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

• ixabepilone (Drug), also known as IXEMPRA, BMS-247550: 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.
• ixabepilone + cetuximab (Drug), also known as IXEMPRA, BMS-247550, ERBITUX, BMS-564717: 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.

Primary outcomes

• 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.
• 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 outcomes

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Sex: Female, ages: 18 Years to any

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

Participant flow

Outcome results

• Progression Free Survival (PFS) (Secondary), Median, months: Ixabepilone 40 mg/m^2 4.1 (3.0 to 4.9); Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 4.1 (2.7 to 6.1)
• Time to Response (Secondary), Median, weeks: Ixabepilone 40 mg/m^2 8.8 (5.1 to 12.0); Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 6.5 (5.1 to 18.3)
• Percentage of Participants With Objective Response (OR; Using Response Evaluation Criteria in Solid Tumors [RECIST]) (Primary), Number, percentage of participants: Ixabepilone 40 mg/m^2 30.0 (16.6 to 46.5); Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 35.9 (21.2 to 52.8)
• Duration of Response (Secondary), Median, months: Ixabepilone 40 mg/m^2 4.5 (3.0 to 8.7); Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 4.5 (3.4 to 6.9)
• 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 (Secondary), Number, participants: Ixabepilone 40 mg/m^2 8; Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 9
• Number of Participants With Hematology Abnormalities (Secondary), Number, participants: Ixabepilone 40 mg/m^2 33; Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 34
• Number of Participants With Best Overall Response as Assessed With Response Criteria in Solid Tumors (RECIST) (Primary), Number, participants: Ixabepilone 40 mg/m^2 3; Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 0
• Number of Participants With Serum Chemistry Abnormalities (Secondary), Number, participants: Ixabepilone 40 mg/m^2 9; Cetuximab 250 mg/m^2 + Ixabepilone 40 mg/m^2 17

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])

Serious adverse events by term

Other adverse events by term

27 more terms not shown.

• Bristol-Myers Squibb, Study director, Bristol-Myers Squibb