An Open-Label Phase II Trial to Evaluate the Efficacy and Safety of Neoadjuvant Neratinib
Followed by Weekly Paclitaxel and Carboplatin Plus Neratinib in Early Stage Triple-Negative
Breast Cancer Patients Who Exhibit Enhanced HER2 Signaling by Live Cell HER2 Signaling
Transduction Analysis (FACT-2)
This is a prospective, single arm, open label, interventional study designed to evaluate the
efficacy of neoadjuvant chemotherapy with a pan-HER inhibitor in patients with
ER-/PR-/HER2-(triple-negative) invasive breast cancer who have abnormal HER2-driven signaling
activity determined by the Celcuity CELx HER2 signal function (HSF) test. 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-driven signaling activity (abnormally or normally active). While waiting for results of
the CELx HSF test, patients may receive the first dose of weekly paclitaxel at the
investigator's discretion. Patients whose CELx HSF test indicate they have abnormal
HER2-driven signaling activity will then receive neratinib as a single agent daily for 21
days and then neratinib plus paclitaxel and carboplatin.
The primary endpoint of the study is to evaluate whether patients with triple-negative breast
cancers (estrogen (ER) and progesterone (PR) receptors < 10%; HER2-negative per standard
ASCO/CAP testing criteria), but with abnormal HER2-driven signaling pathways determined by
the Celcuity CELx HSF assay, and who receive HER2-targeted therapy with neoadjuvant
chemotherapy will have a higher rate of pathological complete response (pCR) in the breast
and lymph nodes (pCR breast and lymph nodes) than has been found historically in patients
with triple-negative breast cancer who have received neoadjuvant chemotherapy. 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
It is expected that approximately 135 patients will need to be prescreened in order to enroll
27 patients who have abnormal HER2-driven signaling activity.
- The patient must have consented to participate and must have signed and dated an
appropriate IRB-approved consent form that conforms to federal and i institutional
guidelines for the pre-entry research core biopsy for CELx HSF testing and for
- Patients must be female.
- Patients must be ≥ 18 years old.
- Patient must have an ECOG performance status of 0 or 1
- The diagnosis of invasive adenocarcinoma of the breast must have been made by core
- The primary breast tumor must be palpable and measure ≥ 1.0 cm on physical exam.
- The regional lymph nodes can be cN0 or cN1
- The tumor size can be T1c or T2
- 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 estrogen (ER) and
progesterone (PR) receptors < 10%.
- 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 ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if
reported, average HER2 gene copy number < 4 signals/cells; or
- ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average
HER2 gene copy number < 4 signals/cells.
- Blood counts performed within 6 weeks prior to initiating chemotherapy must meet the
- Absolute neutrophil count (ANC) must be ≥ 1200/mm3;
- platelet count must be ≥ 100,000/mm3; and
- hemoglobin must be ≥ 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 ≤ 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 ≤ 2.5 x ULN for the lab; and
- AST must be ≤ 1.5 x ULN for the lab.
- Alkaline phosphatase and AST may not both be > the ULN. For example, if the
alkaline phosphatase is > the ULN but ≤ 2.5 x ULN, the AST must be ≤ the ULN. If
the AST is > the ULN but ≤ 1.5 x ULN, the alkaline phosphatase must be ≤ ULN.
Note: If ALT is performed instead of AST (per institution's standard practice),
the ALT value must be ≤ 1.5 x ULN; if both were performed, the AST must be ≤ 1.5
- Patients with AST or alkaline phosphatase > 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 criterion 4.2.13 are met.
- Patients with alkaline phosphatase that is > ULN but ≤ 2.5 x ULN or unexplained bone
pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan
performed within 6 weeks prior to initiating chemotherapy does not demonstrate
- Serum creatinine performed within 6 weeks prior to initiating chemotherapy must be ≤
1.5 x ULN for the lab.
- The left ventricular ejection fraction (LVEF) assessment by echocardiogram or MUGA
scan performed within 90 days prior to initiating chemotherapy must be ≥ 50%
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 therapy.
- Patients are candidates for weekly paclitaxel and carboplatin chemotherapy as
determined by treating physician.
- Patients with multifocal breast cancer are included as long as none of the tumors are
HER2 positive by IHC or FISH and targeted lesion meets current inclusion criteria.
- Conditions for patient eligibility (Study Enrollment) A patient cannot be considered
eligible for this study unless all of the following conditions are met:
- The patient must have consented to participate and must have signed and dated an
appropriate IRB-approved consent form that conforms to federal and institutional
guidelines for the FACT-2 study treatment.
- Tumor determined to have abnormal HER2-driven signaling activity based on the CELx HSF
- T3 or 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 DCIS or 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
- 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
- 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 > 150 mmHg or diastolic BP
> 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) ≥ 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 ≥ 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
- 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.
- Evidence after a clinical examination that the subject's tumor is progressing after
treatment with one week of paclitaxel and before a CELx HSF test result is available.
- For participation in adherence monitoring: no access to the web via smart phone,
tablet or computer