Novel Epothilone 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:	Breast Cancer Metastases
Interventions:	Drug: Ixabepilone + Capecitabine Drug: Capecitabine

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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	Ixabepilone + Capecitabine	Capecitabine
STARTED	375	377
Never Treated	5	10
Still on Treatment	0	1
COMPLETED	370^[1]	366^[2]
NOT COMPLETED	5	11
Randomized but Never Treated	5	10
Still on Treatment as of CSR date	0	1

[1]	Participants who are off treatment
[2]	Participants who are off treatment

	Ixabepilone + Capecitabine	Capecitabine	Total
Number of Participants [units: participants]	375	377	752
Age, Customized [units: participants]
<65 years	336	322	658
>= 65 years	39	54	93
<50 years	135	145	280
>= 50 years	240	231	471
Unknown	0	1	1
Age [units: years] Median ( Full Range )	53.0 ( 25.0 to 76.0 )	52.0 ( 25.0 to 79.0 )	53.0 ( 25.0 to 79.0 )
Gender [units: participants]
Female	375	376	751
Male	0	1	1
Race/Ethnicity, Customized [units: participants]
American Indian or Alaska Native	1	0	1
Asian	83	87	170
Black or African American	11	11	22
White	257	247	504
Other	23	32	55
Disease Sites [units: participants]
Ascites	14	14	28
Bone	168	162	330
Breast	61	63	124
Chest Wall	53	53	106
Effusion	57	55	112
Lymph Node	250	249	499
Other	20	18	38
Peritoneum	7	14	21
Pleura	29	35	64
Skin/Soft Tissue	60	62	122
Visceral, Liver	245	228	473
Visceral, Lung	180	174	354
Visceral, Other	34	28	62
Disease Sites at Baseline [units: participants]
Liver ± Lung ± Skin/Soft Tissue ± Bone	245	228	473
Lung ± Skin/Soft Tissue ± Bone	71	87	158
Skin/Soft Tissue ± Bone	49	52	101
Bone	0	3	3
Other	6	5	11
Karnofsky Performance Status^[1] [units: Units on a scale]
100	108	105	213
90	145	132	277
80	86	102	188
70	33	34	67
<70	0	1	1
Not reported	3	3	6
Menopausal Status [units: participants]
Premenopausal	54	51	105
Perimenopausal	19	23	42
Postmenopausal	288	289	577
Not reported	14	14	28
Number of Disease Sites [units: participants]
1 disease site	39	34	73
2 disease sites	85	98	183
3 disease sites	110	121	231
4 disease sites	79	69	148
≥5 disease sites	58	53	111
Presence of All Lesions [units: participants]
Subjects with at least 1 lesion	371	375	746
Subjects with no lesions	4	2	6
Visceral Disease in Liver and/or Lung [units: participants]
Yes	316	315	631
No	55	60	115
Missing	4	2	6

[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; 40-0=Unable to care for self; institutional or hospital care needed. Score reported in multiples of 10.

Outcome Measures

1. Primary:

Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC) [ based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity ]

Measure Type	Primary
Measure Title	Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC)
Measure Description	PFS defined as the time in months from randomization to date of progression. Patients who died without a reported prior progression were considered to have progressed on date of death; those who didn’t progress or die were censored on date of last tumor assessment. Median PFS time with 95% CI estimated using the Kaplan Meier product limit method.
Time Frame	based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity
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.
PFS was analyzed on all randomized patients on an intention to treat basis.

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each 21-day cycle, plus oral capecitabine 1000 mg/m2 twice a day (BID) x 14 days
Capecitabine	Capecitabine 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	375	377
Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC) [units: Months] Median ( 95% Confidence Interval )	5.85 ( 5.45 to 6.97 )	4.17 ( 3.81 to 4.50 )

Statistical Analysis 1 for Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC)

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	.0003
Hazard Ratio (HR) ^[4]	0.75
95.17% Confidence Interval	( 0.64 to 0.88 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Study required 615 events to achieve 90% power to detect a hazard ratio of 0.77 using a 2-sided α = 0.05 log-rank test. The analysis was a comparison between the 2 treatment arms using a 2-sided α=0.0483 log-rank test (adjusted for an interim analysis using the O’Brien Fleming spending function) to reject the null hypothesis of equality of progression free survival. The analysis was conducted when 639 events (310 in combination:329 in capecitabine) were observed from the 752 randomized patients.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	95.17% confidence interval is adjusted for the interim analysis.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Test was stratified by 1) presence of visceral metastases in liver or lung, 2) minimum of either doxorubicin 420 mg/m2 or epirubicin 360 mg/m2, and relapse > 6 months in adjuvant setting, and 3) prior chemotherapy for metastatic disease. (yes/no)
[4]	Other relevant estimation information:
	No text entered.

2. Secondary:

Overall Response Rate (ORR) Per IRRC [ based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity ]

Measure Type	Secondary
Measure Title	Overall Response Rate (ORR) Per IRRC
Measure Description	Participants with best response of "Complete" or "Partial" according to Response Evaluation Criteria in Solid Tumors (RECIST) a 4-item scale wherein complete response=disappearance of all target lesions and partial response=30% decrease in the sum of the longest diameter of target lesions
Time Frame	based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity
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.
The analysis of ORR was conducted on all randomized patients on an intent to treat basis.

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each 21-day cycle, plus oral capecitabine 1000 mg/m2 twice a day (BID) x 14 days
Capecitabine	Capecitabine 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	375	377
Overall Response Rate (ORR) Per IRRC [units: percent] Mean ( 95% Confidence Interval )	34.7 ( 29.9 to 39.7 )	14.3 ( 10.9 to 18.3 )

Statistical Analysis 1 for Overall Response Rate (ORR) Per IRRC

Groups ^[1]	All groups
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	<.0001
Odds Ratio (OR) ^[4]	3.15
95% Confidence Interval	( 2.20 to 4.50 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The study had 95 percent power to detect a significant difference in ORR if the true response rate was 32 percent in the combination arm and 20 percent in the capecitabine arm.
[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.

3. Secondary:

Duration of Response Per IRRC [ based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity ]

Measure Type	Secondary
Measure Title	Duration of Response Per IRRC
Measure Description	Computed for all patients with a best response of "Partial" or "Complete" per RECIST (a 4-item scale as described in previous outcome measure), calculated from the time when these criteria were first met until the first date of documented progression or death.
Time Frame	based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity
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.
Results for duration of response apply to only those subjects with a response (defined as complete or partial response).

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each 21-day cycle, plus oral capecitabine 1000 mg/m2 twice a day (BID) x 14 days
Capecitabine	Capecitabine 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	130	54
Duration of Response Per IRRC [units: months] Median ( 95% Confidence Interval )	6.4 ( 5.6 to 7.1 )	5.6 ( 4.2 to 7.5 )

No statistical analysis provided for Duration of Response Per IRRC

4. Secondary:

Time to Response Per IRRC [ based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity ]

Measure Type	Secondary
Measure Title	Time to Response Per IRRC
Measure Description	Time to response was summarized using descriptive statistics and was defined as the time from first dose of study treatment until measurement criteria were first met for Partial Response or Complete Response.
Time Frame	based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity
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.
Results for time to response apply to only those subjects with a response (defined as complete or partial response)

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each 21-day cycle, plus oral capecitabine 1000 mg/m2 twice a day (BID) x 14 days
Capecitabine	Capecitabine 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	130	54
Time to Response Per IRRC [units: weeks] Median ( Full Range )	11.7 ( 4.4 to 61.4 )	12.0 ( 4.3 to 41.9 )

No statistical analysis provided for Time to Response Per IRRC

5. Secondary:

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

Measure Type	Secondary
Measure Title	Overall Survival (OS)
Measure Description	OS was defined as the time from randomization to death. Participants who did not die at the time of the analysis were censored at the latest follow-up date. Median OS with 95% CI was 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.
Overall survival was analyzed on all randomized patients on an intent to treat basis.

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each 21-day cycle, plus oral capecitabine 1000 mg/m2 twice a day (BID) x 14 days
Capecitabine	Capecitabine 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	375	377
Overall Survival (OS) [units: Months] Median ( 95% Confidence Interval )	12.9 ( 11.5 to 14.2 )	11.1 ( 10.0 to 12.5 )

Statistical Analysis 1 for Overall Survival (OS)

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.1936
Hazard Ratio (HR) ^[4]	0.90
95.17% Confidence Interval	( 0.77 to 1.05 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Study required 631 deaths to achieve 80% power to detect a Hazard ratio of 0.8 using a 2-sided α = 0.05 log rank test. The analysis was a comparison between the 2 treatment arms using a 2-sided α=0.05 log-rank test to reject the null hypothesis of equality of survival. The analysis was conducted when 639 deaths (318 in combination:321 in capecitabine) were observed from the 752 randomized patients.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	Test was conducted at the α=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:
	Test was stratified by presence of visceral metastases in liver or lung (y/n), minimum of either doxorubicin 420 mg/m2 or epirubicin 360 mg/m2, and relapse > 6 months in adjuvant setting (y/n), and prior chemotherapy for metastatic disease (y/n).
[4]	Other relevant estimation information:
	Confidence Interval adjusted for interim analysis.

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. ]

Measure Type	Secondary
Measure Title	Treatment-related Safety Summary
Measure Description	Laboratory values, adverse events, and other symptoms were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTC) Version 3.0
Time Frame	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.
Safety Issue	Yes

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.
All treated participants; all participants who received at least 1 dose of study therapy.Participants with baseline hepatic impairment (combination arm, n = 29; capecitabine arm, n = 35), defined as Grade ≥2 AST, ALT or Grade ≥1 total bilirubin, were contraindicated due to disproportionate number of toxic deaths.

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 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	369	368
Treatment-related Safety Summary [units: Participants]
Deaths on-study or within 30 days of last dose	33	40
Treatment-related Serious Adverse Events (SAEs)	91	31
Treatment-related Adverse Events (AEs)	357	330
Treatment-related AEs leading to Discontinuation	137	25

No statistical analysis provided for Treatment-related Safety Summary

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. ]

Measure Type	Secondary
Measure Title	Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI)
Measure Description	Quality of life, as measured by the FBSI, an 8-item, participant-reported instrument to measure symptoms. Each item has 5 possible responses ranging from 0 (not at all) to 4 (very much). The scoring was conducted according to the Functional Assessment of Chronic Illness Therapy manual, Version 4; higher scores reflect fewer symptoms.
Time Frame	Baseline and prior to each 21-day cycle of treatment, and at first posttreatment follow-up assessment.
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 participants on an intent to treat basis.(Note: while table only reports data up to 24 wks, which represents most results, statistical analysis includes ALL assessments through study and follow-up; a few participants were assessed after more than 100 weeks.)

Reporting Groups

	Description
Ixabepilone + Capecitabine	Ixabepilone 40 mg/m2 administered as a 3-hour intravenous (IV) infusion on Day 1 of each 21-day cycle, plus oral capecitabine 1000 mg/m2 twice a day (BID) x 14 days
Capecitabine	Capecitabine 1250 mg/m2 BID x 14 days

Measured Values

	Ixabepilone + Capecitabine	Capecitabine
Number of Participants Analyzed [units: participants]	375	377
Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) [units: units on a scale] Mean ( 95% Confidence Interval )
Week 3 (n=282; n=273)	-0.4 ( -0.97 to 0.20 )	0.3 ( -0.28 to 0.84 )
Week 6 (n=227; n=214)	-0.2 ( -0.90 to 0.48 )	1.1 ( 0.30 to 1.83 )
Week 9 (n=194; n=184)	-0.6 ( -1.31 to 0.19 )	1.8 ( 0.97 to 2.58 )
Week 12 (n=173; n=158)	-1.3 ( -2.19 to -0.42 )	1.4 ( 0.55 to 2.18 )
Week 15 (n=148; n=145)	-0.7 ( -1.65 to 0.27 )	1.7 ( 0.73 to 2.72 )
Week 18 (n=122; n=121)	-1.0 ( -2.18 to 0.13 )	1.7 ( 0.76 to 2.63 )
Week 21 (n=116; n=101)	-0.7 ( -1.63 to 0.28 )	1.1 ( 0.01 to 2.21 )
Week 24 (n=95; n=82)	-0.8 ( -1.89 to 0.38 )	2.3 ( 1.13 to 3.41 )

Statistical Analysis 1 for Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI)

Groups ^[1]	All groups
Method ^[2]	Wei-Lachin
P Value ^[3]	.0002

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	There was a statistically significant difference between groups in change from baseline FBSI score favoring capecitabine. A mean change from baseline of 2.5 was considered a clinically meaningful difference (minimally important difference or MID). On-treatment mean changes in the FBSI did not reach the MID in either group.
[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.

Responsible Party:	Bristol-Myers Squibb ( Study Director )
Study ID Numbers:	CA163-046
Study First Received:	March 26, 2004
Results First Received:	May 1, 2009
Last Updated:	November 16, 2009
ClinicalTrials.gov Identifier:	NCT00080301 History of Changes
Health Authority:	United States: Food and Drug Administration