Trial Information

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

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.