A Trial of 2 Schedules of Ixabepilone Plus Bevacizumab and Paclitaxel Plus Bevacizumab for Breast Cancer

Study Overview
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Brief Summary
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The purpose of this clinical research study is to learn if ixabepilone plus bevacizumab is effective in shrinking or stopping the growth of cancer when given as first-line chemotherapy in participants with metastatic breast cancer. The study will also assess the safety of this combination treatment.

Official Title
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A Phase II Open Label, Randomized, 3 Arm Trial of 2 Schedules of Ixabepilone Plus Bevacizumab and Paclitaxel Plus Bevacizumab as First Line Therapy for Locally Recurrent or Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg
* Drug: Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg
* Drug: Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Locally recurrent or metastatic breast cancer, previously untreated with chemotherapy for advanced disease. At least 1 target lesion per RECIST criteria. Locally recurrent disease must not be amenable to resection with curative intent. No previous cytotoxic chemotherapy for locally recurrent/metastatic disease. Relapse 12 months or more after completing prior adjuvant or neoadjuvant taxane therapy. No previous breast cancer known to overexpress or amplify the human epidermal growth factor receptor 2 gene. Prior hormonal therapy in adjuvant, recurrent, or metastatic setting allowed but must have been discontinued at least 2 weeks before randomization. Karnofsky performance status of 80 to 100 or Eastern Cooperative Oncology Group performance status of 0 to 1. Estimated life expectancy of at least 12 weeks. Recovery from recent therapy (except for alopecia), including chemotherapy, immunotherapy, biologic therapy, or investigational product. Any such therapy must have been completed at least 3 weeks before randomization and at least 6 weeks from use of nitrosourea, or mitomycin. Recovery from recent surgery and radiation therapy. At least 1 week since minor surgery and/or focal/palliative radiation therapy; at least 3 weeks from radiation; at least 4 weeks from major surgery; and at least 8 weeks from liver resection, thoracotomy, or neurosurgery. Absolute neutrophil count ≥1500/mm^3. Hemoglobin ≥9 g/dL. Platelets ≥100,000/mm^3. Total bilirubin ≤1.5 times the upper limit of normal (ULN). Aspartate aminotransferase or alanine aminotransferase ≤2.5*ULN. Normal partial thromboplastin time and either international normalized ratio or prothrombin time <1.5*ULN. Serum creatinine ≤1.5*ULN or 24-hour creatinine clearance >60 mL/min. Urine dipstick for proteinuria <2+ (negative, trace, or +1). Participants with ≥2+ proteinuria at baseline were to undergo 24-hour urine collection and demonstrate ≤1g of protein in 24 hours to be eligible. Exclusion criteria: Women of child-bearing potential (WOCBP) unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and up to 6 months after treatment with bevacizumab. Women who were pregnant or breastfeeding. Women with a positive pregnancy test on enrollment or prior to study drug administration. Sexually active fertile men, whose partners were WOCBP, not using an adequate method of birth control. Evidence of baseline sensory or motor neuropathy. Serious infection or nonmalignant medical illnesses uncontrolled or the control of which could be jeopardized by this therapy. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, serious gastric ulcer, or bone fracture within 6 months of study entry. History of hypertensive crisis or hypertensive encephalopathy. Significant vascular disease. Clinically significant cardiovascular disease. Baseline left ventricular ejection fraction by multiple-gated acquisition scan or echocardiogram for subjects with prior exposure to anthracyclines not within institutional normal limits. Symptomatic peripheral vascular disease. History of high dose chemotherapy with bone marrow transplant or peripheral blood stem cell transplant within the previous 2 years. Evidence of bleeding diathesis or coagulopathy. Prior treatment with an epothilone or any antiangiogenic agent. Concurrent nonhealing wound, ulcer, or fracture. Any current or history of brain and/or leptomeningeal metastases. Psychiatric disorders or other conditions rendering the participant incapable of complying with the requirements of the protocol. Any concurrent active malignancy other than nonmelanoma skin cancer or carcinoma in situ of the cervix. Known allergy to any of the study drugs or their excipients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg<br> | Drug: Ixabepilone, 16 mg/m^2 + Bevacizumab, 10 mg/kg<br>* Ixabepilone,16 mg/m^2, administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.<br>* Other names: BMS-247550;|
| Experimental: Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg<br> | Drug: Ixabepilone, 40 mg/m^2 + Bevacizumab, 15 mg/kg<br>* Ixabepilone, 40 mg/m^2, administered as a 3-hour IV infusion on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity (After Cycle 4, dose reduction to 32 mg/m^2 was to be implemented for all subsequent cycles.) Bevacizumab, 15 mg/kg, administered as IV infusion every 3 weeks. Bevacizumab to be infused over 90 minutes for the first dose, and if well tolerated for 60 minutes, for the second dose. Then if still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.<br>* Other names: BMS-247550;|
| Active Comparator: Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg<br> | Drug: Paclitaxel, 90 mg/m^2 + Bevacizumab, 10 mg/kg<br>* Paclitaxel, 90 mg/m^2, given as a 1-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity. Bevacizumab, 10 mg/kg, administered as IV infusion every 2 weeks. Bevacizumab infused over 90 minutes for the first dose, and if well tolerated, over 60 minutes for the second dose. If still tolerated, over 30 minutes for subsequent infusions. Bevacizumab was to be dosed until disease progression or unacceptable toxicity.<br>* Other names: BMS-181339;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Best Tumor Response of Partial Response (PR) or Complete Response (CR) While On-study | CR=Disappearance of all clinical and radiologic evidence of target lesions; PR=At least 30% reduction in the sum of the longest diameter of all target lesions. | Baseline visit and then every 8 weeks to 12 months, then every 3 months until disease progression | 
| Number of Participants With Best Response As Assessed With Response Evaluation Criteria in Solid Tumors (RECIST) | Best tumor response was assessed with RECIST. Complete response (CR)=Disappearance of all evidence of target lesions; Partial response (PR)=At least 30% reduction from baseline in the sum of the longest diameter (LD) of all target lesions; Progressive disease (PD)=At least a 20% increase from baseline in the sum of LD of target lesions or the appearance of 1 or more new lesions; Stable disease (SD)=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. A response was confirmed if noted on 2 examinations at least 4 weeks apart. | Baseline visit and then every 8 weeks to 12 months, then every 3 months until disease progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Progression-free Survival at Week 24 | Week 24 Progression-free Survival was defined as the number of participants who neither progressed nor died before Week 24. Computed using Kaplan-Meier estimates, only at the time of Interim Analysis, when all participants had been followed for 6 months. | Date of randomization to Week 24 | 
| Median Progression-free Survival (PFS) | PFS was defined as the time from randomization to progression or to death from any cause without prior documentation of progression. Participants who did not progress or die were to be censored on the date of their last tumor assessment. | Date of randomization to date of progression, death, or last tumor assessment (maximum participant PFS of 29 months) | 
| Median Time to Response | Time to response was defined as the time from the first dose of study therapy until measurement criteria were first met for a PR or CR, whichever was recorded first. Time to response was computed only for participants whose best response was PR or CR. | Date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant time to response of 67 weeks) | 
| Median Duration of Response | Duration of response was computed for participants whose best response was either PR or CR. Duration of overall response was defined as the period from the time that measurement criteria were first met for PR or CR, whichever was recorded first, until the first date of documented PD or death. Participants who neither relapsed nor died were to be censored on the date of their last tumor assessment. | Date of first PR or CR assessment to date of progression, death, or last tumor assessment (maximum participant duration of response of 25 weeks) | 
| Percentage of Participants Surviving at 1 Year | One year survival rates were computed using Kaplan-Meier estimates. | Date first participant enrolled to 1 year | 
| Number of Participants With Death as Outcome, Serious Adverse Events (SAEs) Treatment-related SAEs, Treatment-related Adverse Events (AEs) Leading to Discontinuation, AEs Leading to Discontinuation, Treatment-related AEs | An AE is any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical event that at any dose: results in death, persistent or significant disability/incapacity, drug dependency or abuse; is life-threatening, an important medical event, a congenital anomaly/birth defect; requires inpatient hospitalization; or prolongs existing hospitalization. Treatment related=possibly, probably, or certainly related to and of unknown relationship to study treatment. | At initiation of treatment throughout study, to a minimum of 30 days after last dose of study drug | 
| Number of Participants With Abnormalities in Hematology Laboratory Results by Worst Common Terminology Criteria (CTC) Grade | CTC, Version 3 used to assess parameters. CTC Gr=Grade; WBC=white blood cells; ANC=absolute neutrophil count. LLN=lower level of normal. WBC Gr 1:<LLN to 3.0*10^9/L, Gr 2:<3.0 to 2.0*10^9/L, Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L; ANC Gr 1:<LLN to 1.5*10^9/L, Gr 2:<1.5 to 1.0*10^9/L, Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L; Platelet count Gr 1:LLN to 75.0*10^9/L, Gr 2:<75.0 to 50.0*10^9/L, Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L; Hemoglobin Gr 1:<LLN to 10.0 g/dL, Gr 2:<10.0 to 8.0 g/dL, Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. | At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle | 
| Number of Participants With Abnormalities in Liver Function by Worst CTC Grade | ULN=Upper limit of normal.ALT Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; AST Gr 1: >ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; ALP Gr 1:>ULN to 2.5*ULN, Gr 2: >2.5 to 5.0*ULN, Gr 3: >5.0 to 20.0*ULN, Gr 4: >20.0*ULN; Total bilirubin Gr 1: >ULN to 1.5*ULN, Gr 2: >1.5 to 3.0*ULN, Gr 3: >3.0 to 10.0*ULN, Gr 4: >10.0*ULN. | At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle | 
| Number of Participants With Abnormalities in Renal Function by Worst CTC Grade | Creatine Gr 1: >ULN to 1.5*ULN, Gr 2: 1.5 to 3.0*ULN, Gr 3: >3.0 to 6.0*ULN, Gr 4: >6.0*ULN. | At initiation of treatment and throughout study, to a minimum of 30 days after last dose of study drug. Laboratory tests performed within 72 hours before start of each cycle |