Randomized Phase II Study of Ixabepilone Alone and Ixabepilone Plus Cetuximab as First-Line Treatment for Female Subjects With Triple Negative Locally Advanced Non-resectable and/or Metastatic Breast Cancer

• Sponsor: R-Pharm (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00633464
• Collaborator: (none)
• Enrollment: 79
• Locations: 19
• Arms: 2
• Duration (Months): 35
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to estimate the response rate of ixabepilone monotherapy, and the combination of ixabepilone plus cetuximab as first-line treatment of female subjects with triple negative (estrogen receptor [ER], progesterone receptor [PR], Human Epidermal Growth Factor Receptor 2 [HER2] negative) locally advanced non-resectable and/or metastatic breast cancer

Condition or Disease	Intervention/Treatment	Phase
Triple Negative Locally Advanced Non-resectable Breast Cancer; Metastatic Breast Cancer	Drug: ixabepilone; Drug: ixabepilone + cetuximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 79 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of Ixabepilone Alone and Ixabepilone Plus Cetuximab as First-Line Treatment for Female Subjects With Triple Negative (ER, PR, Her2 Negative) Locally Advanced Non-resectable and/or Metastatic Breast Cancer
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (ixabepilone 40 mg^2) ixabepilone 40 mg/m^2 every 3 weeks	Drug: ixabepilone; injection, intravenous (IV), until unacceptable toxicity or progression or 15 months after the Last Subject First Visit (LSFV), whichever comes first. Ixabepilone 40 mg/m^2 was administered as a 3-hour IV continuous infusion on Day 1 in a 21-day cycle provided the participant met the re-treatment criteria.; Other Names: IXEMPRA BMS-247550
Experimental: Arm B (cetuximab 250 mg/m^2 + ixabepilone 40 mg/m^2) cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks	Drug: ixabepilone + cetuximab; Ixabepilone: injection, IV, until unacceptable toxicity or progression or 15 months after the LSFV, whichever comes first. Ixabepilone 40 mg/m^2 was administered as a 3-hour IV continuous infusion on Day 1 in a 21-day cycle provided the participant meets the re-treatment criteria. Cetuximab: injection, IV, until unacceptable toxicity or progression or 15 months after the LSFV, whichever comes first. Cetuximab 400 mg/m^2 was administered as a 2-hour IV loading dose via in-line filtration with an infusion pump, gravity drip, or a syringe pump on Day 1 of first cycle then 250 mg/m^2 1-hour IV once a week, i.e. on Days 1, 8, and 15 of each cycle provided the participant meets the re-treatment criteria.; Other Names: IXEMPRA BMS-247550 ERBITUX BMS-564717

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Objective Response (OR; Using Response Evaluation Criteria in Solid Tumors [RECIST]) [Assessed every 6 weeks for first 12 months from randomization thereafter every 3 months until disease progression (maximum participant objective response of 18.3 weeks)]

   The participant had an OR if her best overall response (BOR) during the study was either a complete response (CR) or a partial response (PR) according to the RECIST as determined by the investigator. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions. Confidence interval (CI) was Computed using Clopper-Pearson method.

2. Number of Participants With Best Overall Response as Assessed With Response Criteria in Solid Tumors (RECIST) [Assessed at 6 week intervals for first 12 months from randomization, thereafter every 3 months (to a maximum follow-up for tumor response of 17 months).]

   PD = At least a 20% increase in the sum of LD of target lesions in reference to the smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall; Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions.

Secondary Outcome Measures

1. Progression Free Survival (PFS) [From the date of randomization to date of progression, death, or last tumor assessment (maximum participant PFS of 17 months)]

   PFS is defined as the time interval from date of randomization until the first date of documented progressive disease (PD) or death from any cause without prior documentation of progression. The PFS was estimated using the Kaplan-Meier product-limit method, and a two-sided 95% CI for the median PFS time was computed using the method of Brookmeyer and Crowley. PD: At least 20% increase in sum of LD of target lesions in reference to smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall.

2. Time to Response [Assessed every 6 weeks for first 12 months from randomization thereafter every 3 months until CR or PR (maximum participant time to response of 18.3 weeks.)]

   Time to response is defined as the time from the date of start of treatment until measurement criteria are first met for PR or CR (whichever is recorded first). CR: Disappearance of all target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the LD of all target lesions with reference to the baseline sum LD. Time to response was estimated using the Kaplan-Meier product-limit method.

3. Duration of Response [From the date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 15.6 months)]

   Defined as period from the time that measurement criteria are first met for CR or PR until first date of documented PD or death. Estimated using the Kaplan-Meier product-limit method; CI was computed using Brookmeyer and Crowley method. CR: Disappearance of all target and non-target lesions. PR: At least 30% reduction from baseline in the sum of LD of all target lesions with reference to baseline sum LD. PD: At least 20% increase in sum of LD of target lesions in reference to smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall.

4. Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs), and AEs Leading to Discontinuation of Study Therapy Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 [Assessed from the date of first dose until at least 30 days after the last dose of study drug. Median time on ixapebilone therapy was 15 weeks (range: 3-54 weeks for ixabepilone arm; 3-36 weeks for ixabepilone+cetuximab arm)]

   AE: New untoward medical occurrence or worsening of a preexisting medical condition that does not have causal relationship with this treatment. SAE: Untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency/abuse; life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization/prolongs existing hospitalization. Grade (GR) 3=Severe; and GR4=Life-threatening or disabling. Other reasons for death included hepatic failure and respiratory distress.

5. Number of Participants With Hematology Abnormalities [Assessed prior to 1st cycle, at beginning of each cycle, weekly (cetuximab treatment), and every 4 weeks within 30 days after last dose of study drug. Median time on ixapebilone therapy: 15 weeks (range:3-54:ixabepilone arm;3-36:ixapebilone+cetuximab arm)]

   Grading: NCI CTCAE, Version 3.0. GR1=mild, GR2=moderate, GR3=severe, GR4=life threatening or disabling. Normal ranges provided by local laboratory and may also vary by age and sex. Hemoglobin:GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3:<8.0-6.5g/dL, GR4:<6.5g/dL. Platelets:GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3:<50.0-25.0*10^9/L, GR4:<25.0*10^9/L. Absolute Neutrophil Count (ANC):GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3:<1.0-0.5*10^9/L; GR4:<0.5*10^9/L. White blood cell (WBC):GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3:<2.0-1.0*10^9/L; GR4:<1.0*10^9/L. LLN=lower limit of normal.

6. Number of Participants With Serum Chemistry Abnormalities [Assessed prior to 1st cycle, at beginning of each cycle, weekly (cetuximab treatment), and every 4 weeks within 30 days after last dose of study drug. Median time on ixapebilone therapy: 15 weeks (range:3-54:ixabepilone arm;3-36:ixapebilone+cetuximab arm)]

   Grading: NCI CTCAE, Version 3.0. GR1=mild, GR2=moderate, GR3=severe, GR4=life threatening or disabling. Normal ranges provided by local laboratory and may also vary by age and sex. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase: GR1=>ULN-2.5*ULN (upper limit of normal); GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4:>20.0*ULN. Total bilirubin:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Female subjects with triple negative (ER, PR, and HER2 negative) locally advanced non-resectable and/or metastatic breast cancer

• Prior adjuvant or neoadjuvant anthracycline-based chemotherapy

Exclusion Criteria:

• Tumors that are fluorescence in situ hybridization test (FISH) positive or immunohistochemistry (IHC) 3+

• Neuropathy > Grade 1

• Prior systemic therapy for metastatic disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Local Institution	Graz		Austria	8036
2	Local Institution	Wien		Austria	1090
3	Local Institution	Brno		Czech Republic	656 53
4	Local Institution	Prague 5		Czech Republic	150 06
5	Local Institution	Praha 2		Czech Republic	128 08
6	Local Institution	Bayonne		France	64100
7	Local Institution	Dijon Cedex		France	21079
8	Local Institution	Lyon		France	69008
9	Local Institution	Paris Cedex 13		France	75651
10	Local Institution	Saint Brieuc		France	22015
11	Local Institution	Saint Herblain Cedex		France	44805
12	Local Institution	Toulouse Cedex		France	31052
13	Local Institution	Thessaloniki		Greece	54642
14	Local Institution	Napoli		Italy	80131
15	Local Institution	Gdansk		Poland	80952
16	Local Institution	Olsztyn		Poland	10-513
17	Local Institution	Barcelona		Spain	08036
18	Local Institution	Barcelona		Spain	08208
19	Local Institution	Barcelona		Spain	08221

Sponsors and Collaborators

• R-Pharm

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: R-Pharm
• ClinicalTrials.gov Identifier: NCT00633464
• Other Study ID Numbers: CA163-139
• First Posted: Mar 12, 2008
• Last Update Posted: Mar 10, 2016
• Last Verified: Feb 1, 2016

• Additional relevant MeSH terms: Breast Neoplasms; Cetuximab; Epothilones

Study Results

Participant Flow

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Period Title: Overall Study
STARTED	40	39
Treated	40	37
COMPLETED	40	37
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2	Total
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks	Total of all reporting groups
Overall Participants	40	39	79
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	53.0	50.0	53.0
Age, Customized (participants) [Number]
< 65	35 87.5%	32 82.1%	67 84.8%
>=65	5 12.5%	7 17.9%	12 15.2%
Sex/Gender, Customized (participants) [Number]
Female	40 100%	39 100%	79 100%
Race/Ethnicity, Customized (participants) [Number]
White	39 97.5%	39 100%	78 98.7%
Black/African American	1 2.5%	0 0%	1 1.3%
Karnofsky Performance Status (participants) [Number]
100	23 57.5%	23 59%	46 58.2%
90	6 15%	5 12.8%	11 13.9%
80	11 27.5%	10 25.6%	21 26.6%
Not Reported	0 0%	1 2.6%	1 1.3%
Setting of Prior Chemotherapy (participants) [Number]
Adjuvant therapy	28 70%	22 56.4%	50 63.3%
Neo-adjuvant therapy	20 50%	20 51.3%	40 50.6%
Adjuvant and Neo-adjuvant	8 20%	3 7.7%	11 13.9%

Outcome Measures

1. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS is defined as the time interval from date of randomization until the first date of documented progressive disease (PD) or death from any cause without prior documentation of progression. The PFS was estimated using the Kaplan-Meier product-limit method, and a two-sided 95% CI for the median PFS time was computed using the method of Brookmeyer and Crowley. PD: At least 20% increase in sum of LD of target lesions in reference to smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall.
Time Frame	From the date of randomization to date of progression, death, or last tumor assessment (maximum participant PFS of 17 months)

Outcome Measure Data

Analysis Population Description

All randomized participants. Participants who did not progress or die were censored on the date of their last tumor assessment.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	40	39
Median (95% Confidence Interval) [months]	4.1	4.1

2. Secondary Outcome

Title	Time to Response
Description	Time to response is defined as the time from the date of start of treatment until measurement criteria are first met for PR or CR (whichever is recorded first). CR: Disappearance of all target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the LD of all target lesions with reference to the baseline sum LD. Time to response was estimated using the Kaplan-Meier product-limit method.
Time Frame	Assessed every 6 weeks for first 12 months from randomization thereafter every 3 months until CR or PR (maximum participant time to response of 18.3 weeks.)

Outcome Measure Data

Analysis Population Description

Randomized participants with response of CR or PR.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	12	14
Median (Full Range) [weeks]	8.8	6.5

3. Primary Outcome

Title	Percentage of Participants With Objective Response (OR; Using Response Evaluation Criteria in Solid Tumors [RECIST])
Description	The participant had an OR if her best overall response (BOR) during the study was either a complete response (CR) or a partial response (PR) according to the RECIST as determined by the investigator. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions. Confidence interval (CI) was Computed using Clopper-Pearson method.
Time Frame	Assessed every 6 weeks for first 12 months from randomization thereafter every 3 months until disease progression (maximum participant objective response of 18.3 weeks)

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	40	39
Number (95% Confidence Interval) [percentage of participants]	30.0 75%	35.9 92.1%

4. Secondary Outcome

Title	Duration of Response
Description	Defined as period from the time that measurement criteria are first met for CR or PR until first date of documented PD or death. Estimated using the Kaplan-Meier product-limit method; CI was computed using Brookmeyer and Crowley method. CR: Disappearance of all target and non-target lesions. PR: At least 30% reduction from baseline in the sum of LD of all target lesions with reference to baseline sum LD. PD: At least 20% increase in sum of LD of target lesions in reference to smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall.
Time Frame	From the date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 15.6 months)

Outcome Measure Data

Analysis Population Description

Randomized participants with response of CR or PR. Participants who did not relapse or die were censored on the date of their last tumor assessment.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	12	14
Median (95% Confidence Interval) [months]	4.5	4.5

5. Secondary Outcome

Title	Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs), and AEs Leading to Discontinuation of Study Therapy Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0
Description	AE: New untoward medical occurrence or worsening of a preexisting medical condition that does not have causal relationship with this treatment. SAE: Untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency/abuse; life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization/prolongs existing hospitalization. Grade (GR) 3=Severe; and GR4=Life-threatening or disabling. Other reasons for death included hepatic failure and respiratory distress.
Time Frame	Assessed from the date of first dose until at least 30 days after the last dose of study drug. Median time on ixapebilone therapy was 15 weeks (range: 3-54 weeks for ixabepilone arm; 3-36 weeks for ixabepilone+cetuximab arm)

Outcome Measure Data

Analysis Population Description

All treated participants: Participants who received any treatment (ixabepilone or cetuximab).

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	40	37
All Deaths	8 20%	9 23.1%
Deaths due to Disease Progression	8 20%	7 17.9%
Deaths due to Other Reasons	0 0%	2 5.1%
At least one SAE (Any Grade)	9 22.5%	12 30.8%
At least one SAE (Grade 3 to 4)	4 10%	11 28.2%
At least one Related SAE (Any Grade)	3 7.5%	6 15.4%
At least one Related SAE (Grade 3 to 4)	2 5%	6 15.4%
At least one AE (Any Grade)	40 100%	37 94.9%
At least one AE (Grade 3 to 4)	21 52.5%	25 64.1%
At least one Related AE	37 92.5%	37 94.9%
At least one Related AE (Grade 3 to 4)	18 45%	22 56.4%
AEs leading to discontinuation (Any Grade)	8 20%	13 33.3%
AEs leading to discontinuation (Grade 3 to 4)	3 7.5%	7 17.9%

6. Secondary Outcome

Title	Number of Participants With Hematology Abnormalities
Description	Grading: NCI CTCAE, Version 3.0. GR1=mild, GR2=moderate, GR3=severe, GR4=life threatening or disabling. Normal ranges provided by local laboratory and may also vary by age and sex. Hemoglobin:GR1=<LLN-10.0g/dL; GR2=<10.0-8.0g/dL; GR3:<8.0-6.5g/dL, GR4:<6.5g/dL. Platelets:GR1=<LLN-75.0*10^9/L; GR2=<75.0-50.0*10^9/L; GR3:<50.0-25.0*10^9/L, GR4:<25.0*10^9/L. Absolute Neutrophil Count (ANC):GR1=<LLN-1.5*10^9 /L; GR2=<1.5-1.0*10^9/L; GR3:<1.0-0.5*10^9/L; GR4:<0.5*10^9/L. White blood cell (WBC):GR1=<LLN-3.0*10^9/L; GR2=<3.0-2.0*10^9/L; GR3:<2.0-1.0*10^9/L; GR4:<1.0*10^9/L. LLN=lower limit of normal.
Time Frame	Assessed prior to 1st cycle, at beginning of each cycle, weekly (cetuximab treatment), and every 4 weeks within 30 days after last dose of study drug. Median time on ixapebilone therapy: 15 weeks (range:3-54:ixabepilone arm;3-36:ixapebilone+cetuximab arm)

Outcome Measure Data

Analysis Population Description

Treated participants: Participants who received any treatment (ixabepilone or cetuximab). n=number of participants with measures available at the time.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	40	37
White Blood cell (WBC) GR 1-4	33 82.5%	34 87.2%
WBC GR 3-4	13 32.5%	16 41%
Absolute Neutrophil Count(ANC) GR 1-4 (n=39; n=37)	33 82.5%	31 79.5%
ANC GR 3-4 (n=39; n=37)	19 47.5%	18 46.2%
Platelet Count GR 1-4 (n=39; n=37)	11 27.5%	4 10.3%
Platelet Count GR 3-4 (n=39; n=37)	0 0%	0 0%
Hemoglobin GR 1-4	29 72.5%	27 69.2%
Hemoglobin GR 3-4	0 0%	0 0%

7. Primary Outcome

Title	Number of Participants With Best Overall Response as Assessed With Response Criteria in Solid Tumors (RECIST)
Description	PD = At least a 20% increase in the sum of LD of target lesions in reference to the smallest sum LD recorded at or following baseline or unequivocal progression of existing non-target lesion(s) overall; Stable Disease (SD) = Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions.
Time Frame	Assessed at 6 week intervals for first 12 months from randomization, thereafter every 3 months (to a maximum follow-up for tumor response of 17 months).

Outcome Measure Data

Analysis Population Description

All randomized participants.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	40	39
Complete Response	3 7.5%	0 0%
Partial Response	9 22.5%	14 35.9%
Stable Disease	17 42.5%	12 30.8%
Progressive Disease	9 22.5%	10 25.6%
Never Treated	0 0%	2 5.1%
Unable to determine	2 5%	1 2.6%

8. Secondary Outcome

Title	Number of Participants With Serum Chemistry Abnormalities
Description	Grading: NCI CTCAE, Version 3.0. GR1=mild, GR2=moderate, GR3=severe, GR4=life threatening or disabling. Normal ranges provided by local laboratory and may also vary by age and sex. Alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase: GR1=>ULN-2.5*ULN (upper limit of normal); GR2=>2.5-5.0*ULN; GR3=>5.0-20.0*ULN; GR4:>20.0*ULN. Total bilirubin:GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3-10*ULN, GR4=>10*ULN. Creatinine: GR1=>ULN-1.5*ULN, GR2=>1.5-3.0*ULN, GR3=>3.0-6.0*ULN, GR4=>6.0*ULN.
Time Frame	Assessed prior to 1st cycle, at beginning of each cycle, weekly (cetuximab treatment), and every 4 weeks within 30 days after last dose of study drug. Median time on ixapebilone therapy: 15 weeks (range:3-54:ixabepilone arm;3-36:ixapebilone+cetuximab arm)

Outcome Measure Data

Analysis Population Description

Treated participants: Participants who received any treatment (ixabepilone or cetuximab). n=number of participants with measures available at the time.

Arm/Group Title	Ixabepilone 40 mg/m^2	Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks	cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
Measure Participants	40	37
Alkaline Phosphatase (ALP) GR 1-4 (n=38; n=35)	9 22.5%	17 43.6%
ALP GR 3-4 (n=38; n=35)	0 0%	1 2.6%
Alanine Aminotransferase (ALT) GR 1-4 (n=39; n=35)	10 25%	18 46.2%
ALT GR 3-4 (n=39; n=35)	1 2.5%	0 0%
Aspartate Aminotransferase (AST) GR1-4(n=39; n=35)	11 27.5%	17 43.6%
AST GR 3-4 (n=39; n=35)	1 2.5%	3 7.7%
Total Bilirubin GR 1-4 (n=39; n=35)	1 2.5%	3 7.7%
Total Bilirubin GR 3-4 (n=39; n=35)	1 2.5%	0 0%
Creatinine GR 1-4 (n=40; n=36)	3 7.5%	1 2.6%
Creatinine GR 3-4 (n=40; n=36)	0 0%	0 0%

Adverse Events

Time Frame	Assessed from the date of first dose until at least 30 days after the last dose of study drug (Median number of ixabepilone cycles were 5 [range: 1-18 cycles for ixabepilone arm; 1-12 cycles for cetuximab + ixabepilone arm])
Arm/Group Title	Ixabepilone 40 mg/m^2		Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
Arm/Group Description	ixabepilone 40 mg/m^2 every 3 weeks		cetuximab 400 mg/m^2 loading dose then 250 mg/m^2 weekly + ixabepilone 40 mg/m^2 every 3 weeks
All Cause Mortality
	Ixabepilone 40 mg/m^2		Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ixabepilone 40 mg/m^2		Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/40 (22.5%)		12/37 (32.4%)
Blood and lymphatic system disorders
FEBRILE NEUTROPENIA	0/40 (0%)		2/37 (5.4%)
NEUTROPENIA	0/40 (0%)		2/37 (5.4%)
Cardiac disorders
TACHYCARDIA	0/40 (0%)		2/37 (5.4%)
SINUS ARRHYTHMIA	1/40 (2.5%)		0/37 (0%)
Gastrointestinal disorders
STOMATITIS	0/40 (0%)		1/37 (2.7%)
VOMITING	1/40 (2.5%)		1/37 (2.7%)
ABDOMINAL PAIN	0/40 (0%)		1/37 (2.7%)
RECTAL HAEMORRHAGE	0/40 (0%)		1/37 (2.7%)
GASTROINTESTINAL HAEMORRHAGE	1/40 (2.5%)		0/37 (0%)
DIARRHOEA	0/40 (0%)		1/37 (2.7%)
General disorders
PYREXIA	2/40 (5%)		0/37 (0%)
CHEST PAIN	0/40 (0%)		1/37 (2.7%)
FATIGUE	0/40 (0%)		1/37 (2.7%)
ASTHENIA	0/40 (0%)		1/37 (2.7%)
INFLAMMATION	1/40 (2.5%)		0/37 (0%)
Infections and infestations
SKIN INFECTION	1/40 (2.5%)		0/37 (0%)
SEPSIS	1/40 (2.5%)		0/37 (0%)
Injury, poisoning and procedural complications
OVERDOSE	0/40 (0%)		1/37 (2.7%)
Musculoskeletal and connective tissue disorders
PAIN IN EXTREMITY	1/40 (2.5%)		0/37 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASM MALIGNANT	2/40 (5%)		0/37 (0%)
METASTASES TO CENTRAL NERVOUS SYSTEM	1/40 (2.5%)		0/37 (0%)
Respiratory, thoracic and mediastinal disorders
PLEURAL EFFUSION	0/40 (0%)		1/37 (2.7%)
HYPOXIA	0/40 (0%)		1/37 (2.7%)
DYSPNOEA	0/40 (0%)		5/37 (13.5%)
Vascular disorders
THROMBOPHLEBITIS	1/40 (2.5%)		0/37 (0%)
HAEMORRHAGE	1/40 (2.5%)		0/37 (0%)
SUBCLAVIAN VEIN THROMBOSIS	0/40 (0%)		1/37 (2.7%)
Other (Not Including Serious) Adverse Events
	Ixabepilone 40 mg/m^2		Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		37/37 (100%)
Blood and lymphatic system disorders
LEUKOPENIA	6/40 (15%)		9/37 (24.3%)
LYMPHOPENIA	1/40 (2.5%)		2/37 (5.4%)
ANAEMIA	8/40 (20%)		8/37 (21.6%)
FEBRILE NEUTROPENIA	2/40 (5%)		0/37 (0%)
NEUTROPENIA	18/40 (45%)		19/37 (51.4%)
THROMBOCYTOPENIA	1/40 (2.5%)		2/37 (5.4%)
Cardiac disorders
TACHYCARDIA	0/40 (0%)		2/37 (5.4%)
Ear and labyrinth disorders
VERTIGO	1/40 (2.5%)		3/37 (8.1%)
TINNITUS	1/40 (2.5%)		2/37 (5.4%)
Eye disorders
LACRIMATION INCREASED	2/40 (5%)		1/37 (2.7%)
CONJUNCTIVITIS	0/40 (0%)		3/37 (8.1%)
Gastrointestinal disorders
STOMATITIS	3/40 (7.5%)		3/37 (8.1%)
VOMITING	15/40 (37.5%)		11/37 (29.7%)
ABDOMINAL PAIN	3/40 (7.5%)		8/37 (21.6%)
CONSTIPATION	10/40 (25%)		12/37 (32.4%)
DYSPEPSIA	1/40 (2.5%)		4/37 (10.8%)
DYSPHAGIA	2/40 (5%)		1/37 (2.7%)
GASTROOESOPHAGEAL REFLUX DISEASE	0/40 (0%)		4/37 (10.8%)
ABDOMINAL PAIN UPPER	3/40 (7.5%)		2/37 (5.4%)
APHTHOUS STOMATITIS	1/40 (2.5%)		2/37 (5.4%)
HAEMORRHOIDS	1/40 (2.5%)		2/37 (5.4%)
NAUSEA	13/40 (32.5%)		19/37 (51.4%)
DIARRHOEA	4/40 (10%)		14/37 (37.8%)
DRY MOUTH	2/40 (5%)		2/37 (5.4%)
General disorders
PYREXIA	3/40 (7.5%)		12/37 (32.4%)
CHEST PAIN	4/40 (10%)		2/37 (5.4%)
INFLUENZA LIKE ILLNESS	2/40 (5%)		1/37 (2.7%)
MUCOSAL INFLAMMATION	7/40 (17.5%)		8/37 (21.6%)
FATIGUE	8/40 (20%)		8/37 (21.6%)
ASTHENIA	17/40 (42.5%)		20/37 (54.1%)
PAIN	2/40 (5%)		2/37 (5.4%)
OEDEMA PERIPHERAL	1/40 (2.5%)		5/37 (13.5%)
CHILLS	1/40 (2.5%)		2/37 (5.4%)
Immune system disorders
HYPERSENSITIVITY	2/40 (5%)		2/37 (5.4%)
Infections and infestations
NASOPHARYNGITIS	2/40 (5%)		2/37 (5.4%)
BRONCHITIS	2/40 (5%)		1/37 (2.7%)
URINARY TRACT INFECTION	1/40 (2.5%)		4/37 (10.8%)
PARONYCHIA	1/40 (2.5%)		2/37 (5.4%)
RHINITIS	3/40 (7.5%)		5/37 (13.5%)
Investigations
WEIGHT DECREASED	2/40 (5%)		4/37 (10.8%)
ALANINE AMINOTRANSFERASE INCREASED	0/40 (0%)		3/37 (8.1%)
ASPARTATE AMINOTRANSFERASE INCREASED	0/40 (0%)		3/37 (8.1%)
Metabolism and nutrition disorders
DECREASED APPETITE	5/40 (12.5%)		10/37 (27%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	11/40 (27.5%)		8/37 (21.6%)
BONE PAIN	3/40 (7.5%)		4/37 (10.8%)
NECK PAIN	0/40 (0%)		2/37 (5.4%)
MUSCULOSKELETAL CHEST PAIN	2/40 (5%)		2/37 (5.4%)
BACK PAIN	3/40 (7.5%)		5/37 (13.5%)
MUSCULOSKELETAL PAIN	3/40 (7.5%)		2/37 (5.4%)
PAIN IN EXTREMITY	5/40 (12.5%)		2/37 (5.4%)
MYALGIA	15/40 (37.5%)		6/37 (16.2%)
Nervous system disorders
HEADACHE	4/40 (10%)		9/37 (24.3%)
DYSGEUSIA	5/40 (12.5%)		7/37 (18.9%)
PERIPHERAL MOTOR NEUROPATHY	0/40 (0%)		2/37 (5.4%)
NEUROPATHY PERIPHERAL	3/40 (7.5%)		1/37 (2.7%)
DIZZINESS	2/40 (5%)		1/37 (2.7%)
NEUROTOXICITY	2/40 (5%)		0/37 (0%)
PARAESTHESIA	3/40 (7.5%)		5/37 (13.5%)
PERIPHERAL SENSORY NEUROPATHY	17/40 (42.5%)		17/37 (45.9%)
Psychiatric disorders
DEPRESSION	1/40 (2.5%)		3/37 (8.1%)
ANXIETY	4/40 (10%)		5/37 (13.5%)
INSOMNIA	4/40 (10%)		6/37 (16.2%)
Reproductive system and breast disorders
BREAST PAIN	2/40 (5%)		1/37 (2.7%)
Respiratory, thoracic and mediastinal disorders
NASAL DRYNESS	0/40 (0%)		2/37 (5.4%)
EPISTAXIS	0/40 (0%)		3/37 (8.1%)
HAEMOPTYSIS	0/40 (0%)		2/37 (5.4%)
COUGH	8/40 (20%)		12/37 (32.4%)
PLEURAL EFFUSION	0/40 (0%)		2/37 (5.4%)
HYPOXIA	0/40 (0%)		2/37 (5.4%)
DYSPNOEA	7/40 (17.5%)		10/37 (27%)
DYSPHONIA	0/40 (0%)		2/37 (5.4%)
OROPHARYNGEAL PAIN	0/40 (0%)		2/37 (5.4%)
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM	1/40 (2.5%)		10/37 (27%)
RASH	2/40 (5%)		12/37 (32.4%)
ACNE	0/40 (0%)		15/37 (40.5%)
ALOPECIA	23/40 (57.5%)		13/37 (35.1%)
DRY SKIN	3/40 (7.5%)		15/37 (40.5%)
SKIN FISSURES	0/40 (0%)		6/37 (16.2%)
ERYTHEMA	1/40 (2.5%)		4/37 (10.8%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	0/40 (0%)		6/37 (16.2%)
PRURITUS	3/40 (7.5%)		3/37 (8.1%)
NAIL DISORDER	4/40 (10%)		6/37 (16.2%)
Vascular disorders
FLUSHING	2/40 (5%)		0/37 (0%)
HYPERTENSION	3/40 (7.5%)		1/37 (2.7%)
HOT FLUSH	3/40 (7.5%)		0/37 (0%)
HYPOTENSION	0/40 (0%)		3/37 (8.1%)
LYMPHOEDEMA	1/40 (2.5%)		2/37 (5.4%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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.