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A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Chemotherapy Regimens With Weekly Paclitaxel or Eribulin Followed by Doxorubicin and Cyclophosphamide in Women With Locally Advanced HER2-Negative Breast Cancer


Phase 2
18 Years
N/A
Open (Enrolling)
Female
Breast Cancer, HER2-negative Breast Cancer

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Trial Information

A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Chemotherapy Regimens With Weekly Paclitaxel or Eribulin Followed by Doxorubicin and Cyclophosphamide in Women With Locally Advanced HER2-Negative Breast Cancer


Patients will be randomized to one of two neoadjuvant therapy regimens. Patients in Arm 1
will receive WP 80 mg/m2 for 12 doses followed by standard AC every 21 days for 4 cycles.
Patients in Arm 2 will receive 4 cycles of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day
cycle followed by standard AC every 21 days for 4 cycles. As soon as possible following
recovery from chemotherapy, the patient will have either lumpectomy or mastectomy and
axillary staging.

In both arms, clinical response will be assessed by physical exam on day 1 of each study
therapy cycle. MRI of the breast is required within 4 weeks prior to randomization and
following completion of eribulin or WP (before starting AC). Following recovery from
surgery, patients will receive radiation therapy and hormonal therapy as clinically
indicated. Other postoperative therapies are prohibited.

Patients will be randomized to the control arm (Arm 1) and to the investigational arm (Arm
2) in a 1:2 ratio. The sample size will be up to 50 patients with about 30 patients in Arm
2 and about half that number in Arm 1. Accrual is expected to occur over 15 months.


Inclusion Criteria:



- Patients should have a life expectancy of at least 10 years, excluding their
diagnosis of breast cancer. (Comorbid conditions should be taken into consideration,
but not the diagnosis of breast cancer.)

- Patients of reproductive potential must agree to use an effective non-hormonal method
of contraception during therapy and for at least 6 months after the last dose of
study therapy.

- The patient must have consented to participate and must have signed and dated an
appropriate Institutional Review Board (IRB)-approved consent form that conforms to
federal and institutional guidelines.

- Patients must be female.

- Patients must be > 18 years old.

- The Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1.

- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
needle biopsy or by limited incisional biopsy.

- Patients must have ER analysis performed on the primary tumor prior to randomization.
If ER analysis is negative, then Progesterone Receptor (PgR) analysis must also be
performed. (Patients are eligible with either hormone receptor-positive or hormone
receptor-negative tumors.)

- Clinical staging, based on the assessment by physical exam, must be American Joint
Committee on Cancer (AJCC) stage IIB, IIIA, IIIB, or IIIC: cT2 and cN1, cT3 and cN0
or cN1, Any cT and cN2 or cN3, cT4

- The patient must have a mass in the breast or axilla measuring greater than or equal
to 2.0 cm by physical exam, unless the patient has inflammatory breast cancer, in
which case measurable disease by physical exam is not required.

- At the time of randomization, blood counts performed within 4 weeks prior to
randomization must meet the following criteria: Absolute Neutrophil Count (ANC) must
be greater than or equal to 1200/mm3; Platelet count must be greater than or equal to
100,000/mm3; Hemoglobin must be greater than or equal to 10 g/dL.

- The following criteria for evidence of adequate hepatic function performed within 4
weeks prior to randomization must be met: total bilirubin must be less than or equal
to Upper Limit of Normal (ULN) for the lab unless the patient has a bilirubin
elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving
slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to
1.5 x ULN for the lab; and Aspartate aminotransferase (AST) and Alanine
aminotransferase (ALT) must be less than or equal to 1.5 x ULN for the lab.

- Patients with alkaline phosphatase > ULN but less than or equal to 1.5 x ULN are
eligible for inclusion in the study if liver imaging (CT, MRI, PET, or PET-CT scan)
performed within 4 weeks prior to randomization does not demonstrate metastatic
disease and the requirements in the criteria below for unexplained skeletal pain are
met.

- Patients with either unexplained skeletal pain or alkaline phosphatase that is > ULN
but less than or equal to 1.5 x ULN are eligible for inclusion in the study if a bone
scan, PET-CT scan, or PET scan performed within 4 weeks prior to randomization does
not demonstrate metastatic disease. Patients with suspicious findings on bone scan
or PET scan are eligible if suspicious findings are determined to be benign by x-ray,
MRI, or biopsy.

- Serum creatinine performed within 4 weeks prior to randomization must be less than or
equal to 1.5 x ULN for the lab.

- Serum potassium and serum magnesium performed within 4 weeks prior to randomization
must be Within Normal Limits (WNL).

- The Left Ventricular Ejection Fraction (LVEF) assessment by 2-D echocardiogram or
Multigated acquisition (MUGA) scan performed within 90 days prior to randomization
must be greater than or equal to 50% regardless of the facility's Lower Limit of
Normal (LLN).

- ECG performed within 4 weeks before study entry must demonstrate a QTc interval that
is less than or equal to 0.47 seconds.

Exclusion Criteria:

- Tumor that has been determined to be HER2-positive by immunohistochemistry (3+) or by
in situ hybridization (positive for gene amplification), or has been determined to be
HER2-equivocal and the investigator plans to administer trastuzumab or other targeted
therapy.

- Fine Needle Aspiration (FNA) alone to diagnose the primary breast cancer.

- Excisional biopsy or lumpectomy performed prior to randomization.

- Surgical axillary staging procedure prior to randomization. (Procedures that are
permitted prior to study entry include: 1) FNA or core biopsy of an axillary node for
any patient, and 2) although not recommended, a pre-neoadjuvant therapy Sentinal Node
(SN) biopsy for patients with clinically negative axillary nodes.)

- Definitive clinical or radiologic evidence of metastatic disease. (Note: Chest
imaging is mandatory for all patients within 90 days prior to randomization. Other
imaging [if required] must have been performed within 4 weeks prior to
randomization.)

- History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral
Ductal Carcinoma in Situ (DCIS) treated with Radiation Therapy (RT). (Patients with
a history of Lobular Carcinoma in Situ (LCIS), contralateral DCIS [regardless of RT],
or contralateral invasive breast cancer are eligible.)

- History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years
prior to randomization.

- Known metastatic disease from any malignancy (solid tumor or hematologic).

- Previous therapy with anthracyclines, taxanes, cyclophosphamide, or eribulin for any
malignancy.

- Treatment including RT, chemotherapy, and/or targeted therapy, administered for the
currently diagnosed breast cancer prior to randomization.

- Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an
aromatase inhibitor. (Patients are eligible if these medications are discontinued
prior to randomization.)

- Any continued sex hormonal therapy, e.g., birth control pills and ovarian hormone
replacement therapy. Patients are eligible if these medications are discontinued
prior to randomization.

- Requirement for chronic use of any drugs known to prolong the QT interval, including
Na+ and K+ channel blockers. (Patients are eligible if these medications and/or
substances can be discontinued prior to the first dose of eribulin and will not need
to be resumed until after the last dose of eribulin.)

- Active hepatitis B or hepatitis C with abnormal liver function tests.

- Intrinsic lung disease resulting in dyspnea.

- Active infection; or chronic infection requiring chronic suppressive antibiotics.

- Persistent greater than or equal to grade 2 diarrhea regardless of etiology.

- Sensory or motor neuropathy greater than or equal to grade 2, as defined by the NCI
Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.

- Conditions that would prohibit intermittent administration of corticosteroids for
paclitaxel premedication.

- Chronic daily treatment with corticosteroids with a dose of greater than or equal to
10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

- Uncontrolled hypertension defined as a systolic BP > 150 mmHg or diastolic BP > 90
mmHg, with or without anti-hypertensive medications. (Patients with hypertension
that is well-controlled on medication are eligible.)

- Cardiac disease (history of and/or active disease) that would preclude the use of any
of the drugs included in the treatment regimen. This includes but is not confined
to: Active cardiac disease: symptomatic angina pectoris within the past 180 days
that required the initiation of or increase in anti-anginal medication or other
intervention; ventricular arrhythmias except for benign premature ventricular
contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not
controlled with medication; conduction abnormality requiring a pacemaker; valvular
disease with documented compromise in cardiac function; and symptomatic pericarditis.
History of cardiac disease: myocardial infarction documented by elevated cardiac
enzymes or persistent regional wall abnormalities on assessment of Left Ventricular
(LV) function; history of documented Congestive Heart Failure (CHF) documented
cardiomyopathy; and congenital long QT syndrome.

- Other nonmalignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up.

- Pregnancy or lactation at the time of randomization.

- Any psychiatric or addictive disorder or other condition that, in the opinion of the
investigator, would preclude her from meeting the study requirements.

- Use of any investigation agent within 4 weeks prior to randomization.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathologic complete response rate (ypCR) following neoadjuvant therapy in breast and axillary lymph nodes

Outcome Description:

No histologic evidence of cancer.

Outcome Time Frame:

At the time of surgery approximately 24 to 28 weeks.

Safety Issue:

No

Principal Investigator

Norman Wolmark, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

NSABP Foundation, Inc.

Authority:

United States: Food and Drug Administration

Study ID:

NSABP FB-9

NCT ID:

NCT01705691

Start Date:

September 2012

Completion Date:

February 2015

Related Keywords:

  • Breast Cancer
  • HER2-negative Breast Cancer
  • Breast Neoplasms

Name

Location

CCOP - Mount Sinai Medical CenterMiami Beach, Florida  33140
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Providence Hospital - SouthfieldSouthfield, Michigan  48075-9975
Cancer Institute of New JerseyNew Brunswick, New Jersey  08901
Mary Babb Randolph Cancer Center at West Virginia University HospitalsMorgantown, West Virginia  26506
Cancer Centers of the CarolinasGreenville, South Carolina  29605
University of PittsburghPittsburgh, Pennsylvania  15261
Henry Ford Health SystemDetroit, Michigan  48202
Albert Einstein Medical CenterPhiladelphia, Pennsylvania  19141
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Phoebe Putney Memorial HospitalAlbany, Georgia  31703
NSABP Foundation, Inc.Pittsburgh, Pennsylvania  15212
CCOP, Colorado Cancer Research Program, Inc.Denver, Colorado  80224
Allegheny General Hospital/Allegheny-Singer Research InstitutePittsburgh, Pennsylvania  15212
Joe Arrington Cancer Research & Treatment CenterLubbock, Texas  79410
Carolinas Medical Center/Levine Cancer CenterCharlotte, North Carolina  28203