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Paclitaxel, Nab-paclitaxel, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer

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ClinicalTrials.gov Identifier: NCT00785291
Recruitment Status : Active, not recruiting
First Posted : November 5, 2008
Results First Posted : July 2, 2015
Last Update Posted : February 9, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 4, 2008
First Posted Date  ICMJE November 5, 2008
Results First Submitted Date  ICMJE June 5, 2015
Results First Posted Date  ICMJE July 2, 2015
Last Update Posted Date February 9, 2021
Actual Study Start Date  ICMJE November 10, 2008
Actual Primary Completion Date December 31, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 4, 2015)
Progression Free Survival [ Time Frame: Time from randomization to progression or death due to any cause, whichever occurs first (up to 5 years) ]
Progression-free survival (PFS) is defined as the interval from registration until first disease progression, regardless of site, or death resulting from any cause, which ever occurred first. Distribution was estimated using the Kaplan Meier product-limit method. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per Response Evaluation Criteria in Solid Tumors [RECIST] criteria).
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2008)
Progression-free survival
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2015)
  • Objective Tumor Response Rate [ Time Frame: Up to 5 years ]
    Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions).
  • Time to Treatment Failure [ Time Frame: Time from randomization until progression, death, or yearly termination of protocol therapy (up to 5 years) ]
    Time from registration until treatment failure, defined as early termination of protocol therapy for any reason, first disease progression or death without progression. Surviving participants who were failure free were censored as date last known alive and failure free. Distribution was estimated using the Kaplan Meier product-limit method.
  • 12 Month Progression Free Survival [ Time Frame: 12 months ]
    Percentage of participants who were alive and progression free at 12 months. The 12 month progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.
  • Overall Survival [ Time Frame: Time from randomization to death or last follow-up (up to 5 years) ]
    Overall survival was measured as the interval from study entry until death, from any cause, or last contact. Distribution was estimated using the Kaplan Meier product-limit method.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2008)
  • Objective tumor response as assessed by RECIST criteria
  • Duration of tumor response
  • Time to treatment failure
  • Probability of being progression-free at 12 months
  • Treatment-related toxicity as assessed by CTCAE version 3.0
  • Overall survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Paclitaxel, Nab-paclitaxel, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer
Official Title  ICMJE A Randomized Phase III Trial of Weekly Paclitaxel Compared to Weekly Nanoparticle Albumin Bound Nab-paclitaxel or Ixabepilone With or Without Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer
Brief Summary This randomized phase III trial studies the side effects and how well different chemotherapy regimens with or without bevacizumab work in treating patients with stage IIIC or stage IV breast cancer. Drugs used in chemotherapy, such as paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), and ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may block tumor growth by targeting certain cells and slowing the growth of blood vessels to the tumor. It is not yet known which treatment regimen is more effective in treating patients with breast cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) in patients with metastatic breast cancer receiving nab-paclitaxel versus paclitaxel (control arm).

II. To compare PFS in patients receiving ixabepilone versus paclitaxel.

SECONDARY OBJECTIVES:

I. To compare the objective response rate, duration of response, and time to treatment failure in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare these endpoints in patients receiving ixabepilone versus paclitaxel.

II. To compare the 12-month rate of progression in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare this endpoint in patients receiving ixabepilone versus paclitaxel.

III. To determine toxicities in patients receiving nab-paclitaxel as compared to paclitaxel, and in patients receiving ixabepilone as compared to paclitaxel.

IV. To compare overall survival in patients receiving nab-paclitaxel versus paclitaxel, and to separately compare overall survival in patients receiving ixabepilone versus paclitaxel.

V. To evaluate the relationships between secreted protein, acidic, cysteine-rich (SPARC) overexpression and changes in blood levels of caveolin-1 (Cav-1) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel.

VI. To evaluate the relationships between changes in blood levels of circulating tumor cells (CTCs) and circulating endothelial cells (CECs) to PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel.

VII. To evaluate the association of expression levels of the microtubule associated proteins tau and beta-tubulin isotype composition with PFS and secondary endpoints of response during treatment with nab-paclitaxel as compared to paclitaxel, and with ixabepilone as compared to paclitaxel.

VIII. To investigate a potential cytochrome P450, family 2, subfamily C polypeptide 8, 2, 3 (CYP2C8*2/*3) by paclitaxel interaction with respect to progression-free survival (PFS).

IX. To determine if CYP2C8*2 and CPY2C8*3 are associated with paclitaxel-induced peripheral neuropathy.

X. To perform exploratory analysis of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) and ATP-binding cassette, sub-family C (CFTR/MRP), member 2 (ABCC2) polymorphisms with response and toxicity profiles.

XI. To prospectively collect data on sociodemographics, non-cancer morbidities, and receipt of post-trial therapy to evaluate the role of potential disparities on survival from cancer.

XII. To evaluate the relationship between physical activity behaviors at the time of enrollment in the protocol and progression-free and overall survival.

XIII. To identify baseline factors that predict the risk of grade 3, 4, or 5 toxicity in patients receiving treatment with weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab.

XIV. To perform an exploratory analysis of whether other factors included in patient assessments (either individually or in combination) predict the risk of grade 3, 4, or 5 toxicity in patients receiving weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab, with a specific focus on the relationship between pre-existing hypertension or neuropathy.

XV. To compare the associations of baseline factors to grade 3, 4, or 5 toxicity in patients receiving weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab.

XVI. To explore whether longitudinal changes in factors are in association with the occurrence of grade 3, 4, or 5 toxicities in patients with weekly paclitaxel, nab-paclitaxel, or ixabepilone combined with or without bevacizumab.

XVII. To explore the association between grade 2-4 neuropathy and longitudinal changes in the following functional status measures: a) Older Americans Resources and Services (OARS) Multidimensional Functional Assessment Questionnaire (MFAQ) (Instrumental Activities of Daily Living [IADL]); b) Medical Outcomes Study (MOS) Physical Functioning; c) Karnofsky Performance Status Rated Healthcare Professional; d) Timed "Up and Go"; e) OARS Physical Health Section.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A (WEEKLY PACLITAXEL): Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15. Patients may also receive bevacizumab IV over 30-90 minutes on days 1 and 15.

ARM B (WEEKLY NAB-PACLITAXEL): Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in Arm A.

ARM C (WEEKLY IXABEPILONE): Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in Arm A. (closed to accrual as of 7/18/11)

In all arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 6 months for 2 years and then annually for up to 3 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Estrogen Receptor Negative
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • HER2/Neu Positive
  • Progesterone Receptor Negative
  • Progesterone Receptor Positive
  • Recurrent Breast Carcinoma
  • Stage IIIC Breast Cancer AJCC v6
  • Stage IV Breast Cancer AJCC v6 and v7
Intervention  ICMJE
  • Biological: Bevacizumab
    Given IV
    Other Names:
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF rhuMAb
    • Avastin
    • Bevacizumab awwb
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Bevacizumab Biosimilar CBT 124
    • Bevacizumab Biosimilar CT-P16
    • Bevacizumab Biosimilar FKB238
    • Bevacizumab Biosimilar GB-222
    • Bevacizumab Biosimilar HD204
    • Bevacizumab Biosimilar HLX04
    • Bevacizumab Biosimilar IBI305
    • Bevacizumab Biosimilar LY01008
    • Bevacizumab Biosimilar MIL60
    • Bevacizumab Biosimilar Mvasi
    • Bevacizumab Biosimilar QL 1101
    • Bevacizumab Biosimilar RPH-001
    • Bevacizumab Biosimilar SCT501
    • Bevacizumab Biosimilar Zirabev
    • Bevacizumab-awwb
    • Bevacizumab-bvzr
    • BP102
    • BP102 Biosimilar
    • HD204
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Mvasi
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
    • SCT501
    • Zirabev
  • Drug: Ixabepilone
    Given IV
    Other Names:
    • (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione
    • Azaepothilone B
    • BMS 247550
    • BMS-247550
    • BMS247550
    • Epothilone
    • Epothilone-B BMS 247550
    • Ixempra
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Nab-paclitaxel
    Given IV
    Other Names:
    • ABI 007
    • ABI-007
    • Abraxane
    • Albumin-bound Paclitaxel
    • Albumin-Stabilized Nanoparticle Paclitaxel
    • Nanoparticle Albumin-bound Paclitaxel
    • Nanoparticle Paclitaxel
    • Paclitaxel Albumin
    • paclitaxel albumin-stabilized nanoparticle formulation
    • Protein-bound Paclitaxel
  • Drug: Paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • Bristaxol
    • Praxel
    • Taxol
    • Taxol Konzentrat
  • Other: Questionnaire Administration
    Ancillary studies
Study Arms  ICMJE
  • Active Comparator: Arm A (Paclitaxel)
    Patients receive 90 mg/m^2 paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
    Interventions:
    • Biological: Bevacizumab
    • Other: Laboratory Biomarker Analysis
    • Drug: Paclitaxel
    • Other: Questionnaire Administration
  • Experimental: Arm B (Nab-paclitaxel)
    Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15.
    Interventions:
    • Biological: Bevacizumab
    • Other: Laboratory Biomarker Analysis
    • Drug: Nab-paclitaxel
    • Other: Questionnaire Administration
  • Experimental: Arm C (Ixabepilone)
    Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive 10 mg/kg bevacizumab IV over 30-90 minutes on days 1 and 15. (closed to accrual as of 7/18/11)
    Interventions:
    • Biological: Bevacizumab
    • Drug: Ixabepilone
    • Other: Laboratory Biomarker Analysis
    • Other: Questionnaire Administration
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 11, 2014)
799
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2008)
900
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date December 31, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologic confirmation of invasive cancer of the breast
  • Stage IV disease or stage IIIC disease (using American Joint Committee on Cancer [AJCC] criteria, 6th edition) not amenable to local therapy
  • Patients may not have a "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse
  • Patients with human epidermal growth factor receptor 2 (HER2) negative disease are eligible; patients with HER2+ disease are eligible providing they have previously received trastuzumab or lapatinib; documentation of progression on HER2 directed therapy is not required; Her2/neu status must be known at the time of protocol registration
  • Estrogen receptor (ER) and progesterone receptor (PgR) status must be known at the time of registration; ER and/or PgR >= 1% cells will be considered positive
  • Prior treatment may include adjuvant or neoadjuvant taxane, however, the interval between completion of adjuvant or neoadjuvant therapy and disease recurrence must be >= 12 months
  • No prior chemotherapy for metastatic breast cancer
  • Any number of prior hormonal therapies are allowed; the last dose should have been administered at least 7 days prior to the initiation of protocol therapy
  • Prior radiotherapy must be completed at least 2 weeks prior to study entry
  • Treatment with bisphosphonates is allowed and recommended as per American Society of Clinical Oncology (ASCO) guidelines
  • Prior trastuzumab or lapatinib required for patients with HER2 overexpressing tumors
  • Prior treatment with bevacizumab is allowed
  • Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study registration, and must have fully recovered from any such procedure

    • The following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies and routine dental procedures
  • Patients must not have anticipation of need for a major surgical procedure during the course of the study
  • There are no restrictions on core biopsies, placement of a vascular access device or other minor procedures prior to registration

    • Placement of a vascular access device after starting study therapy should be performed between day 15 and 28 of a treatment cycle (but not less than 48 hours before the next dose of bevacizumab) to allow for sufficient healing
  • Patients must have measurable disease (target lesions): measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2.0 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan

    • Lesions that are considered non-measurable include the following:

      • Bone lesions
      • Leptomeningeal disease
      • Ascites
      • Pleural/pericardial effusion
      • Inflammatory breast disease
      • Lymphangitis cutis/pulmonitis
      • Abdominal masses that are not confirmed and followed by imaging techniques
      • Cystic lesions
  • Patients with pre-existing peripheral neuropathy >= grade 2 are not eligible for this study
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status of =< 1 to be eligible for this trial
  • Women must not be pregnant or breast feeding; premenopausal women must have a negative serum or urine beta-human chorionic gonadotropin (Hcg)
  • Patients with a history of Common Terminology Criteria for Adverse Events (CTCAE) grade >= 3 hypersensitivity to paclitaxel or Cremophor® EL are not eligible
  • Patients with a history of abdominal fistula, or intra-abdominal abscess within 6 months prior to study registration are not eligible
  • Patients with a history of gastrointestinal (GI) perforation within 12 months prior to registration are not eligible
  • Patients with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within 6 months prior to registration are not eligible
  • Patients must not have a history of clinically significant cardiovascular disease that includes the following:

    • Uncontrolled hypertension defined as systolic blood pressure > 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications or any prior history of hypertensive crisis or hypertensive encephalopathy
    • History of myocardial infarction or unstable angina within past 6 months
    • New York Heart Association (NYHA) congestive heart failure grade 2 or greater
    • Symptomatic peripheral vascular disease
    • Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or arterial thrombotic events
  • Patients on full dose anticoagulants must be on a stable dose of warfarin, or be on a stable dose of low molecular weight (LMW) heparin; patients receiving anti-platelet or on daily prophylactic dose aspirin are eligible, as are patients receiving stable doses of anticoagulation for atrial fibrillation
  • Patients may not have a history of stroke or transient ischemic attack within 6 months prior to study registration
  • Patients with a history of seizures must be well controlled with standard medication
  • Patients must not have progressing or untreated central nervous system (CNS) metastases or leptomeningeal disease; patients with a history of resected brain metastases with stable magnetic resonance imaging (MRI) scans for 3 months including within 4 weeks of study start are eligible; patients with a history of gamma knife radiosurgery or whole brain radiation with stable MRI scans for 3 months including within 4 weeks of study start are eligible
  • No serious, non-healing wound, ulcer or bone fracture
  • Life expectancy of >= 12 weeks
  • Granulocytes >= 1,500/ul
  • Platelet count >= 100,000/ul
  • Creatinine =< 2.0 mg/dL
  • Bilirubin < 1.5 mg/dL (unless due to Gilbert's syndrome)
  • Transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) =< 2.5 x upper limit of normal (ULN)
  • Serum or urine beta-Hcg negative in premenopausal women of child-bearing potential
  • Urine protein =< 1+ protein* or urine protein: creatinine ratio (UPC) < 1

    • Patients discovered to have >= 2+ proteinuria at baseline must undergo a 24-hour urine collection that must demonstrate < 1 g of protein/24 hr or UPC ratio =< 1 to allow participation in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00785291
Other Study ID Numbers  ICMJE NCI-2009-00476
NCI-2009-00476 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CTSU 40502
CDR0000617539
NCCTG N063H
CALGB-40502
PCALGB-40502_A11PAMDREVW01
CALGB 40502 ( Other Identifier: Alliance for Clinical Trials in Oncology )
CALGB-40502 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA031946 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hope S Rugo Alliance for Clinical Trials in Oncology
PRS Account National Cancer Institute (NCI)
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP