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Paclitaxel, Nab-paclitaxel, o...

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

Last Updated: 2022-10-10

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

799 participants

Study Classification

INTERVENTIONAL

Study Start Date

2008-10-13

Study Completion Date

2017-06-15

Brief Summary

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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.

Conditions

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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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type OTHER

Ancillary studies

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Hope S Rugo

Role: PRINCIPAL_INVESTIGATOR

Alliance for Clinical Trials in Oncology

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Stover DG, Salgado R, Savenkov O, Ballman K, Mayer EL, Magbanua MJM, Loi S, Vater M, Glover K, Watson M, Wen Y, Symmans WF, Perou C, Carey LA, Partridge AH, Rugo HS. Association between tumor-infiltrating lymphocytes and survival in patients with metastatic breast cancer receiving first-line chemotherapy: analysis of CALGB 40502. NPJ Breast Cancer. 2024 Aug 21;10(1):75. doi: 10.1038/s41523-024-00683-x.

Reference Type DERIVED

PMID: 39169033 (View on PubMed)

Quintanilha JCF, Wang J, Sibley AB, Jiang C, Etheridge AS, Shen F, Jiang G, Mulkey F, Patel JN, Hertz DL, Dees EC, McLeod HL, Bertagnolli M, Rugo H, Kindler HL, Kelly WK, Ratain MJ, Kroetz DL, Owzar K, Schneider BP, Lin D, Innocenti F. Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients. Br J Cancer. 2022 Feb;126(2):265-274. doi: 10.1038/s41416-021-01557-w. Epub 2021 Oct 6.

Reference Type DERIVED

PMID: 34616010 (View on PubMed)

Mehrotra S, Sharma MR, Gray E, Wu K, Barry WT, Hudis C, Winer EP, Lyss AP, Toppmeyer DL, Moreno-Aspitia A, Lad TE, Valasco M, Overmoyer B, Rugo H, Ratain MJ, Gobburu JV. Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone: CALGB 40502 (Alliance). AAPS J. 2017 Sep;19(5):1411-1423. doi: 10.1208/s12248-017-0101-9. Epub 2017 Jun 15.

Reference Type DERIVED

PMID: 28620884 (View on PubMed)

Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. doi: 10.1200/JCO.2014.59.5298. Epub 2015 Jun 8.

Reference Type DERIVED

PMID: 26056183 (View on PubMed)

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180821

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U10CA031946

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2009-00476

Identifier Type: -

Identifier Source: org_study_id

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Study Results

Basic Information

Brief Summary

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Detailed Description

Conditions

Study Design

Study Groups

Arm A (Paclitaxel)

Bevacizumab

Laboratory Biomarker Analysis

Paclitaxel

Questionnaire Administration

Arm B (Nab-paclitaxel)

Bevacizumab

Laboratory Biomarker Analysis

Nab-paclitaxel

Questionnaire Administration

Arm C (Ixabepilone)

Bevacizumab

Ixabepilone

Laboratory Biomarker Analysis

Questionnaire Administration

Interventions

Bevacizumab

Ixabepilone

Laboratory Biomarker Analysis

Nab-paclitaxel

Paclitaxel

Questionnaire Administration

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Sponsors

National Cancer Institute (NCI)

Responsible Party

Principal Investigators

Hope S Rugo

Locations

Mayo Clinic in Arizona

Sparks Regional Medical Center

Mercy Hospital Fort Smith

NEA Baptist Memorial Hospital

Kaiser Permanente-Anaheim

Kaiser Permanente-Deer Valley Medical Center

PCR Oncology

Kaiser Permanente-Baldwin Park

Kaiser Permanente-Bellflower

Alta Bates Summit Medical Center-Herrick Campus

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Mills-Peninsula Medical Center

East Bay Radiation Oncology Center

Eden Hospital Medical Center

Valley Medical Oncology Consultants-Castro Valley

City of Hope Comprehensive Cancer Center

Bay Area Breast Surgeons Inc

Kaiser Permanente-Fontana

Kaiser Permanente-Fremont

Valley Medical Oncology Consultants-Fremont

Kaiser Permanente-Fresno

Marin Cancer Care Inc

Marin General Hospital

Kaiser Permanente - Harbor City

Kaiser Permanente-Irvine

Loma Linda University Medical Center

Kaiser Permanente Los Angeles Medical Center

Kaiser Permanente West Los Angeles

Contra Costa Regional Medical Center

El Camino Hospital

Sutter Cancer Research Consortium

Highland General Hospital

Alta Bates Summit Medical Center - Summit Campus

Bay Area Tumor Institute

Hematology and Oncology Associates-Oakland