Trastuzumab, Ixabepilone, and Carboplatin in Treating Patients With HER2/Neu-Positive Metastatic Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00077376
• Collaborator: (none)
• Enrollment: 61
• Location: 1
• Arm: 1
• Duration (Months): 72
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving trastuzumab together with ixabepilone and carboplatin works in treating patients with HER2/neu-positive metastatic breast cancer. Monoclonal antibodies, such as trastuzumab, can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as ixabepilone and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining trastuzumab with ixabepilone and carboplatin may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer	Biological: trastuzumab; Drug: ixabepilone; Drug: carboplatin; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the response rate (as determined by RECIST criteria) to combination therapy with Ixabepilone (BMS-247550), trastuzumab, and carboplatin in patients with metastatic breast cancer known to overexpress HER2.

SECONDARY OBJECTIVES:

1. To determine time to disease progression (TTP) and time to treatment failure (TTF) after treatment with Ixabepilone (BMS-247550), trastuzumab and carboplatin in patients with metastatic breast cancer known to overexpress HER2.

2. To determine the toxicity of combination therapy with Ixabepilone (BMS-247550), trastuzumab and carboplatin in patients with metastatic breast cancer known to overexpress HER2.

3. To evaluate overall survival (OS) of combination therapy with Ixabepilone (BMS-247550), trastuzumab, and carboplatin in patients with metastatic breast cancer known to overexpress HER2.

4. To correlate levels of phospho-STAT3 with levels of HER2, Survivin and EGFR expression as measured in tissue by immunohistochemistry.

OUTLINE: This is a multicenter study.

Induction therapy: Patients receive trastuzumab (Herceptin®) IV over 30 minutes* on days 1, 8, 15, and 22 and ixabepilone IV over 1 hour and carboplatin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity.

NOTE: *Trastuzumab is given over 90 minutes on day 1 of course 1 (induction therapy) only.

Maintenance therapy: Patients receive trastuzumab IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years from study entry.

PROJECTED ACCRUAL: A total of 10-60 patients will be accrued for this study within 1-6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Trastuzumab Plus Weekly Ixabepilone(BMS-247550) and Carboplatin in Patients With HER2/Neu-Positive Metastatic Breast Cancer
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (trastuzumab, ixabepilone, carboplatin) Induction therapy: Patients receive trastuzumab (Herceptin®) IV over 30 minutes* on days 1, 8, 15, and 22 and ixabepilone IV over 1 hour and carboplatin IV over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 courses in the absence of unacceptable toxicity. NOTE: *Trastuzumab is given over 90 minutes on day 1 of course 1 (induction therapy) only. Maintenance therapy: Patients receive trastuzumab IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: trastuzumab; Given IV; Other Names: anti-c-erB-2 Herceptin MOAB HER2 ; Drug: ixabepilone; Given IV; Other Names: BMS-247550 epothilone B lactam Ixempra ; Drug: carboplatin; Given IV; Other Names: Carboplat CBDCA JM-8 Paraplat Paraplatin ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Objective Response for HER2+ Patients (Best Objective Response a Patient Has Ever Experienced on Study) [Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years]

   To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.

Secondary Outcome Measures

1. Objective Response for All Treated Patients (the Best Response a Patient Has Ever Experienced on Study) [Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years]

   To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.

2. Time to Disease Progression for HER2+ Patients [Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years]

   This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.

3. Time to Disease Progression for All Treated Patients [Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years]

   This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.

4. Time to Treatment Failure for HER2+ Patients [Assessed every cycle until treatment discontinuation]

   Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.

5. Time to Treatment Failure for All Treated Patients [Assessed every cycle until treatment discontinuation]

   Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.

6. Kaplan-Meier Estimate of Overall Survival at 3 Years for HER2+ Patients [Assessed every 3 months for 2 years, then every 6 months for 3 years]

   Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.

7. Kaplan-Meier Estimate of Overall Survival at 3 Years for All Treated Patients [Assessed every 3 months for 2 years, then every 6 months for 3 years]

   Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with histologically confirmed adenocarcinoma of the breast which is metastatic and is known to overexpress HER2/neu who have received no prior chemotherapy for metastatic breast cancer; prior hormonal therapy for metastatic disease is allowed; NOTE: for this protocol, HER2 overexpression will be defined as 3+ HER2 positivity as measured by immunohistochemistry using the HercepTest (DAKO) or HER2 gene amplification as measured by fluorescent in-situ hybridization (FISH, e.g. Vysis); representative diagnostic tissue must be submitted for central diagnostic review

• Patients must not be pregnant or breast feeding because of the teratogenic potential of these drugs; it is recommended that all females of childbearing potential have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective non-hormonal method of contraception

• Patients must have at least one objective measurable disease parameter; baseline measurements and evaluations using RECIST criteria guidelines must be obtained within 4 weeks prior to registration to the study; NOTE: all areas of disease should be recorded and followed

• Patients must have an ECOG performance status of 0 or 1

• Patients must be disease free of prior malignancy for >= 5 years with the exception of curatively treated basal cell carcinoma or squamous cell carcinomas of the skin or carcinoma in situ of the cervix

• Patients must not have a history of untreated brain metastasis or brain metastasis currently undergoing radiation; patients with brain metastasis representing the sole site of disease are not eligible for this study; patients with previously treated brain metastasis who have responded to brain radiotherapy and/or surgery and continue in response are eligible provided the brain is not the only site of measurable disease

• Patients must not have peripheral neuropathy of any grade

• Patients must not have a history of prior severe (grade 3 or 4) hypersensitivity reaction to a drug formulated in polyoxyethylated castor oil (Cremophor EL)

• Patients must have left ventricular ejection fraction by MUGA scan or echocardiogram that is at or above the lower institutional limits of normal obtained within 6 weeks prior to registration

• Patients must not have a history of New York Heart Association class 3 or 4 heart failure

• Serum creatinine =< 1.5 mg/dl

• Granulocytes >= 1500/mm^3

• Platelets >= 100,000/mm^3

• SGOT(AST) and SGPT(ALT) =< 1.5 x upper limit of normal (unless liver is involved by tumor, in which case SGOT(AST) and SGPT(ALT) can be =< 2.0 x upper limit of normal)

• Patients must have no history of prior therapy with trastuzumab (Herceptin), Ixabepilone (BMS-247550) or carboplatin for metastatic disease; patients who develop metastatic disease =< 6 months after completing adjuvant trastuzumab (Herceptin), paclitaxel, docetaxel, carboplatin, or Ixabepilone (BMS-247550) are considered to have had prior therapy for metastatic disease and are excluded from study participation

• Patients must not have received a cumulative dose of doxorubicin of greater than 360 mg/m^{2 or epirubicin of greater than 640 mg/m}2

• Concurrent use of hormonal therapy is not permitted; concurrent radiation therapy is not permitted; hormonal therapy must have been discontinued >= 1 week prior to registration; radiation therapy must have been completed >= 2 weeks prior to registration

• Patients may have had prior radiation therapy, but the previously irradiated tumors cannot be used to assess a clinical response; patients will not be eligible if they do not have other areas of measurable disease; an exception will be given for patients who have had tumor recurrence in an area that received adjuvant radiation treatments, such as the axilla or chest wall

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Eastern Cooperative Oncology Group	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stacy Moulder, Eastern Cooperative Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00077376
• Other Study ID Numbers: NCI-2012-02946; NCI-2012-02946; U10CA023318; E2103; E2103; U10CA021115
• First Posted: Feb 12, 2004
• Last Update Posted: May 21, 2014
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Carboplatin; Trastuzumab; Epothilone B; Epothilones

Study Results

Participant Flow

Recruitment Details	The study was activated on March 19th, 2004. Accrual was suspended on December 16th, 2004 after reaching the first stage accrual goal. After a pre-planned toxicity analysis, accrual resumed on March 4th, 2005. The study was completed on March 24th, 2006, after accruing 61 patients.

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Period Title: Overall Study
STARTED	61
Treated	59
HER2+ in Central Testing	39
COMPLETED	39
NOT COMPLETED	22

Baseline Characteristics

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Overall Participants	59
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	59 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Objective Response for HER2+ Patients (Best Objective Response a Patient Has Ever Experienced on Study)
Description	To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.
Time Frame	Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years

Outcome Measure Data

Analysis Population Description

HER2+ patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	39
Complete Response	3 5.1%
Partial Response	13 22%
No Change/ Stable	10 16.9%
Progression	11 18.6%
Unevaluable	2 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab/Ixabepilone/Carboplatin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Objective response rate
	Estimated Value	41
	Confidence Interval	(2-Sided) 95%; 26 to 58
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Objective Response for All Treated Patients (the Best Response a Patient Has Ever Experienced on Study)
Description	To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. The same method of assessment and the same technique should be used to characterize each lesion at baseline and during follow-up. The best overall response based on RECIST is the best response recorded from registration until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since registration. The best response was determined based on the tumor responses in target and nontarget lesions, with or without new lesions. To be assigned a status of complete or partial response, changes in tumor measurements must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 8 weeks.
Time Frame	Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	59
Compelete Response	4 6.8%
Partial Response	22 37.3%
No Change/ Stable	15 25.4%
Progression	16 27.1%
Unevaluable	2 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab/Ixabepilone/Carboplatin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Objective response rate
	Estimated Value	44
	Confidence Interval	(2-Sided) 95%; 31 to 58
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Disease Progression for HER2+ Patients
Description	This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.
Time Frame	Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years

Outcome Measure Data

Analysis Population Description

HER2+ patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	39
Median (95% Confidence Interval) [Months]	7.1

4. Secondary Outcome

Title	Time to Disease Progression for All Treated Patients
Description	This interval will be measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression based on RECIST. Patients progression-free at last follow-up were censored.
Time Frame	Assessed every 3 cycles during induction therapy and every 6 cycles during maintenance therapy until disease progression or up to 5 years

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	59
Median (95% Confidence Interval) [Months]	8.2

5. Secondary Outcome

Title	Time to Treatment Failure for HER2+ Patients
Description	Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.
Time Frame	Assessed every cycle until treatment discontinuation

Outcome Measure Data

Analysis Population Description

HER2+ patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	39
Median (95% Confidence Interval) [Months]	5.4

6. Secondary Outcome

Title	Time to Treatment Failure for All Treated Patients
Description	Time from study entry to the date at which a patient was removed from treatment due to progression, toxicity, refusal or death. If a patient was considered to be a major treatment violation or was taken off study as a non-protocol failure, the patient would be censored on the date he/she was removed from treatment.
Time Frame	Assessed every cycle until treatment discontinuation

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	59
Median (95% Confidence Interval) [Months]	5.9

7. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival at 3 Years for HER2+ Patients
Description	Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.
Time Frame	Assessed every 3 months for 2 years, then every 6 months for 3 years

Outcome Measure Data

Analysis Population Description

HER2+ patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	39
Number (95% Confidence Interval) [Percentage of Participants]	50 84.7%

8. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival at 3 Years for All Treated Patients
Description	Survival estimate from the Kaplan-Meier curve of the proportion of patients alive at 3 years.
Time Frame	Assessed every 3 months for 2 years, then every 6 months for 3 years

Outcome Measure Data

Analysis Population Description

All treated patients

Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
Measure Participants	59
Number (95% Confidence Interval) [Percentage of Participants]	48 81.4%

Adverse Events

Time Frame	Assessed every cycle (1 induction cycle = 4 weeks, 1 maintenance cycle = 3 weeks) while on treatment and for 30 days after the end of treatment.
Arm/Group Title	Trastuzumab/Ixabepilone/Carboplatin
Arm/Group Description	During the induction phase, patients were treated with Ixabepilone (BMS-247550) 15mg/m2 intravenously (IV) followed by carboplatin (AUC=2 IV) on days 1, 8 and 15 of a 28-day cycle for a maximum of 6 cycles. Trastuzumab was administered weekly (4mg/kg loading dose then 2mg/kg IV) starting on day 1. Routine premedication included H1 blocker (diphenhydramine 50 mg orally (PO) or IV), H2 blocker (ranitidine 150 mg PO or 50 mg IV or another equivalent H2 blocker), and at least a 5-HT3 antagonist and dexamethasone. After completion of 24 weekly trastuzumab doses (induction therapy), trastuzumab were given at a dose of 6 mg/kg IV every 3 weeks (maintenance therapy) beginning one week after the 24th weekly dose. Trastuzumab were repeated every 21 days until disease progression or prohibitive toxicity.
All Cause Mortality
	Trastuzumab/Ixabepilone/Carboplatin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Trastuzumab/Ixabepilone/Carboplatin
	Affected / at Risk (%)	# Events
Total	39/59 (66.1%)
Blood and lymphatic system disorders
Anemia	7/59 (11.9%)
Hematologic-other	1/59 (1.7%)
Gastrointestinal disorders
Diarrhea w/o prior colostomy	4/59 (6.8%)
Nausea	4/59 (6.8%)
Vomiting	2/59 (3.4%)
Abdomen, pain	1/59 (1.7%)
General disorders
Fatigue	7/59 (11.9%)
Death NOS	1/59 (1.7%)
Immune system disorders
Allergic reaction	2/59 (3.4%)
Infections and infestations
Infection with Grade 0-2 neutrophils, urinary tract	2/59 (3.4%)
Investigations
Leukopenia	19/59 (32.2%)
Neutropenia	29/59 (49.2%)
Thrombocytopenia	8/59 (13.6%)
Weight loss	1/59 (1.7%)
Alkaline phosphatase increased	1/59 (1.7%)
AST increased	1/59 (1.7%)
Metabolism and nutrition disorders
Anorexia	3/59 (5.1%)
Dehydration	3/59 (5.1%)
Hyperglycemia	2/59 (3.4%)
Hypokalemia	1/59 (1.7%)
Hypernatremia	1/59 (1.7%)
Hyponatremia	1/59 (1.7%)
Musculoskeletal and connective tissue disorders
Nonneuropathic generalized weakness	1/59 (1.7%)
Extremity-limb, pain	1/59 (1.7%)
Joint, pain	1/59 (1.7%)
Muscle, pain	1/59 (1.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/59 (1.7%)
Nervous system disorders
Encephalopathy	1/59 (1.7%)
Neuropathy-sensory	4/59 (6.8%)
Syncope	1/59 (1.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/59 (1.7%)
Vascular disorders
Hypertension	1/59 (1.7%)
Hypotension	1/59 (1.7%)
Thrombosis/thrombus/embolism	2/59 (3.4%)
Other (Not Including Serious) Adverse Events
	Trastuzumab/Ixabepilone/Carboplatin
	Affected / at Risk (%)	# Events
Total	59/59 (100%)
Blood and lymphatic system disorders
Anemia	55/59 (93.2%)
Cardiac disorders
Left ventricular systolic dysfunction	6/59 (10.2%)
Gastrointestinal disorders
Constipation	24/59 (40.7%)
Diarrhea w/o prior colostomy	33/59 (55.9%)
Dyspepsia	11/59 (18.6%)
Muco/stomatitis by exam, oral cavity	17/59 (28.8%)
Nausea	42/59 (71.2%)
Vomiting	20/59 (33.9%)
Abdomen, pain	6/59 (10.2%)
General disorders
Fatigue	51/59 (86.4%)
Fever w/o neutropenia	5/59 (8.5%)
Rigors/chills	3/59 (5.1%)
Edema limb	10/59 (16.9%)
Chest/thoracic pain NOS	5/59 (8.5%)
Immune system disorders
Allergic reaction	8/59 (13.6%)
Infections and infestations
Infection with Grade 0-2 neutrophils, skin	3/59 (5.1%)
Infection with Grade 0-2 neutrophils, urinary tract	3/59 (5.1%)
Investigations
Leukopenia	54/59 (91.5%)
Neutropenia	44/59 (74.6%)
Thrombocytopenia	37/59 (62.7%)
Weight loss	10/59 (16.9%)
Alkaline phosphatase increased	17/59 (28.8%)
ALT increased	24/59 (40.7%)
AST increased	20/59 (33.9%)
Bilirubin increased	4/59 (6.8%)
Creatinine increased	4/59 (6.8%)
Metabolism and nutrition disorders
Anorexia	22/59 (37.3%)
Hypoalbuminemia	3/59 (5.1%)
Hyperglycemia	28/59 (47.5%)
Hypoglycemia	3/59 (5.1%)
Hypomagnesemia	3/59 (5.1%)
Hypokalemia	4/59 (6.8%)
Musculoskeletal and connective tissue disorders
Back, pain	3/59 (5.1%)
Joint, pain	14/59 (23.7%)
Muscle, pain	16/59 (27.1%)
Nervous system disorders
Taste disturbance	21/59 (35.6%)
Dizziness	7/59 (11.9%)
Neuropathy-motor	4/59 (6.8%)
Neuropathy-sensory	36/59 (61%)
Head/headache	8/59 (13.6%)
Psychiatric disorders
Insomnia	7/59 (11.9%)
Anxiety	3/59 (5.1%)
Respiratory, thoracic and mediastinal disorders
Nose, hemorrhage	5/59 (8.5%)
Cough	6/59 (10.2%)
Dyspnea	11/59 (18.6%)
Skin and subcutaneous tissue disorders
Sweating	3/59 (5.1%)
Dry skin	4/59 (6.8%)
Alopecia	33/59 (55.9%)
Pruritus/itching	4/59 (6.8%)
Rash/desquamation	10/59 (16.9%)
Vascular disorders
Hot flashes	3/59 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.