Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To test the hypothesis that the combination of chemotherapy and atezolizumab will increase
tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in patients
with newly diagnosed triple negative breast cancer (TNBC) being treated with neoadjuvant
chemotherapy.

II. To test the hypothesis that the combination of chemotherapy and atezolizumab will
increase the pathologic complete response (pCR) rate compared to chemotherapy alone in
patients with newly diagnosed TNBC being treated with neoadjuvant chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate the safety of the treatment combination of atezolizumab + carboplatin +
paclitaxel.

EXPLORATORY OBJECTIVES:

I. To evaluate potential biomarkers of response to chemotherapy in combination with
atezolizumab in patients with newly diagnosed TNBC.

II. To evaluate the impact of chemotherapy in combination with atezolizumab on the immune
response in patients with newly diagnosed TNBC.

III. To evaluate the impact of chemotherapy in combination with atezolizumab on
neoantigen-specific T cell responses in patients with newly diagnosed TNBC.

IV. To evaluate the impact of chemotherapy in combination with atezolizumab on long-term
clinical endpoints such as overall survival (OS) and disease-free survival (DFS) in patients
with newly diagnosed TNBC.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM A: Patients receive carboplatin intravenously (IV) over 30 minutes once every 3 weeks
(Q3W) and paclitaxel IV over 1 hour once weekly (QW). Treatment repeats every 3 weeks for up
to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV over 30 minutes
Q3W, and paclitaxel IV over 1 hour QW. Treatment repeats every 3 weeks for up to 4 courses in
the absence of disease progression or unacceptable toxicity.

In both arms, within 3-6 weeks, patients undergo mastectomy or lumpectomy.

After completion of study treatment, patients are followed up at 6 months and 1 year.

Inclusion Criteria:

- Patients must have histologically confirmed new diagnosis of breast cancer

- Estrogen receptor (ER) and progesterone receptor (PR) < Allred score of 3 or =< 5%
positive staining cells in the invasive component of the tumor (provided the patient
is being treated as triple negative breast cancer)

- Human epidermal growth factor receptor 2 (HER2) negative by fluorescence in situ
hybridization (FISH) or immunohistochemistry (IHC) staining 0 or 1+ according to
National Comprehensive Cancer Network (NCCN) guidelines

- Clinical stage T2-T4c, any N, M0 primary tumor by American Joint Committee on Cancer
(AJCC) 7th edition clinical staging

- Eligible for neoadjuvant chemotherapy

- No prior therapy for this disease

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Leukocytes >= 2,500/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 150,000/mcL

- Hemoglobin >= 10 g/dL

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients
with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
3 x ULN

- Alkaline phosphatase =< 2.5 x ULN

- Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault

- International normalized ratio (INR) =< 1.5 x ULN (this applies only to patients who
do not receive therapeutic anticoagulation; patients receiving therapeutic
anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a
stable dose)

- Activated partial thromboplastin time (aPPT) =< 1.5 x ULN (this applies only to
patients who do not receive therapeutic anticoagulation; patients receiving
therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should
be on a stable dose)

- Administration of atezolizumab may have an adverse effect on pregnancy and poses a
risk to the human fetus, including embryo-lethality; women of child-bearing potential
and men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation,
and for 180 days after the last dose of paclitaxel; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately

- Ability to understand and the willingness to sign an Institutional Review Board (IRB)
approved written informed consent document

Exclusion Criteria:

- Known metastatic disease

- Invasive cancer in the contralateral breast

- Patients with a previous history of non-breast malignancy are eligible only if they
meet the following criteria for a cancer survivor: (1), and (2)

- Has undergone potentially curative therapy for all prior malignancies

- Has been considered disease-free for at least 1 year (with the exception of basal
cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix)

- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation

- Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1

- Treatment with systemic immunosuppressive medications (including, but not limited to,
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1

- Patients who have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled

- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed

- Patients taking bisphosphonate therapy for symptomatic hypercalcemia; use of
bisphosphonate therapy for other reasons (e.g., osteoporosis) is allowed

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to other agents used in study

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

- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible

- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

- History or risk 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, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis

- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible

- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible

- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:

- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations

- Rash must cover less than 10% of body surface area (BSA)

- Disease is well controlled at baseline and only requiring low potency
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)

- No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors; high potency or
oral steroids)

- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan; history of radiation pneumonitis in the radiation field
(fibrosis) is permitted

- Patients with active tuberculosis (TB) are excluded

- 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 infection within 2 weeks prior to cycle 1, day 1

- Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1;
patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or chronic obstructive pulmonary disease) are eligible

- 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 with the exception
of the planned breast cancer surgery that is part of the trial design

- 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
and up to 5 months after the last dose of atezolizumab

- Influenza vaccination should be given during influenza season only (approximately
October to March); patients must not receive live, attenuated influenza vaccine
within 4 weeks prior to cycle 1, day 1 or at any time during the study

- Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot
discontinue it before treatment with atezolizumab

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia (including symptomatic sinus bradycardia), or psychiatric illness/social
situations that would limit compliance with study requirements

- Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this
study, but HIV-positive patients must have:

- A stable regimen of highly active anti-retroviral therapy (HAART)

- No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections

- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
PCR-based tests

- Pregnant women are excluded from this study because atezolizumab is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with atezolizumab, breastfeeding should be discontinued if the mother is
treated with atezolizumab; these potential risks may also apply to other agents used
in this study