A Randomized Phase III Trial of Eribulin Compared to Standard Weekly Paclitaxel as First- or Second-Line Therapy for Locally Recurrent or Metastatic Breast Cancer

• Objective tumor response as defined by RECIST 1.1 [ Time Frame: Baseline until death, or up to 4 years ] [ Designated as safety issue: No ]
• Duration of tumor response [ Time Frame: Baseline until death, or up to 4 years ] [ Designated as safety issue: No ]
• Time-to-treatment-failure of eribulin mesylate [ Time Frame: Baseline until death, or up to 4 years ] [ Designated as safety issue: No ]
• Treatment-related toxicity of eribulin mesylate [ Time Frame: Baseline until death, or up to 4 years ] [ Designated as safety issue: No ]
  To assess the toxicities in patients receiving eribulin versus standard weekly paclitaxel.
• Progression-Free Survival (PFS) defined as the time from randomization to progression (under RECIST 1.1 criteria) or death due to any cause, whichever occurs first [ Time Frame: Baseline until death, or up to 4 years ] [ Designated as safety issue: Yes ]

This is a two arm Phase III trial in first- and second-line HER2 negative patients with locally recurrent or metastatic breast cancer. The primary endpoint is overall survival (OS), and the objective is to test for the superiority of eribulin mesylate over standard weekly paclitaxel. Patients will be randomized between the experimental and control arm with equal allocation (1:1) within strata defined by prior adjuvant taxanes, hormone receptor status, and line of therapy. Subjects will continue protocol directed therapy until documentation of disease progression, development of unacceptable toxicity, or withdrawal of consent. Those who discontinue study treatment without radiological progression will be followed with repeat imaging studies every 12 weeks. All subjects will be followed until death, withdrawal of consent, or study termination.

• Metastatic Breast Cancer
• Locally Recurrent Breast Cancer

• Drug: Eribulin
• Drug: Paclitaxel

• Experimental: A
  Eribulin on Days 1 and 8 of each cycle (cycle length: 21 days)
  Intervention: Drug: Eribulin
• Active Comparator: B
  Paclitaxel on Days 1, 8, and 15 of each cycle (cycle length: 28 days)
  Intervention: Drug: Paclitaxel

Inclusion Criteria:

1. Histologic confirmation of invasive adenocarcinoma originating in the breast.
2. Stage IV disease or Stage IIIC disease (using the 7th edition AJCC criteria) not amenable to local therapy.
3. Radiographically measurable disease as per RECIST guidelines (version 1.1).
4. Radiographic evidence of disease progression.
5. Documentation of HER2 negative breast cancer at the time of protocol registration.
6. Known hormone receptor status at the time of protocol registration.

7. Prior systemic therapy as per the following criteria:

   1. Patients must demonstrate resolution of all prior chemotherapy or radiation-related toxicities to grade less than or equal to 1, including peripheral neuropathy, with the exception of alopecia (any grade permissible).
   2. No more than one prior chemotherapy regimen for advanced or metastatic breast cancer is allowed. Prior chemotherapy for metastatic disease must have been completed greater than or equal to 14 days prior to randomization.
   3. Prior treatment may include a taxane in the adjuvant or neoadjuvant setting, provided that the interval between the completion of adjuvant therapy and disease recurrence is greater than 12 months.
   4. Any number of prior hormonal therapies is allowed.
   5. Any number of biologic therapies (e.g., bevacizumab) or immunotherapies is allowed in the absence of co-administered chemotherapy and must have been completed greater than or equal to 28 days prior to randomization.
   6. Prior treatment with an investigational agent is allowed but must have been completed greater than or equal to 28 days prior to randomization.

8. Prior local therapy as per the following criteria:

   1. Minor surgical procedures must be completed greater than or equal to 7 days prior to randomization with documentation of adequate recovery from associated complications to grade less than or equal to 1.
   2. Major surgical procedures and open biopsies must be completed greater than or equal to 28 days prior to randomization with documentation of adequate recovery from associated complications to grade less than or equal to 1.
   3. Prior radiotherapy must be completed greater than or equal to 14 days prior to randomization with documentation of adequate recovery from associated toxicities to grade less than or equal to 1.

9. Concurrent supportive therapy as per the following criteria:

   1. Treatment with bisphosphonates or denosumab is allowed and recommended per the standard of care.
   2. Therapeutic anticoagulation is allowed for patients on a stable dose of warfarin or low molecular weight heparin.
10. ECOG performance status of 0, 1, or 2.
11. Life expectancy of greater than 12 weeks.

12. History of brain metastases as per the following criteria:

    1. Patients with a history of resected brain metastases are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including less than 28 days of study registration.
    2. Patients who receive stereotactic radiosurgery or whole brain radiation for brain metastases are eligible only if they are asymptomatic and have stable MRI scans for 3 consecutive months, including less than 28 days of study registration.

13. Adequate organ function per blood work obtained less than 7 days prior to registration.

    1. Absolute neutrophil count greater than or equal to 1500/uL.
    2. Platelet count greater than or equal to 100,000/uL.
    3. Hemoglobin greater than or equal to 9 g/dL.
    4. Total bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome.
    5. SGOT (AST) and SGPT (ALT) less than 3 x ULN except in the case of liver metastases, where less than or equal to 5 x ULN is allowed.
    6. Creatinine less than or equal to 2.0 mg/dL or creatinine clearance greater than 50 mL/min.
    7. QTc interval ≤500 msec on the baseline electrocardiogram.
    8. Negative pregnancy test done less than or equal to 72 hours prior to registration for women of childbearing potential only.
14. Ability to complete questionnaire(s) independently or with assistance.
15. Willingness to provide blood and tissue samples for correlative research purposes.
16. Ability to comprehend and respond to questions using a telephone keypad.

Exclusion Criteria:

1. Prior malignancy, other than carcinoma in situ of the cervix and non-melanoma skin cancers, unless the prior malignancy was diagnosed and definitively treated greater than or equal to 5 years previously, there is no subsequent evidence of recurrence, and the patient is considered by a physician to be at less than 30% risk of relapse.

2. Any of the following because this study involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown:

   1. Pregnant women
   2. Nursing women
   3. Men or women of childbearing potential who are unwilling to employ adequate contraception
3. Presence of a serious nonhealing wound, ulcer, or bone fracture.
4. History of CTCAE grade greater than 3 hypersensitivity to paclitaxel or Cremophor EL.
5. Pre-existing peripheral neuropathy grade less than 2 at registration.
6. Significant cardiovascular impairment (e.g., New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia).
7. Subjects with known positive HIV status.
8. History of stroke or transient ischemic attack less than 6 months prior to registration.
9. History of uncontrolled seizures.
10. Severe or uncontrolled intercurrent illness/infection.
11. Concurrent administration of any other investigational agent considered to have potential efficacy in the treatment of breast cancer.
12. Prior exposure to eribulin mesylate.