Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1
Neoadjuvant Therapy in TRIPle Negative Breast Cancer With antiPDL1
This study that aims to evaluate the addition of MPDL3280A (atezolizumab) to carboplatin and
 nab-paclitaxel in patients with early high-risk and locally advanced triple negative breast
 cancer. compared to the control arm of carboplatin and abraxane. Half of participants will
 receive MPDL3280A in combination with carboplatin and abraxane, while the other half will
 receive only carboplatin and abraxane.
Emerging evidence shows that many breast cancers with triple negative and basal like features
 have infiltration by mononuclear cells and lymphocytes. Irrespective of the entity of tumor
 infiltration by mononuclear cells, expression of immune regulatory checkpoints such as PD-1
 and its ligand B7-H1 (or PD-L1) negatively affect the results of treatments. These data
 suggest that a subset of patients have an ongoing immune response within the tumor
 micro-environment, and that PD-L1 expression is an adaptive method of tumor resistance to
 tumor infiltrating lymphocytes, which in turn are needed for response to chemotherapy.
 Overall, the data suggests a role for immune regulation of response to chemotherapy, and
 support the concept that blockade of immune check-points may favor the achievement of durable
 response by immune mechanisms themselves, and in combination with classical chemotherapy.

 MPDL3280A (atezolizumab) is a human monoclonal antibody containing an engineered Fc-domain to
 optimize efficacy and safety that targets PD-L1 and blocks binding of its receptors,
 including PD-1 and B7.1. Based on these considerations, we plan to conduct a study of the
 combination of abraxane and carboplatin with or without PDL1-directed antibody in women with
 locally advanced breast cancer suitable for neoadjuvant therapy with the aim to improve
 event-free survival
Inclusion Criteria:

 1. Female patients aged 18 years or older with early high-risk and locally advanced or
 inflammatory breast cancers

 2. Histologically confirmed unilateral breast cancer with invasive ductal histology not
 otherwise specified (NOS) of high proliferation or grade

 3. HER2 negative disease

 4. Negative estrogen receptor (ER) and progesterone receptor (PgR), both < 1% locally
 assessed

 5. Representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for
 confirmation of HER2, ER and PgR eligibility, for assessment of PDL-1 expression and
 for further exploratory biomarker evaluation is mandatory

 6. ECOG performance status 0 or 1

 7. Written informed consent to participate in the trial (approved by the Institutional
 Review Board [IRB]/ Independent Ethics Committee [IEC]) obtained prior to any study
 specific screening procedures

 8. Willing and able to comply with the protocol

 9. Consent to the collection of blood samples

 10. For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea)
 or surgically sterile (absence of ovaries and/or uterus): agreement to remain
 abstinent or use single or combined contraceptive methods that result in a failure
 rate of < 1% per year during the treatment period and for at least 90 days after the
 last dose of study drug.

 Exclusion Criteria:

 1. Evidence of bilateral breast cancer or metastatic disease (M1)

 2. Cases with an histology different from invasive ductal NOS of high proliferation or
 grade

 3. Patients with HER2-positive disease according to ASCO/CAP guidelines 2013

 4. Pregnant or lactating women. Documentation of a negative pregnancy test must be
 available for premenopausal women with intact reproductive organs and for women less
 than one year after the last menstrual cycle

 5. Previous treatment with chemotherapy, hormonal therapy or an investigational drug for
 any type of malignancy

 6. Previous investigational treatment for any condition within 4 weeks of randomization
 date

 7. Administration of a live, attenuated vaccine within 4 weeks before cycle 1 Day 1 or
 anticipation that such a live attenuated vaccine will be required during the study

 8. Previous or concomitant invasive malignancy of any other type or previous invasive
 breast cancer. Patients with curatively treated basal cell carcinoma of the skin or in
 situ cervix cancer are generally eligible

 9. Pre-existing motor or sensory neuropathy of grade > 1 for any reason

 10. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
 chimeric or humanized antibodies or fusion proteins

 11. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
 ovary cells or any component of the MPDL3280A formulation

 12. Patients with prior allogeneic stem cell or solid organ transplantation

 13. History of autoimmune disease including, but not limited to, systemic lupus
 erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
 associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
 syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or
 glomerulonephritis

 14. History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
 organizing pneumonia) or evidence of active pneumonitis on screening chest computed
 tomography scan

 15. Known clinically significant liver disease, including active viral, alcoholic, or
 other hepatitis, cirrhosis, fatty liver, and inherited liver disease

 16. History of HIV infection, active hepatitis B (chronic or acute), or hepatitis C
 infection. Patients with past or resolved hepatitis B infection (defined as having a
 negative HBsAg test and a positive hepatitis B core antigen [anti-HBc] test) are
 eligible.

 Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
 chain reaction assay (PCR) is negative for HCV RNA 17. Active tuberculosis 18. Severe
 infections within 4 weeks prior to cycle 1 Day 1, including, but not limited to,
 hospitalization for complications of infection, bacteremia, or severe pneumonia. Signs or
 symptoms of significant infection within 2 weeks prior to cycle 1 Day 1 19. Received oral
 or IV antibiotics within 2 weeks prior to Cycle 1 Day 1 20. Other serious illness or
 medical condition including: history of documented congestive cardiac failure; New York
 Heart Association (NYHA) Class II or greater CHF; angina pectoris requiring anti-anginal
 medication or unstable angina within 6 months prior to cycle 1 Day 1; evidence of
 transmural infarction on ECG; myocardial infarction stroke or transient ischemic attack
 (TIA) within 6 months prior to cycle 1 Day 1; poorly controlled hypertension (e.g. systolic
 >180 mm Hg or diastolic >100 mm Hg; however, patients with hypertension which is well
 controlled on medication are eligible); clinically significant valvular heart disease;
 high-risk uncontrolled arrhythmias 21. Patients with a history of uncontrolled seizures,
 central nervous system disorders or psychiatric disability judged by the investigator to be
 clinically significant and precluding informed consent or adversely affecting compliance
 with study drugs 22. Serious uncontrolled infections (bacterial or viral) or poorly
 controlled diabetes mellitus 23. Abnormal baseline hematological values 24. Abnormal
 baseline laboratory tests for serum total bilirubin, liver function tests, alkaline
 phosphatase, serum creatinine, INR and aPTT 25. Baseline left ventricular ejection fraction
 (LVEF) < 50% by echocardiography or multi-gated scintigraphic scan (MUGA) 26. Major
 surgical procedure within 28 days prior to cycle 1 Day 1 or anticipation of need for a
 major surgical procedure during the course of the study 27. Influenza vaccination should be
 given during influenza season only (approximately October to March). Patients must not
 receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to cycle 1
 Day 1 or at any time during the study.

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