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: July 22, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Male Breast Cancer
Recurrent Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: paclitaxel albumin-stabilized nanoparticle formulation
Biological: bevacizumab
Drug: paclitaxel
Drug: ixabepilone
Other: questionnaire administration
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 799
Study Start Date: October 2008
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
Other: questionnaire administration
Ancillary studies
Other: laboratory biomarker analysis
Optional correlative studies
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.
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
Other: questionnaire administration
Ancillary studies
Other: laboratory biomarker analysis
Optional correlative studies
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.
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: ixabepilone
Given IV
Other Names:
  • BMS-247550
  • epothilone B lactam
  • Ixempra
Other: questionnaire administration
Ancillary studies
Other: laboratory biomarker analysis
Optional correlative studies

  Hide Detailed Description

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00785291

  Show 704 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Hope Rugo Cancer and Leukemia Group B
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00785291     History of Changes
Other Study ID Numbers: NCI-2009-00476, NCI-2009-00476, CDR0000617539, CALGB 40502, CALGB-40502, U10CA031946, P30CA014236
Study First Received: November 4, 2008
Last Updated: July 22, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Breast Neoplasms, Male
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Paclitaxel
Epothilone B
Epothilones
Bevacizumab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on July 22, 2014