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Paclitaxel, Paclitaxel Albumin-Stabilized Nanoparticle Formulation, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00785291
First received: November 4, 2008
Last updated: February 7, 2014
Last verified: February 2014

November 4, 2008
February 7, 2014
October 2008
January 2100   (final data collection date for primary outcome measure)
Progression-free survival (PFS) of each experimental arm to the PFS of the control arm [ Time Frame: Time from randomization to progression or death due to any cause, whichever occurs first, assessed up to 5 years ] [ Designated as safety issue: No ]
The primary analysis will use the stratified log-rank tests to identify differences in PFS for each experimental arm as compared to control arm (based upon the trial's stratification factors: prior adjuvant taxanes, hormone receptor status, and concomitant bevacizumab). Any efficacy claim will be based solely on this primary statistical analysis. As a secondary analysis we will use the stratified log-rank test to test for a difference between arms after adjusting for disease-free interval and visceral metastases versus bone/soft tissue metastases.
Progression-free survival [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00785291 on ClinicalTrials.gov Archive Site
  • Objective tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Arm differences in response rate will be tested at the final analysis with the proportional hazards and logistic models, respectively. All tests of secondary objectives will use a one-sided alpha of 0.027.
  • Duration of tumor response [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Arm differences in duration of tumor response will be tested at the final analysis with the proportional hazards and logistic models, respectively. All tests of secondary objectives will use a one-sided alpha of 0.027.
  • Time to treatment failure [ Time Frame: Interval from randomization until progression, toxicity, withdrawn consent, or going on non-protocol therapy, assessed up to 5 years ] [ Designated as safety issue: No ]
    The proportional hazards model to compare the control arm to each of the experimental arms on time-to-treatment-failure will be used. All tests of secondary objectives will use a one-sided alpha of 0.027.
  • Probability of being progression-free [ Time Frame: At 12 months ] [ Designated as safety issue: No ]
  • Treatment-related toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and by the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG) Neurotoxicity Subscale (C-669 v5) [ Time Frame: At baseline and day 1 of each course, assessed up to 28 days ] [ Designated as safety issue: Yes ]
    The primary objective is to evaluate the association of baseline factors to the overall rate of grade 3, 4, or 5 toxicity across the three treatment arms. Each factor will be examined using a logistic regression model that includes covariates for the three treatment arms and the stratification factors defined by physician decision of bevacizumab, prior adjuvant taxanes (y/n) and hormone receptor status (pos/neg). An exploratory analysis of associations between toxicity and baseline clinical factors all statistical tests will be conducted using two-sided alpha = 0.05
  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    The proportional hazards model to compare the control arm to each of the experimental arms on overall survival, controlling for the covariates listed above.
  • Objective tumor response as assessed by RECIST criteria [ Designated as safety issue: No ]
  • Duration of tumor response [ Designated as safety issue: No ]
  • Time to treatment failure [ Designated as safety issue: No ]
  • Probability of being progression-free at 12 months [ Designated as safety issue: No ]
  • Treatment-related toxicity as assessed by CTCAE version 3.0 [ Designated as safety issue: Yes ]
  • Overall survival [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Paclitaxel, Paclitaxel Albumin-Stabilized Nanoparticle Formulation, or Ixabepilone With or Without Bevacizumab in Treating Patients With Stage IIIC or Stage IV Breast Cancer
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

This randomized phase III trial is studying different chemotherapy regimens with or without bevacizumab and their side effects and comparing how well they work in treating patients with stage IIIC or stage IV breast cancer. Drugs used in chemotherapy, such as paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, and ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known which treatment regimen is more effective in treating patients with breast cancer.

PRIMARY OBJECTIVES:

I. To compare the progression-free survival of patients with stage IIIC or IV breast cancer treated with paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel) versus ixabepilone versus paclitaxel with or without bevacizumab.

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 treated with these regimens.

III. To compare treatment-related toxicities in patients receiving these regimens, according to the rates of grade 3/4 sensory neuropathy and the rates of peripheral neuropathy assessed by the FACT/GOG neurotoxicity subscale.

IV. To compare overall survival of patients receiving these regimens. V. 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.

VI. To evaluate the relationships between SPARC overexpression and changes in blood levels of caveolin-1 (Cav-1) to PFS and secondary endpoints of response during treatment in these patients.

V. 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 in these patients.

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.

VIII. To investigate a potential 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 CYP3A4, CYP3A5, ABCB1 and 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 study enrollment 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. (Exploratory) 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, nabpaclitaxel, or ixabepilone combined with or without bevacizumab. (Exploratory) XVII. To explore the association between grade 2-4 neuropathy and longitudinal changes in the following functional status measures: a) OARS MFAQ (IADL); b) MOS Physical Functioning; c) Karnofsky Performance Status Rated Healthcare Professional; d) Timed "Up and Go"; e) OARS Physical Health Section.

(Exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to taxane as adjuvant therapy (yes or no), estrogen receptor (ER) or progesterone receptor (PgR) status (ER-positive or PgR-positive vs both ER-negative and PgR-negative), physician's decision to use bevacizumab (yes vs no). Patients are randomized to 1 of 3 treatment arms.

ARM I: (weekly paclitaxel) Patients receive paclitaxel 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 II: (weekly paclitaxel albumin-stabilized nanoparticle formulation [nab-paclitaxel]) Patients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in arm I.

ARM III: (weekly ixabepilone) Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in arm I.

In all arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients complete questionnaires about peripheral neuropathy at baseline and before each course of therapy. They also complete questionnaires about sociodemographics, non-cancer comorbidities, social support, physical activity, and post-trial therapy at baseline and periodically thereafter. Blood samples may be collected at baseline and periodically during study for correlative studies. Tumor tissue samples from diagnosis may be also collected.

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

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    Given IV
    Other Names:
    • ABI-007
    • nab paclitaxel
    • nab-paclitaxel
    • nanoparticle albumin-bound paclitaxel
  • Biological: bevacizumab
    Given IV
    Other Names:
    • anti-VEGF humanized monoclonal antibody
    • anti-VEGF monoclonal antibody
    • Avastin
    • rhuMAb VEGF
  • Drug: paclitaxel
    Given IV
    Other Names:
    • Anzatax
    • Asotax
    • TAX
    • Taxol
  • Drug: ixabepilone
    Given IV
    Other Names:
    • BMS-247550
    • epothilone B lactam
    • Ixempra
  • Other: questionnaire administration
    Ancillary studies
  • Other: laboratory biomarker analysis
    Optional correlative studies
  • Active Comparator: Arm I (chemotherapy, monoclonal antibody therapy)
    Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Patients may receive bevacizumab IV over 30-90 minutes on days 1 and 15.
    Interventions:
    • Biological: bevacizumab
    • Drug: paclitaxel
    • Other: questionnaire administration
    • Other: laboratory biomarker analysis
  • Experimental: Arm II (chemotherapy, monoclonal antibody therapy)
    Patients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in arm I.
    Interventions:
    • Drug: paclitaxel albumin-stabilized nanoparticle formulation
    • Biological: bevacizumab
    • Other: questionnaire administration
    • Other: laboratory biomarker analysis
  • Experimental: Arm III (chemotherapy, monoclonal antibody therapy)
    Patients receive ixabepilone IV over 60 minutes on days 1, 8, and 15. Patients may also receive bevacizumab as in arm I.
    Interventions:
    • Biological: bevacizumab
    • Drug: ixabepilone
    • Other: questionnaire administration
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
900
Not Provided
January 2100   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically confirmed invasive breast cancer

    • Stage IIIC or IV (locally recurrent or metastatic) disease not amenable to local therapy
  • Measurable disease (target lesions), defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 2.0 cm with conventional techniques or as ≥ 1 cm with spiral CT scan
  • No non-measurable lesions, including any of the following:

    • Ascites
    • Pleural/pericardial effusion
    • Inflammatory breast disease
    • Lymphangitis cutis/pulmonitis
    • Bone lesions
    • Leptomeningeal disease
    • Cystic lesions
    • Abdominal masses not confirmed and followed by imaging techniques
  • HER2/neu status must be known

    • HER2-positive disease allowed provided patient received prior trastuzumab (Herceptin®) or lapatinib (documentation of progression on HER2-directed therapy is not required)
  • No progressing or untreated CNS metastases or leptomeningeal disease

    • History of resected brain metastases with stable MRI scans for 3 months, including within the past 4 weeks allowed
    • History of gamma-knife radiosurgery or whole-brain radiation with stable MRI scans for 3 months, including within the past 4 weeks allowed
  • Hormone receptor status must be known

    • Estrogen receptor (ER)- and progesterone receptor (PgR)-positive if ≥ 1% cells are positive
  • Menopausal status not specified
  • ECOG (Zubrod) performance status 0-1
  • Life expectancy ≥ 12 weeks
  • Granulocytes ≥ 1,500/μL
  • Platelet count ≥ 100,000/μL
  • Creatinine ≤ 2.0 mg/dL
  • Bilirubin < 1.5 mg/dL (unless due to Gilbert's syndrome)
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Urine protein ≤ 1+ OR urine protein: creatinine ratio < 1

    • Patients with proteinuria ≥ 2+ at baseline must undergo a 24-hoururine collection that demonstrates < 1 g of protein/24 hr or UPC ratio ≤ 1
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • History of seizures allowed if well controlled with standard medication
  • No history of hypersensitivity to paclitaxel or Cremophor® EL CTCAE grade ≥ 3
  • No other active malignancy except nonmelanoma skin cancer (patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to have less than 30% risk of relapse)
  • No history of abdominal fistula or intra-abdominal abscess within 6 months prior to study registration
  • No history of gastrointestinal (GI) perforation within the past 12 months
  • No history of significant bleeding episodes (e.g., hemoptysis, upper or lower GI bleeding) within the past 6 months
  • No history of stroke or transient ischemic attack within the past 6 months
  • No history of clinically significant cardiovascular disease including any of the following:

    • Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg and/or diastolic BP > 90 mm Hg on antihypertensive medications
    • Prior history of hypersensitivity or hypertensive encephalopathy
    • History of myocardial infarction or unstable angina within past 6 months
    • NYHA congestive heart failure class II-IV
    • Symptomatic peripheral vascular disease
    • Significant vascular disease (e.g., aortic aneurysm or aortic dissection) or arterial thrombotic events
  • No serious, non-healing wound, ulcer, or bone fracture
  • No significant traumatic injury in the past 28 days
  • No peripheral neuropathy ≥ grade 2
  • Concurrent full-dose anticoagulants allowed but patient must be on a stable dose of warfarin or low molecular weight heparin

    • Anti-platelet therapy or on daily prophylactic-dose aspirin allowed
    • Stable doses of anticoagulation for atrial fibrillation allowed
  • No prior chemotherapy regimen for metastatic disease
  • Adjuvant or neoadjuvant taxane allowed provided interval between completion of adjuvant therapy and disease recurrence is ≥ 12 months
  • At least 2 weeks since prior radiotherapy
  • At least 28 days since prior major surgical procedure or open biopsy and fully recovered

    • There are no restrictions on core biopsies, placement of a vascular access device, or other minor procedures prior to registration.
  • At least 7 days since prior hormonal therapy

    • Any number of prior hormonal therapies allowed
  • Prior trastuzumab or lapatinib ditosylate for HER2-overexpressing tumors allowed
  • Prior bevacizumab allowed
  • Prior and concurrent bisphosphonate treatment allowed
  • No concurrent major surgical procedure
  • No concurrent palliative radiotherapy
  • No concurrent aprepitant
  • No concurrent pegfilgrastim
  • No other concurrent chemotherapy or anticancer hormone therapy
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Puerto Rico
 
NCT00785291
NCI-2009-00476, NCI-2009-00476, CDR0000617539, CALGB 40502, CALGB-40502, U10CA031946, P30CA014236
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Hope Rugo Cancer and Leukemia Group B
National Cancer Institute (NCI)
February 2014

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