Clinical Trials /

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

NCT03412643

Description:

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.

Related Conditions:
  • Breast Adenocarcinoma
  • Breast Lobular Carcinoma In Situ
  • Ductal Carcinoma In Situ
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Neoadjuvant Chemotherapy Plus Trastuzumab and Pertuzumab in HER2-Negative Breast Cancer Patients With Abnormal HER2 Signaling
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: NSABP FB-12
  • NCT ID: NCT03412643

Conditions

  • HER2-negative Breast Cancer

Interventions

DrugSynonymsArms
DoxorubicinArm 1
CyclophosphamideArm 1
Weekly PaclitaxelArm 1
TrastuzumabArm 1
PertuzumabArm 1

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalCelcuity 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
  • Doxorubicin
  • Cyclophosphamide
  • Weekly Paclitaxel
  • Trastuzumab
  • Pertuzumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic complete response (PCR) to study therapy (both breast and lymph node-combined; ypT0/Tis ypN0)
Time Frame:From initiation of study therapy to time of surgery, which is usually performed 3 to 4 weeks after completion of study therapy
Safety Issue:
Description: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

Secondary Outcome Measures

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NSABP Foundation Inc

Trial Keywords

  • NSABP
  • Celcuity
  • HER2-negative
  • invasive
  • breast cancer
  • Open-label
  • Neoadjuvant
  • Early stage
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel
  • Trastuzumab
  • Pertuzumab
  • CELx HSF
  • HER2 Signaling Function test
  • anti-HER2 Antibodies

Last Updated

April 6, 2020