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EA1131

A Randomized Phase III Post-Operative Trial of Platinum Based Chemotherapy Vs. Capecitabine in Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy

Eligibility criteria for screening (Step 0)
  • Age ≥ 18 years.

  • ECOG Performance Status 0 or 1 within 2 weeks prior to screening.

  • Female and male patients must have histologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, clinical stage II-III at diagnosis (AJCC 7th edition) based on initial evaluation by clinical examination and/or breast imaging.

  • ER- and PR- should meet one of the following criteria:

    • ≤ 10% cells stain positive, with weak intensity score (Allred score ≤ 3)

    • ≤ 1% cells stain positive, with weak or intermediate intensity score (Allred score ≤ 3)

  • HER2 negative (not eligible for anti-HER2 therapy) will be defined as:

    • IHC 0, 1+ without ISH HER2/neu chromosome 17 ratio OR

    • IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells OR

    • ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC)

  • Patients must have completed neoadjuvant taxane +/- anthracycline. Patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen.

 NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll.

  • Must have completed definitive resection of primary tumor.

  • Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy. Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible.

  • Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable.

  • Sentinel node biopsy post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) is allowed. Axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory.

  •  Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery. Residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring ≥ 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination.      

NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not qualify as residual invasive disease in the breast.

  • Post-mastectomy radiotherapy is required for all patients with the following:

    •  Primary tumor ≥ 5 cm (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery.

    • Patients with primary tumors < 5 cm or with < 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post-mastectomy radiotherapy is at the discretion of the treating physician.

NOTE: Radiation of regional nodal basins is at the discretion of the treating radiation oncologist. Patients enrolled in clinical trials addressing local therapy after neoadjuvant chemotherapy are allowed to enroll.

  • Whole breast radiotherapy is required for patients who underwent breast-conserving therapy, including lumpectomy or partial mastectomy.

  • Adequate bone marrow and organ function based on the following tests. Laboratory values must be obtained within 8 weeks prior to screening for protocol therapy.

    • Hemoglobin (Hgb) > 9.0 g/dL Hgb

    • Platelets > 100,000 cells/mm3

    • Absolute neutrophil count (ANC) > 1500 cells/mm3

    • Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula

    • Bilirubin ≤ 1.5 x ULN upper limit of normal (except in patients with documented Gilbert’s disease, who must have a total bilirubin ≤ 3.0 mg/dL)

    • Aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN

    • Alanine aminotransferase (ALT, SGPT) ≤ 2.5 × ULNNo stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.

  • No clinically significant infections as judged by the treating investigator.

  • Patients with active ≥ grade 2 neuropathy are ineligible.

  • Adjuvant chemotherapy after surgery other than that specified in this protocol is not allowed. LHRH agonists and adjuvant bisphosphonate use is allowed.

  • Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratisfication.

Eligibility Criteria for Randomization (Step 1)
  • Screened patients will remain on the study and be randomized if they meet the above and following criteria. For patients randomized to the chemotherapy arm, Cycle 1/ Day 1 (platinum based or capecitabine) must start within 1 week (5 working days) following randomization.

  • Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery

  • ECOG Performance Status 0 or 1 within 2 weeks prior to randomization.

  • Patients must have completed adjuvant radiotherapy ≥ 2 weeks prior to randomization for protocol therapy, if applicable.

  • Patients must have completed treatment with any investigational agent ≥ 30 days prior to randomization for protocol therapy, if applicable.

  • Patients must be randomized within 24 weeks from surgery

  • Women must not be pregnant or breast-feeding due to risk of teratogenicity/ toxicity with capecitabine or platinum based therapy. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy.

  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months.

  • Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study.

  • Adequate bone marrow and organ function based on the following tests. Laboratory values must be obtained within 2 weeks prior to randomization.

    • Hemoglobin (Hgb) > 9.0 g/dL

    • Platelets > 100,000 cells/mm3

    • Absolute neutrophil count (ANC) > 1500 cells/mm3

    • INR ≤ 2 for subjects not on anticoagulants; INR ≤ 3 for subjects on warfarin

    • Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula

    • Bilirubin ≤ 1.5 x ULN (except in patients with documented Gilbert’s disease, who must have a total bilirubin ≤ 3.0 mg/dL)

    • Aspartate aminotransferase (AST, SGOT) ≤ 2.5 × ULN

    • Alanine aminotransferase (ALT, SGPT) ≤ 2.5 × ULN

Treatment Plan

ARM A: 

    Arm A observation closed to accrual.

ARM B:  

    Cisplatin day 1 every 3 weeks OR Carboplatin day 1 every 3 weeks x 4 cycles (12 weeks)

ARM C: 

    Capecitabine PO twice daily, on days 1-14 every 3 weeks for a total of 6 cycles (18 weeks)

NOTE: Choice of platinum agent will be per treating physician discretion. Once a platinum agent is picked, no changes are allowed.