Study of Neoadjuvant Chemotherapy Plus Trastuzumab and Pertuzumab in HER2-Negative Breast Cancer Patients With Abnormal HER2 Signaling
Study of Neoadjuvant Chemotherapy Plus Trastuzumab and Pertuzumab in HER2-Negative Breast Cancer Patients With Abnormal HER2 Signaling
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.
Inclusion Criteria:

 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
 biopsy.

 The primary breast tumor must be palpable and measure greater than or equal 2.0 cm on
 physical exam.

 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
 initiating chemotherapy.

 -  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
 negative;

 -  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
 following criteria:

 -  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
 test.

 ______________

 Exclusion Criteria:

 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
 eligible.)

 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
 chemotherapy.)

 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
 initiating chemotherapy.

 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
 cardiomyopathy.

 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.