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Title A Randomized Phase III Trial of Adjuvant Therapy comparing chemotherapy alone (Six Cycles of Docetaxel plus cyclophosphamide of four cycles of doxorubicin plus cyclophosphamide followed by weekly Paclitaxel) to chemotherapy plus Trastuzumab in Women with Node-Positive of High-Risk Node Negative HER2-Low invasive Breast Cancer.

IRB NSABPB47

CC 13-1408

Hospital Fairview, Main Campus

Phase Phase 3

Disease Breast

Drug Trastuzumab

Description

Primary Objective

• To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves invasive disease-free survival (IDFS) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

Secondary Objectives

• To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves DFS-DCIS in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.
• To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves BCFS in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.
• To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves RFI in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.
• To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves DRFI in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.
• To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves OS in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.
• To evaluate the associations between amenorrhea and circulating reproductive hormone levels, and the associations between chemotherapy regimen, amenorrhea, and IDFS benefit in premenopausal women eligible at baseline for the menstrual history assessments.
• To evaluate the toxicity associated with each of the regimens.
• To test the hypothesis that the HER2 mRNA level is the predictor of the degree of benefit from trastuzumab and the threshold for benefit in the adjuvant setting is lower than defined by current ASCO/CAP Guidelines for HER2 assays (IHC and FISH).
• To identify and/or validate molecular predictors of the degree of benefit from the addition of trastuzumab to chemotherapy (TC or AC→WP).
• To test the alternative hypothesis that the main determinant of trastuzumab response in the adjuvant setting of HER2-low breast cancer is through ADCC by demonstrating that the polymorphism of the Fcγ receptor gene is predictive of the degree of benefit from the addition of trastuzumab to chemotherapy (TC or AC→WP).
• To examine the relationship between behavioral host factors (obesity, tobacco, alcohol) and comorbid conditions that may influence systemic inflammation and breast cancer outcomes, controlling for tumor/stage characteristics and treatment assignment.
• To examine the relationship between medication exposures that may influence systemic inflammation and breast cancer outcomes, controlling for tumor/stage characteristics and treatment assignment.
• To examine the relationship between comorbid conditions, medication exposures and behavioral host factors together and breast cancer outcomes, controlling for tumor/stage characteristics and treatment assignment.

Inclusion Criteria

1. The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.
2. The patient must be female.
3. The patient must be ≥ 18 years old.
4. The patient must have an ECOG performance status of 0 or 1 (see Appendix A).
5. The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
6. All of the following staging criteria (according to the 7th edition of the AJCC Cancer Staging Manual) must be met:
   • By pathologic evaluation, primary tumor must be pT1-3;
   • By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b
   • If pN0, one of the following criteria must be met:
     • pT2 and ER negative and PgR negative; or
     • pT2 and ER positive (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX Recurrence Score of ≥ 25; or
     • pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX� Recurrence Score.
7. HER2 status of the primary tumor must be evaluated prior to randomization; all testing performed must indicate that the tumor is HER2-low as defined below.
   • IHC must be performed and the IHC staining results must indicate a score of 1+ (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be performed and must indicate that the tumor is HER2-low as described below).
   • If ISH testing is performed, test results must be as follows and IHC must be 1+ or 2+: The ratio of HER2 to CEP17 must be < 2.0 or, if a ratio was not performed, the HER2 gene copy number must be < 4 per nucleus.

   Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+ to 2+, the higher intensity score in the range should be used to determine eligibility.

8. The patient must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy). (Patients who have had a nipple-sparing mastectomy are eligible.)
9. For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. (Patients with margins positive for LCIS are eligible without additional resection.)
10. For patients who undergo mastectomy, margins must be free of gross residual tumor. (Patients with microscopic positive margins are eligible as long as post-mastectomy RT of the chest wall will be administered.)
11. The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below.
    • Sentinel lymphadenectomy alone:
      • If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b;
      • If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes.
    • Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or
    • Axillary lymphadenectomy with or without SN isolation procedure.
12. The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days.
13. The patient must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed. (Either the core biopsy or surgical resection specimen can be used for ER/PgR testing.) Patients with a primary tumor that is hormone receptor-positive or receptor-negative are eligible.
14. The most recent postoperative blood counts, performed within 6 weeks prior to randomization, must meet the following criteria:
• ANC must be ≥ 1200/mm³;
• Platelet count must be ≥ 100,000/mm³; and
• Hemoglobin must be ≥ 10 g/dL.
15. The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests performed within 6 weeks prior to randomization:
    • total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilberts 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 x ULN.

16. 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 90 days prior to randomization does not demonstrate metastatic disease and the requirements in criterion 4.2.15 are met.
17. 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 90 days prior to randomization does not demonstrate metastatic disease.
18. The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be ≤ ULN for the lab.
19. LVEF assessment must be performed within 90 days prior to randomization. LVEF assessment performed by 2-D echocardiogram is preferred; however, MUGA scan may be substituted based on institutional preferences.
    • For patients who will receive the TC chemotherapy regimen, the LVEF must be ≥ 50% regardless of the cardiac imaging facilitys lower limit of normal.
    • For patients who will receive the AC -> WP chemotherapy regimen, the LVEF must be ≥ 55% regardless of the cardiac imaging facility's lower limit of normal.

    Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment. If the baseline LVEF is > 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and repeat the test if the accuracy is uncertain. (See Sections 5.2 and 5.3 for LVEF instructions.)

Exclusion Criteria

1. Primary tumor with any of the following HER2 testing results:
   • IHC staining intensity: 0 on all evaluations of specimens, 3+ on evaluation of any specimen
   • ISH with a ratio of HER2 to CEP17 ≥ 2.0 on evaluation of any specimen
   • ISH result indicating HER2 gene copy number ≥ 4 per nucleus on evaluation of any specimen.
2. T4 tumors including inflammatory breast cancer.
3. Definitive clinical or radiologic evidence of metastatic disease. (Note: Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.)
4. Synchronous or previous contralateral invasive breast cancer. (Patients with synchronous and/or previous contralateral DCIS or LCIS are eligible.)
5. Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS. (Patients with synchronous or previous ipsilateral LCIS are eligible.)
6. 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 5 years prior to randomization.
7. Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy.
8. Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization.
9. Whole breast RT prior to randomization or partial breast RT that cannot be completed on or before the date of randomization (see Sections 9.8 and 9.10.3).
10. Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. Patients are eligible if these medications are discontinued prior to randomization (see Section 9.9).
11. Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization (see Section 4.1).
12. 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 current 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 LV function;
    • history of documented CHF; and
    • documented cardiomyopathy.
13. Hypertension defined according to the following ineligibility criteria:
    • For patients who will receive TC (regardless of the patient's age): Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg. (Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria.)
    • For patients < 50 years old who will receive AC → WP: Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg. Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria.
    • For patients ≥ 50 years old who will receive AC → WP:
      • Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg.
      • Controlled hypertension (systolic BP & le; 150 mmHg and diastolic BP ≤ 90 mmHg), if anti-hypertensive medication(s) are needed.

      Note: Patients who are not eligible based on the AC → WP regimen BP criteria but who meet the TC regimen BP criteria are eligible for B → 47, if the intended chemotherapy regimen is changed to TC.

14. Active hepatitis B or hepatitis C with abnormal liver function tests.
15. Intrinsic lung disease resulting in dyspnea.
16. Poorly controlled diabetes mellitus.
17. Active infection or chronic infection requiring chronic suppressive antibiotics.
18. Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) ≥ grade 2, per the CTCAE v4.0.
19. Conditions that would prohibit administration of corticosteroids.
20. Chronic daily treatment with corticosteroids with a dose of ≥ 10 mg/day methylprednisolone equivalent (excluding inhaled steroids).
21. Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor EL.
22. Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards for women of childbearing potential.)
23. Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
24. Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
25. Use of any investigational product within 30 days prior to randomization.