
Not Treated	12	11
Ineligible	2	1
Noncompliance	2	1
New primary cancer	1	0
Impending surgery	0	1

[1]	Participants who received 18 or more cycles of treatment.
[2]	Participants who received 18 or more cycles of treatment.

Baseline Characteristics

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Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone in combination with capecitabine (combination group): Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each cycle only, plus oral capecitabine 1000 mg/m2 twice a day (BID) (2000 mg/m2 daily dose) x 14 days, followed by 1 week of rest.
Capecitabine	Capecitabine alone: Capecitabine 1250 mg/m2 BID (2500 mg/m2 daily dose) x 14 days, followed by 1 week of rest.

Baseline Measures

	Ixabepilone + Capecitabine	Capecitabine	Total
Number of Participants [units: participants]	609	612	1221
Age, Customized [units: participants]
<65 years	532	531	1063
≥65 years	77	81	158
<50 years	225	235	460
≥50 years	384	377	761
Age [units: years] Median ( Full Range )	53.0 ( 23.0 to 78.0 )	53.0 ( 24.0 to 81.0 )	53.0 ( 23.0 to 81.0 )
Gender [units: participants]
Female	609	612	1221
Male	0	0	0
Race/Ethnicity, Customized [units: participants]
American Indian or Alaska Native	1	2	3
Asian	90	69	159
Black or African American	25	21	46
White	480	502	982
Unknown or Not Reported	13	18	31
Karnofsky performance Status^[1] [units: units on a scale]
100	219	265	484
90	187	188	375
80	151	130	281
70	44	26	70
<70	2	2	4
not reported	6	1	7
Menopausal Status [units: participants]
Premenopausal	93	90	183
Perimenopausal	32	32	64
Postmenopausal	475	481	956
Not Reported	9	9	18
Organ Sites [units: participants]
Ascites	13	16	29
Bone	283	287	570
Brain	0	1	1
Breast	41	54	95
Chest Wall Mass	47	38	85
CNS	1	0	1
Cutaneous	64	57	121
Effusion	7	7	14
Intestine	1	1	2
Lymph Node	236	233	469
Mediastinum	54	52	106
Other	17	30	47
Pleura	86	84	170
Subcutaneous	23	24	47
Visceral, Liver	273	276	549
Visceral, Lung	221	217	438
Visceral, Other	24	26	50
Presence with at least 1 lesion [units: participants]	606	612	1218

[1]	Karnofsky Performance Scale Index measures a patient's functional impairment: 100-80=able to carry on normal activity and work, no special care; 70-50=unable to work; able to live at home and care for most personal needs with assistance; 40=unable to care for self; requires institutional or hospital care. Score reported in multiples of 10.

Outcome Measures

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1. Primary:

Overall Survival (OS) [ from date of randomization until death ]

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Measure Type	Primary
Measure Title	Overall Survival (OS)
Measure Description	Overall survival was defined as the time in months from randomization until the date of death. For those patients who had not died, survival duration was censored at the last date the patient was known to be alive. Median OS with 95% CI estimated using the Kaplan-Meier Product Limit Method.
Time Frame	from date of randomization until death
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analysis was conducted on all randomized patients on an intent to treat basis. This study required at least 846 events (deaths) to ensure the 2-sided, α = 0.05 level, log-rank test to have 90% power to show a statistically significant difference in OS between treatment groups when the hazard ratio (HR) is 0.8.

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone in combination with capecitabine (combination group): Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each cycle only, plus oral capecitabine 1000 mg/m2 twice a day (BID) (2000 mg/m2 daily dose) x 14 days, followed by 1 week of rest.
Capecitabine	Capecitabine alone: Capecitabine 1250 mg/m2 BID (2500 mg/m2 daily dose) x 14 days, followed by 1 week of rest.

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	609	612
Overall Survival (OS) [units: months] Median ( 95% Confidence Interval )	16.39 ( 14.95 to 17.91 )	15.64 ( 13.86 to 17.02 )

Statistical Analysis 1 for Overall Survival (OS)

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	.1162
Hazard Ratio (HR) ^[4]	.90
95% Confidence Interval	( .78 to 1.03 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	This primary analysis was a comparison between the 2 treatment arms using a 2-sided, α=0.05 level log-rank test (to reject the null hypothesis of equality of survival). The analysis was conducted when 880 deaths (430 in combination:450 in capecitabine) were observed from the 1221 randomized participants.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	The analysis was conducted at the 0.05 level and no adjustments were performed
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The test was stratified by (taxane resistance [yes/no], measurable disease versus non-measurable disease, prior chemotherapy for metastatic disease [yes/no], and anthracycline resistance [yes/no]).
[4]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Overall Survival (OS)

Groups ^[1]	All groups
Method ^[2]	Regression, Cox
P Value ^[3]	.0231
Hazard Ratio (HR) ^[4]	.85
95% Confidence Interval	( .75 to .98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	This prespecified secondary analysis was a Cox model adjusted for age, Karnofsky performance status, number of organ sites, estrogen receptor status, hepatic impairment, time from diagnosis, liver/lung metastases.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	No text entered.
[4]	Other relevant estimation information:
	No text entered.

2. Secondary:

Progression-Free Survival (PFS) [ every 6 weeks (± 3 days) from randomization while on treatment until documented progression ]

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3. Secondary:

Response Rate (RR) [ every 6 weeks (± 3 days) from randomization while on treatment until documented progression ]

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4. Secondary:

Duration of Response [ every 6 weeks (± 3 days) from randomization while on treatment until documented progression ]

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5. Secondary:

Time to Response [ every 6 weeks (± 3 days) from randomization while on treatment until documented progression ]

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6. Secondary:

Treatment-Related Safety Summary [ safety was assessed on a continual basis every cycle while on-treatment and every 4 weeks post treatment until toxicities resolved or were deemed irreversible. ]

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7. Secondary:

Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) [ Baseline and prior to each 21-day cycle of treatment, and at first posttreatment follow-up assessment ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial’s primary publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com

No publications provided

Responsible Party:	Bristol-Myers Squibb ( Study Director )
Study ID Numbers:	CA163-048
Study First Received:	May 7, 2004
Results First Received:	May 1, 2009
Last Updated:	November 16, 2009
ClinicalTrials.gov Identifier:	NCT00082433 History of Changes
Health Authority:	United States: Food and Drug Administration