Breast Cancer, Metastases
Conditions
Keywords
Metastatic Breast Cancer
Brief summary
The purpose of this clinical research study is to learn if BMS-247550 added to the approved therapy of capecitabine is better than capecitabine alone in shrinking or slowing the growth of the cancer in women with metastatic breast cancer who are resistant to taxane and received anthracycline chemotherapy. The safety of this treatment will also be studied.
Interventions
Ixabepilone - Intravenous Solution, IV 40mg/m², Day 1 every 21 days, Until progression/unacceptable toxicity Capecitabine (Active Comparator) - Tablet, Oral, 2000 mg/m², Bid Days 1-14 every 21 days, Until progression/unacceptable toxicity
DRUGCapecitabine
Tablet, Oral, 2500 mg/m², Bid Days 1-14 every 21 days, Until progression/unacceptable toxicity
Sponsors
R-Pharm
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have received either 2 or 3 prior chemotherapy regimens including adjuvant or neoadjuvant therapy. * Prior treatment must have included both an anthracycline (i.e., doxorubicin or epirubicin) and a taxane (i.e., paclitaxel or docetaxel). * Patients must have received a minimum cumulative dose of anthracycline or must be resistant to an anthracycline. * Patients must be resistant to taxane therapy. * Patients may not have any history of brain and/or leptomeningeal metastases. * Patients may not have CTC Grade 2 or greater neuropathy (motor or sensory). * Patients may have not have had prior treatment with an epothilone and/or capecitabine (i.e., Xeloda)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response Per IRRC | based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity | 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 to Response Per IRRC | based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity | 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. |
| Overall Response Rate (ORR) Per IRRC | based on assessments every 6 weeks while on treatment until documented disease progression/unacceptable toxicity | 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 |
| 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. | 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 |
| 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. | 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. |
| Overall Survival (OS) | from date of randomization until death | 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. |
Countries
Argentina, Belgium, Brazil, Canada, China, France, Germany, Greece, Hungary, Italy, Malaysia, Mexico, Peru, Philippines, Poland, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 375 |
| Capecitabine Capecitabine 1250 mg/m2 BID x 14 days | 377 |
| Total | 752 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomized but Never Treated | 5 | 10 |
| Overall Study | Still on Treatment as of CSR date | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Capecitabine | Ixabepilone + Capecitabine |
|---|---|---|---|
| Age, Continuous | 53.0 years | 52.0 years | 53.0 years |
| Age, Customized <50 years | 280 participants | 145 participants | 135 participants |
| Age, Customized >= 50 years | 471 participants | 231 participants | 240 participants |
| Age, Customized <65 years | 658 participants | 322 participants | 336 participants |
| Age, Customized >= 65 years | 93 participants | 54 participants | 39 participants |
| Age, Customized Unknown | 1 participants | 1 participants | 0 participants |
| Disease Sites Ascites | 28 participants | 14 participants | 14 participants |
| Disease Sites Bone | 330 participants | 162 participants | 168 participants |
| Disease Sites Breast | 124 participants | 63 participants | 61 participants |
| Disease Sites Chest Wall | 106 participants | 53 participants | 53 participants |
| Disease Sites Effusion | 112 participants | 55 participants | 57 participants |
| Disease Sites Lymph Node | 499 participants | 249 participants | 250 participants |
| Disease Sites Other | 38 participants | 18 participants | 20 participants |
| Disease Sites Peritoneum | 21 participants | 14 participants | 7 participants |
| Disease Sites Pleura | 64 participants | 35 participants | 29 participants |
| Disease Sites Skin/Soft Tissue | 122 participants | 62 participants | 60 participants |
| Disease Sites Visceral, Liver | 473 participants | 228 participants | 245 participants |
| Disease Sites Visceral, Lung | 354 participants | 174 participants | 180 participants |
| Disease Sites Visceral, Other | 62 participants | 28 participants | 34 participants |
| Disease Sites at Baseline Bone | 3 participants | 3 participants | 0 participants |
| Disease Sites at Baseline Liver ± Lung ± Skin/Soft Tissue ± Bone | 473 participants | 228 participants | 245 participants |
| Disease Sites at Baseline Lung ± Skin/Soft Tissue ± Bone | 158 participants | 87 participants | 71 participants |
| Disease Sites at Baseline Other | 11 participants | 5 participants | 6 participants |
| Disease Sites at Baseline Skin/Soft Tissue ± Bone | 101 participants | 52 participants | 49 participants |
| Karnofsky Performance Status 100 | 213 Units on a scale | 105 Units on a scale | 108 Units on a scale |
| Karnofsky Performance Status 70 | 67 Units on a scale | 34 Units on a scale | 33 Units on a scale |
| Karnofsky Performance Status <70 | 1 Units on a scale | 1 Units on a scale | 0 Units on a scale |
| Karnofsky Performance Status 80 | 188 Units on a scale | 102 Units on a scale | 86 Units on a scale |
| Karnofsky Performance Status 90 | 277 Units on a scale | 132 Units on a scale | 145 Units on a scale |
| Karnofsky Performance Status Not reported | 6 Units on a scale | 3 Units on a scale | 3 Units on a scale |
| Menopausal Status Not reported | 28 participants | 14 participants | 14 participants |
| Menopausal Status Perimenopausal | 42 participants | 23 participants | 19 participants |
| Menopausal Status Postmenopausal | 577 participants | 289 participants | 288 participants |
| Menopausal Status Premenopausal | 105 participants | 51 participants | 54 participants |
| Number of Disease Sites 1 disease site | 73 participants | 34 participants | 39 participants |
| Number of Disease Sites 2 disease sites | 183 participants | 98 participants | 85 participants |
| Number of Disease Sites 3 disease sites | 231 participants | 121 participants | 110 participants |
| Number of Disease Sites 4 disease sites | 148 participants | 69 participants | 79 participants |
| Number of Disease Sites ≥5 disease sites | 111 participants | 53 participants | 58 participants |
| Presence of All Lesions Subjects with at least 1 lesion | 746 participants | 375 participants | 371 participants |
| Presence of All Lesions Subjects with no lesions | 6 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 170 participants | 87 participants | 83 participants |
| Race/Ethnicity, Customized Black or African American | 22 participants | 11 participants | 11 participants |
| Race/Ethnicity, Customized Other | 55 participants | 32 participants | 23 participants |
| Race/Ethnicity, Customized White | 504 participants | 247 participants | 257 participants |
| Sex: Female, Male Female | 751 Participants | 376 Participants | 375 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants |
| Visceral Disease in Liver and/or Lung Missing | 6 participants | 2 participants | 4 participants |
| Visceral Disease in Liver and/or Lung No | 115 participants | 60 participants | 55 participants |
| Visceral Disease in Liver and/or Lung Yes | 631 participants | 315 participants | 316 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 350 / 368 | 360 / 369 |
| serious Total, serious adverse events | 127 / 368 | 151 / 369 |
Outcome results
Primary
Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC)
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
Population: PFS was analyzed on all randomized patients on an intention to treat basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone + Capecitabine | Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC) | 5.85 Months |
| Capecitabine | Progression-free Survival (PFS) Per Independent Radiology Review Committee (IRRC) | 4.17 Months |
Comparison: 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.p-value: 0.000395.17% CI: [0.64, 0.88]Log Rank
Secondary
Duration of Response Per IRRC
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
Population: Results for duration of response apply to only those subjects with a response (defined as complete or partial response).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone + Capecitabine | Duration of Response Per IRRC | 6.4 months |
| Capecitabine | Duration of Response Per IRRC | 5.6 months |
Secondary
Overall Response Rate (ORR) Per IRRC
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
Population: The analysis of ORR was conducted on all randomized patients on an intent to treat basis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ixabepilone + Capecitabine | Overall Response Rate (ORR) Per IRRC | 34.7 percent |
| Capecitabine | Overall Response Rate (ORR) Per IRRC | 14.3 percent |
Comparison: 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.p-value: <0.000195% CI: [2.2, 4.5]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
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
Population: Overall survival was analyzed on all randomized patients on an intent to treat basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone + Capecitabine | Overall Survival (OS) | 12.9 Months |
| Capecitabine | Overall Survival (OS) | 11.1 Months |
Comparison: 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.p-value: 0.193695.17% CI: [0.77, 1.05]Log Rank
Secondary
Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI)
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.
Population: 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.)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 6 (n=227; n=214) | -0.2 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 24 (n=95; n=82) | -0.8 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 9 (n=194; n=184) | -0.6 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 21 (n=116; n=101) | -0.7 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 12 (n=173; n=158) | -1.3 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 3 (n=282; n=273) | -0.4 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 15 (n=148; n=145) | -0.7 units on a scale |
| Ixabepilone + Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 18 (n=122; n=121) | -1.0 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 18 (n=122; n=121) | 1.7 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 21 (n=116; n=101) | 1.1 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 24 (n=95; n=82) | 2.3 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 3 (n=282; n=273) | 0.3 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 6 (n=227; n=214) | 1.1 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 9 (n=194; n=184) | 1.8 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 12 (n=173; n=158) | 1.4 units on a scale |
| Capecitabine | Symptom Assessment Score Changes From Baseline for Functional Assessment of Cancer Therapy-Breast Symptom Index (FBSI) | Week 15 (n=148; n=145) | 1.7 units on a scale |
Comparison: 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.p-value: 0.0002Wei-Lachin
Secondary
Time to Response Per IRRC
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
Population: Results for time to response apply to only those subjects with a response (defined as complete or partial response)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone + Capecitabine | Time to Response Per IRRC | 11.7 weeks |
| Capecitabine | Time to Response Per IRRC | 12.0 weeks |
Secondary
Treatment-related Safety Summary
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.
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ixabepilone + Capecitabine | Treatment-related Safety Summary | Deaths on-study or within 30 days of last dose | 33 Participants |
| Ixabepilone + Capecitabine | Treatment-related Safety Summary | Treatment-related Adverse Events (AEs) | 357 Participants |
| Ixabepilone + Capecitabine | Treatment-related Safety Summary | Treatment-related Serious Adverse Events (SAEs) | 91 Participants |
| Ixabepilone + Capecitabine | Treatment-related Safety Summary | Treatment-related AEs leading to Discontinuation | 137 Participants |
| Capecitabine | Treatment-related Safety Summary | Treatment-related Serious Adverse Events (SAEs) | 31 Participants |
| Capecitabine | Treatment-related Safety Summary | Deaths on-study or within 30 days of last dose | 40 Participants |
| Capecitabine | Treatment-related Safety Summary | Treatment-related AEs leading to Discontinuation | 25 Participants |
| Capecitabine | Treatment-related Safety Summary | Treatment-related Adverse Events (AEs) | 330 Participants |