Clinical Trial of Neoadjuvant Chemotherapy With Atezolizumab or Placebo in Patients With Triple-Negative Breast Cancer Followed After Surgery by Atezolizumab or Placebo

Inclusion Criteria:

• The patient must have consented to participate and, prior to beginning specific studyprocedures, must have signed and dated an appropriate IRB-approved consent form thatconforms to federal and institutional guidelines for study treatment and forsubmission of tumor samples from a research biospy as required by NSABP B-59/GBG 96-GeparDouze for baseline correlative science studies.
• The diagnosis of invasive adenocarcinoma of the breast must have been made by coreneedle biopsy.
• Local testing on the diagnostic core must have determined the tumor to be ER-negative,PgR-negative, and HER2-negative by current ASCO/CAP guidelines. (If local testing hasdetermined a tumor to be HER2 equivocal or to have a borderline ER/PgR status (% IHCstaining < 10% for both) and other eligibility criteria are met, material may besubmitted for central testing to determine eligibility.)
• Central testing for ER, PgR, and HER2 will be performed, and the tumor must bedetermined to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAPGuidelines Recommendations.
• The tumor specimen used for central ER, PgR, and HER2 testing must also be used forcentral testing of PD-L1 status using the Ventana PD-L1 testing result including PD-L1indeterminate Patients will be classifies as positive, negative, or indeterminate forstratification purposes.
• Patients must be ≥ 18 years old.
• Patient may be female or male.
• The ECOG performance status must be 0-1.
• The primary tumor can be clinical stage T2 or T3, if clinically node negativeaccording to AJCC 7th Edition. If the regional lymph nodes are cN1 and cytologicallyor histologically positive or cN2-N3 with or without a biopsy, the primary breasttumor can be clinically T1c, T2, or T3.
• Ipsilateral axillary lymph nodes must be evaluated by imaging (mammogram, ultrasound,and/or MRI) within 84 days prior to study entry. If suspicious or abnormal, FNA orcore biopsy is recommended. Findings of these evaluations will be used to define thenodal status prior to study entry according to the following criteria:
• Nodal status - negative (Imaging of the axilla is negative; Imaging is suspiciousor abnormal but the FNA or core biopsy of the questionable node[s] on imaging isnegative)
• Nodal status - positive (FNA or core biopsy of the node[s] is cytologically orhistologically suspicious or positive; Imaging is suspicious or abnormal but FNAor core biopsy was not performed.)
• Patients with synchronous bilateral or multicentric HER2-negative breast cancer areeligible as long as the highest risk tumor is ER-negative and PgR-negative and meetsstage eligibility criteria. All of the other invasive tumors must also beHER2-negative by ASCO/CAP Guidelines based on local testing. Central testing toconfirm TNBC status is only required for the highest risk tumor.
• Blood counts performed within 28 days prior to randomization must meet the followingcriteria:
• ANC must be ≥ 1500/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 28days prior to randomization must be met:
• total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubinelevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndromeinvolving slow conjugation of bilirubin; and
• alkaline phosphatase must be ≤ 2.5 x ULN for the lab; and
• AST and ALT must be ≤ 1.5 x ULN for the lab.
• Patients with AST or ALT or alkaline phosphatase > ULN are eligible for inclusion inthe study if liver imaging (CT, MRI, abdominal ultrasound, PET-CT, or PET scan)performed within 28 days prior to randomization does not demonstrate metastaticdisease and the requirements in criterion (just above) are met.
• Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULNor with unexplained bone pain are eligible for inclusion in the study if bone imaging (bone scan, PET-CT scan, or PET scan) supported by additional studies when indicated (CT, x-ray, MRI) performed within 28 days prior to randomization does not demonstratemetastatic disease.
• Patients with N2 or N3 nodal disease or T3 primary disease must undergo liver and boneimaging (as described in 4.1.13 and 4.1.14) within 28 days prior to randomization,irrespective of baseline lab results, and studies must not demonstrate metastaticdisease. Chest imaging with chest x-ray PA and Lateral, CT of the chest, or PET-CTmust also be performed.
• Creatinine clearance ≥ 50 mL/min (see Section 7.2.1 for instructions regardingcalculation of creatinine clearance) performed within 28 days prior to randomization.
• PT/INR ≤ ULN within 28 days of randomization. Patients receiving therapeuticanti-coagulants are not eligible.
• A serum TSH and AM (morning) cortisol performed within 28 days prior to randomizationto obtain a baseline value. Patients with abnormal TSH or AM cortisol baseline levelsshould be further evaluated and managed per institutional standards. Asymptomaticpatients who require initiation or adjustment of medication or are followed withoutinitiating treatment based on endocrinologist's recommendations are eligible.
• LVEF assessment must be performed within 42 days prior to randomization. (LVEFassessment performed by echocardiogram is preferred; however, MUGA scan may besubstituted based on institutional preferences.) The LVEF must be ≥ 55% regardless ofthe cardiac imaging facility's lower limit of normal.
• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods that result in a failure rateof < 1% per year during the treatment period and for at least 5 months after the lastdose of atezolizumab/placebo or 12 months after the last dose of chemotherapy.
• A woman is considered to be of childbearing potential if she is notpostmenopausal, has not reached a postmenopausal state (≥ 12 continuous months ofamenorrhea with no identified cause other than menopause), and has not undergonesurgical sterilization (removal of ovaries and/or uterus).
• Examples of contraceptive methods with a failure rate of < 1% per year include:bilateral tubal ligation; male partner sterilization; hormonal contraceptivesthat inhibit ovulation; hormone-releasing intrauterine devices; copperintrauterine devices.
• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical study and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods ofcontraception.
• Patient must be willing and able to comply with scheduled visits, treatment plans,laboratory tests, and other study procedures.

Exclusion Criteria:

• Excisional biopsy or lumpectomy performed prior to study entry.
• FNA alone to diagnose the breast cancer.
• Surgical axillary staging procedure prior to randomization. Exception: FNA or corebiopsy of an axillary node is permitted for any patient. A pre-neoadjuvant therapysentinel lymph node biopsy for patients with clinically negative axillary nodes isprohibited.
• Definitive clinical or radiologic evidence of metastatic disease.
• Previous history of contralateral invasive breast cancer. (Patients with synchronousand/or previous contralateral DCIS or LCIS are eligible.)
• Previous history of ipsilateral invasive breast cancer or ipsilateral DCIS. (Patientswith synchronous or previous ipsilateral LCIS are eligible.)
• History of non-breast malignancies (except for in situ cancers treated only by localexcision and basal cell and squamous cell carcinomas of the skin) within 5 years priorto study entry.
• Treatment including radiation therapy, chemotherapy, or targeted therapy, for thecurrently diagnosed breast cancer prior to randomization.
• Previous therapy with anthracyclines or taxanes for any malignancy.
• Cardiac disease (history of and/or active disease) that would preclude the use of thedrugs included in the treatment regimens. This includes but is not confined to:
• Active cardiac disease: angina pectoris that requires the use of anti-anginalmedication; ventricular arrhythmias except for benign premature ventricularcontractions; supraventricular and nodal arrhythmias requiring a pacemaker or notcontrolled with medication; conduction abnormality requiring a pacemaker;valvular disease with documented compromise in cardiac function; or symptomaticpericarditis.
• History of cardiac disease: myocardial infarction documented by elevated cardiacenzymes or persistent regional wall abnormalities on assessment of leftventricular function within 6 months prior to randomization; history ofdocumented CHF; or documented cardiomyopathy.
• Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP > 90 mmHg. (Patients with initial BP elevations are eligible if initiation oradjustment of BP medication lowers pressure to meet entry criteria.) Patientsrequiring ≥ 3 BP medications are not eligible.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
• Known allergy or hypersensitivity to the components of the atezolizumab formulation.
• Known allergy or hypersensitivity to the components of the doxorubicin, epirubicin,cyclophosphamide, carboplatin, or paclitaxel formulations.
• Known allergy or hypersensitivity to liposomal or pegylated G-CSF formulations.
• Active or history of autoimmune disease or immune deficiency, including but notlimited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidsyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, ormultiple sclerosis for a more comprehensive list of autoimmune diseases and immunedeficiencies) with the following exceptions:
• Patients with a history of autoimmune-related hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible for this study.
• Patients with controlled Type 1 diabetes mellitus on a stable dose of insulinregimen may be eligible for this study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are permitted provided all of following conditions are met: Rash mustcover < 10% of body surface area; Disease is well controlled at baseline andrequires only low-potency topical corticosteroids; No occurrence of acuteexacerbations of the underlying condition requiring psoralen plus ultraviolet Aradiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,or high-potency or oral corticosteroids within the previous 12 months.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of activepneumonitis on screening chest CT scan.
• Patients known to be HIV positive.
• Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis Bsurface antigen (HBsAg) test at screening. Patients with a past or resolved HBVinfection, defined as having a negative HBsAg test and a positive total hepatitis Bcore antibody (HBcAb) test at screening, are eligible for the study if active HBVinfection is ruled out on the basis of HBV DNA viral load per local guidelines.
• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibodytest at screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA.
• Patients with clinically active tuberculosis.
• Severe infection within 28 days prior to randomization, including but not limited tohospitalization for complications of infection, bacteremia, or severe pneumonia.
• Prior allogeneic stem cell or solid organ transplantation.
• Administration of a live, attenuated vaccine within 28 days prior to randomization oranticipation that such vaccine will be required during the study. Patients must agreenot to receive live, attenuated influenza vaccine (e.g., FluMist) within 28 days priorto randomization, during treatment or within 5 months following the last dose ofatezolizumab/placebo.
• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplications.
• Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, includinganti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
• Treatment with systemic immunosuppressive medications (including but not limited tointerferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer,prior to randomization.
• Treatment with systemic immunosuppressive medications (including but not limited toprednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumornecrosis [anti-TNF] factor agents) within 14 days prior to randomization oranticipation of need for systemic immunosuppressive medications during the study.
• Nervous system disorder (paresthesias, peripheral motor neuropathy, or peripheralsensory neuropathy) ≥ Grade 2, per the CTCAE v4.0.
• Symptomatic peripheral ischemia.
• Pregnancy or lactation at the time of randomization or intention to become pregnantduring the study. (Note: Negative serum pregnancy test must be obtained within 14 daysprior to randomization).
• Use of any investigational agent within 28 days prior to randomization.