Study of Neoadjuvant Chemotherapy Plus Trastuzumab and Pertuzumab in HER2-Negative Breast Cancer Patients With Abnormal HER2 Signaling (FB-12)

An Open-Label Phase II Trial to Evaluate the Efficacy and Safety of Neoadjuvant Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel Plus Trastuzumab and Pertuzumab in Early Stage HER2-Negative Breast Cancer Patients Selected With a Test Measuring Live Cell HER2 Signaling Transduction (FACT 1)

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.

Study Overview

• Status: Recruiting
• Conditions: HER2-negative Breast Cancer
• Intervention / Treatment: Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Weekly Paclitaxel; Drug: Trastuzumab; Drug: Pertuzumab; Diagnostic test: Celcuity CELx HSF

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Colton, California, United States, 92324
      • Recruiting
      • Arrowhead Regional Medical Center
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Recruiting
      • Mount Sinai Comprehensive Cancer Center
    • Orlando, Florida, United States, 32806
      • Recruiting
      • University of Florida Cancer Center at Orlando Health
  • Illinois
    • Decatur, Illinois, United States, 62526
      • Recruiting
      • Cancer Care Specialists of Central Illinois
    • Naperville, Illinois, United States, 60540-7499
      • Recruiting
      • Edward Hospital Cancer Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Recruiting
      • Fort Wayne Medical Oncology and Hematology, Inc.
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • University of Louisville JG Brown Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Recruiting
      • University Medical Center New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21204
      • Recruiting
      • Greater Baltimore Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Recruiting
      • St. Joseph Mercy Hospital
    • Detroit, Michigan, United States, 48202
      • Recruiting
      • Henry Ford Hospital
    • Flint, Michigan, United States, 48503
      • Recruiting
      • Genesys Hurley Cancer Institute
    • Lansing, Michigan, United States, 48912
      • Recruiting
      • Herbert Herman Cancer Center, Sparrow Hospital
    • Saginaw, Michigan, United States, 48601
      • Recruiting
      • Ascension St. Mary's
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Recruiting
      • Newark Beth Israel Medical Center
  • New York
    • Rochester, New York, United States, 14642
      • Recruiting
      • University of Rochester - Wilmot Cancer Institute
  • Ohio
    • Belpre, Ohio, United States, 45714
      • Recruiting
      • Strecker Cancer Center-Belpre
    • Canton, Ohio, United States, 44710
      • Recruiting
      • Aultman Hospital
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43228
      • Recruiting
      • Doctors Hospital
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Arthur G. James Cancer Hospital & Richard Solove Research Institute
    • Columbus, Ohio, United States, 43214
      • Recruiting
      • Columbus Oncology & Hematology Associates Inc
    • Columbus, Ohio, United States, 43219
      • Recruiting
      • The Mark H. Zangmeister Center
    • Columbus, Ohio, United States, 45601
      • Recruiting
      • Adena Regional Medical Center
    • Dayton, Ohio, United States, 45420
      • Recruiting
      • Dayton Clinical Oncology Program
    • Dayton, Ohio, United States, 45420
      • Recruiting
      • Dayton Physicians LLC
    • Delaware, Ohio, United States, 43015
      • Recruiting
      • Delaware Health Center
    • Marietta, Ohio, United States, 45750
      • Recruiting
      • Marietta Memorial Hospital Cancer Center
    • Marion, Ohio, United States, 43303
      • Recruiting
      • Marion General Hospital
    • Mount Vernon, Ohio, United States, 43050
      • Recruiting
      • Knox Community Hospital
    • Newark, Ohio, United States, 43055
      • Recruiting
      • Licking Memorial Hospital
    • Portsmouth, Ohio, United States, 45662
      • Recruiting
      • Southern Ohio Medical Center
    • Zanesville, Ohio, United States, 43701
      • Recruiting
      • Genesis Health Care
  • Pennsylvania
    • York, Pennsylvania, United States, 17403
      • Recruiting
      • Wellspan Health - York Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Harris Health Systems-Smith Clinic
    • Houston, Texas, United States, 77030
      • Recruiting
      • Lester and Sue Smith Breast Center
  • Virginia
    • Lynchburg, Virginia, United States, 24501
      • Recruiting
      • Centra Lynchburg Hematology Oncology
    • Mechanicsville, Virginia, United States, 23116
      • Recruiting
      • Bon Secours Richmond Community Hospital Medical Oncology Assoc.
    • Midlothian, Virginia, United States, 23114
      • Recruiting
      • Bon Secours St. Francis Medical Center
    • Richmond, Virginia, United States, 23226
      • Recruiting
      • Bon Secours Richmond Community Hospital at St. Mary's
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Recruiting
      • West Virginia University
  • Wisconsin
    • Appleton, Wisconsin, United States, 54915
      • Recruiting
      • Ascension St. Elizabeth Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1; Celcuity CELx HSF Test on tumor material obtained from research core biopsy to select patients with abnormal HER2 signaling tumors Doxorubicin + cyclophosphamide followed by Weekly Paclitaxel +Trastuzumab+Pertuzumab

Drug: Doxorubicin; 60 mg/m2 IV Day 1 every 2 weeks or 3 weeks at investigator's discretion for a total of 4 cycles; Drug: Cyclophosphamide; 600 mg/m2 IV Day 1 every 2 weeks or 3 weeks at investigator's discretion for a total of 4 cycles; Drug: Weekly Paclitaxel; 80 mg/m2 IV weekly for 12 doses; Drug: Trastuzumab; loading dose of 8 mg/kg IV; then 6 mg/kg IV every 3 weeks for Cycles 2-4; Drug: Pertuzumab; loading dose of 840 mg IV; then 420 mg IV every 3 weeks for Cycles 2-4; Diagnostic test: Celcuity CELx HSF; Prior to drug interventions 3, 4,and 5, the Celcuity CELx HSF diagnostic test will be conducted to assess HER2 signaling activity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response (PCR) to study therapy (both breast and lymph node-combined; ypT0/Tis ypN0)	Percentage of patients with absence of residual invasive cancer in H&E slides of resected breast specimens and all sampled regional lymph nodes following the completion of neoadjuvant systemic therapy	From initiation of study therapy to time of surgery, which is usually performed 3 to 4 weeks after completion of study therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response to study therapy (breast)	Percentage of patients with absence of residual invasive cancer in H&E slides of resected breast specimens following the completion of neoadjuvant systemic therapy	From initiation of study therapy to time of surgery, which is usually performed 3 to 4 weeks after completion of study therapy
Clinical complete response (both breast and axilla)	Percentage of patients with clinical complete response (cCR) measured by physical examination of the breast and axilla	From initiation of study therapy to 2-4 weeks after completion of study therapy
Residual cancer burden (RCB)	Combined index of pathologic measurements of residual tumor size and cellularity and number and size of regional lymph nodes	From initiation of study therapy to time of surgery, which is usually performed 3 to 4 weeks after completion of study therapy
Logistic regression	Regression of quantitative CELx scores by pCR outcome	From prior to study entry (time of CELx score assay) to 4-6 weeks after surgery (pCR outcome determination)
Frequency of adverse events assessed by CTCAE 4.0	Frequency of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0	From beginning of study therapy to 4-6 weeks after surgery

Collaborators and Investigators

• Sponsor: NSABP Foundation Inc
• Collaborators: Genentech, Inc.; Celcuity, LLC

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2018
• Primary Completion (Anticipated): October 30, 2023
• Study Completion (Anticipated): October 30, 2023

Study Registration Dates

• First Submitted: January 12, 2018
• First Submitted That Met QC Criteria: January 19, 2018
• First Posted (Actual): January 26, 2018

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 3, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: breast cancer; Open-label; Cyclophosphamide; Doxorubicin; Neoadjuvant; Trastuzumab; Paclitaxel; Pertuzumab; Early stage; HER2-negative; NSABP; invasive; Celcuity; CELx HSF; HER2 Signaling Function test; anti-HER2 Antibodies
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Paclitaxel; Trastuzumab; Doxorubicin; Pertuzumab
• Other Study ID Numbers: NSABP FB-12

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes