This is a prospective, single arm, open label, multicenter interventional study designed to
evaluate the efficacy of neoadjuvant chemotherapy with anti-HER2 antibodies in patients with
HER2-negative invasive breast cancer who have abnormal HER2 signaling activity determined by
the Celcuity CELx HER2 Signaling Function (HSF) testing.
Patients will be required to have a prescreening research core needle biopsy to procure a
fresh tumor specimen that will be sent to Celcuity for CELx HSF testing, in order to assess
the status of their HER2 signaling activity (abnormally or normally active).
Patients who have abnormal HER2 signaling activity will receive weekly paclitaxel plus the
anti-HER2 therapy regimen of trastuzumab and pertuzumab following completion of initial
doxorubicin/cyclophosphamide.The primary endpoint of the study is to evaluate whether
patients with HER2-negative breast cancers based on standard American Society of Clinical
Oncology (ASCO)/College of American Pathologists (CAP) testing criteria, but with abnormal
HER2-driven signaling pathways determined by the Celcuity HSF assay and receive HER2-targeted
therapy with neoadjuvant chemotherapy, will have a higher rate of pathological complete
response in the breast and lymph nodes (pCR breast and lymph nodes) than has been found
historically in patients with HER2-negative breast cancer who have received neoadjuvant
chemotherapy alone. Secondary endpoints include pathologic complete response (breast),
clinical complete response (cCR), residual cancer burden (RCB) 0-1 index, and relationship
between quantitative CELx score and pCR rate.
It is expected that approximately 270 patients will need to be prescreened in order to enroll
54 patients (26 ER-positive/HER2-negative and 28 ER-negative/HER2-negative) who have abnormal
HER2 signaling activity.
SCREENING PRIOR TO INITIATING CHEMOTHERAPY
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle
The primary breast tumor must be palpable and measure greater than or equal 2.0 cm on
The regional lymph nodes can be cN0, cN1, or cN2a.
Histological grade II or III tumor.
Ipsilateral axillary lymph nodes must be evaluated by imaging (mammogram, ultrasound,
and/or MRI) within 6 weeks prior to initiating chemotherapy. If suspicious or abnormal, FNA
or core biopsy is recommended, also within 6 weeks prior to initiating chemotherapy.
Findings of these evaluations will be used to determine the nodal status prior to
- Nodal status - negative: Imaging of the axilla is negative; Imaging is suspicious or
abnormal but the FNA or core biopsy of the questionable node(s) on imaging is
- Nodal status - positive: FNA or core biopsy of the node(s) is cytologically or
histologically suspicious or positive. Imaging is suspicious or abnormal but FNA or
core biopsy was not performed.
Tumor specimen obtained at the time of diagnosis must have ER and progesterone receptor
(PgR) analysis assessed by current ASCO/CAP Guidelines. Patients are eligible with either
hormone receptor-positive or hormone receptor-negative tumors.
Tumor specimen obtained at the time of diagnosis must have been determined to be
HER2-negative as follows:
- Immunohistochemistry (IHC) 0-1+; or
- IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to
chromosome enumeration probe 17 (CEP17) less than 2.0, and if reported, average HER2
gene copy number less than 4 signals/cells; or
- ISH non-amplified with a ratio of HER2 to CEP17 less than 2.0, and if reported,
average HER2 gene copy number less than 4 signals/cells.
Blood counts performed within 6 weeks prior to initiating chemotherapy must meet the
- absolute neutrophil count (ANC) must be greater than or equal 1200/mm3;
- platelet count must be greater than or equal 100,000/mm3; and
- hemoglobin must be greater than or equal 10 g/dL.
The following criteria for evidence of adequate hepatic function performed within 6 weeks
prior to initiating chemotherapy 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 greater than 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 2.5 x ULN for the lab; and
- aspartate aminotransferase (AST) must be less than or equal to 1.5 x ULN for the lab.
- Alkaline phosphatase and AST may not both be greater than the ULN. For example, if the
alkaline phosphatase is greater than the ULN but less than or equal to 2.5 x ULN, the
AST must be less than or equal to the ULN. If the AST is greater than the ULN but less
than or equal to 1.5 x ULN, the alkaline phosphatase must be less than or equal to
ULN. Note: If alanine aminotransferase (ALT) is performed instead of AST (per
institution's standard practice), the ALT value must be less than or equal to 1.5 x
ULN; if both were performed, the AST must be less than or equal to 1.5 x ULN.
Patients with AST or alkaline phosphatase greater than ULN are eligible for inclusion in
the study if liver imaging (CT, MRI, PET-CT, or PET scan) performed within 6 weeks prior to
initiating chemotherapy does not demonstrate metastatic disease and the requirements in
next criteria are met.
Patients with alkaline phosphatase that is greater than ULN but less than or equal to 2.5 x
ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT
scan, or positron emission tomography (PET) scan performed within 6 weeks prior to
initiating chemotherapy does not demonstrate metastatic disease.
Serum creatinine performed within 6 weeks prior to initiating chemotherapy must be less
than or equal to 1.5 x ULN for the lab.
The left ventricular ejection fraction (LVEF) assessment by echocardiogram or multi-gated
acquisition (MUGA) scan performed within 90 days prior to initiating chemotherapy must be
greater than or equal 55 percent regardless of the facility's lower limit of normal (LLN).
Patients with reproductive potential must agree to use an effective non-hormonal method of
contraception during therapy and for at least 7 months after the last dose of study
MAIN STUDY ENROLLMENT
Tumor determined to have abnormal HER2-driven signaling activity based on the CELx HSF
T4 tumors including inflammatory breast cancer.
FNA alone to diagnose the breast cancer.
Excisional biopsy or lumpectomy performed prior to initiating chemotherapy.
Surgical axillary staging procedure prior to initiating chemotherapy. Pre-neoadjuvant
therapy sentinel node biopsy is not permitted. (FNA or core biopsy is acceptable.)
Definitive clinical or radiologic evidence of metastatic disease. Required imaging studies
must have been performed within 6 weeks prior to initiating chemotherapy.
Synchronous bilateral invasive breast cancer. (Patients with synchronous and/or previous
contralateral ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS] are
Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS. (Patients
with synchronous or previous ipsilateral LCIS are eligible.)
Previous therapy with anthracycline, taxanes, trastuzumab, or other HER2 targeted therapies
for any malignancy.
Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy,
etc. (These patients are eligible if this therapy is discontinued prior to initiating
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 2 years prior to
Cardiac disease (history of and/or active disease) that would preclude the use of the drugs
included in the treatment regimens. This includes but is not confined to:
- Active cardiac disease: angina pectoris that requires the use of anti-anginal
medication; 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); and documented
Uncontrolled hypertension defined as sustained systolic BP greater than 150 mmHg or
diastolic BP greater than 90 mmHg. (Patients with initial BP elevations are eligible prior
to initiating chemotherapy if initiation or adjustment of BP medication lowers pressure.)
Active hepatitis B or hepatitis C with abnormal liver function tests. Intrinsic lung
disease resulting in dyspnea.
Poorly controlled diabetes mellitus.
Active infection or chronic infection requiring chronic suppressive antibiotics.
Patients known to be HIV positive.
Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory
neuropathy) greater than or equal to grade 2, per the CTCAE v4.0.
Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel, or
other disease significantly affecting gastrointestinal function.
Other non-malignant systemic disease that would preclude treatment with any of the
treatment regimens or would prevent required follow-up.
Conditions that would prohibit administration of corticosteroids.
Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10
mg/day methylprednisolone equivalent (excluding inhaled steroids).
Known hypersensitivity to any of the study drugs or any of the ingredients or excipients of
these drugs (e.g., Cremophor EL), including sensitivity to benzyl alcohol.
Pregnancy or lactation at the initiation of chemotherapy. (Note: Pregnancy testing must be
performed within 2 weeks prior to initiating chemotherapy according to institutional
standards for women of childbearing potential.)
Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.