Paclitaxel, Trastuzumab, and Pertuzumab With or Without Atezolizumab in Treating Patients With Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of paclitaxel, pertuzumab,
and trastuzumab will improve the progression-free survival (PFS), as assessed by investigator
using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, relative to a
regimen of paclitaxel, pertuzumab, trastuzumab, and placebo in patients with newly documented
HER2-positive measurable metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of paclitaxel, pertuzumab,
and trastuzumab will improve the overall survival (OS) relative to a regimen of paclitaxel,
pertuzumab, trastuzumab, and placebo.

II. To determine whether the addition of atezolizumab to a regimen of paclitaxel, pertuzumab,
and trastuzumab will improve the overall objective response (OR), assessed by investigator
using RECIST 1.1 criteria, relative to a regimen of paclitaxel, pertuzumab, trastuzumab, and
placebo.

III. To determine whether the addition of atezolizumab to a regimen of paclitaxel,
pertuzumab, and trastuzumab will improve PFS, OR, and/or duration of objective response
assessed by retrospective blinded central review using RECIST 1.1 criteria, relative to a
regimen of paclitaxel, pertuzumab, trastuzumab, and placebo.

IV. To determine whether the addition of atezolizumab to a regimen of paclitaxel, pertuzumab,
and trastuzumab will decrease the incidence of subsequent brain metastases in patients
without known brain metastases at study entry relative to a regimen of paclitaxel,
pertuzumab, trastuzumab, and placebo.

V. To determine whether the addition of atezolizumab to a regimen of paclitaxel, pertuzumab,
and trastuzumab will contribute to increased patient-reported fatigue in comparison to a
regimen of paclitaxel, pertuzumab, trastuzumab, and placebo.

VI. To determine the utility of PD-L1 immunohistochemistry (IHC) staining as a predictive and
prognostic biomarker associated with clinical response, as assessed by investigator using
RECIST 1.1 criteria, to atezolizumab in combination with paclitaxel, trastuzumab, and
pertuzumab.

VII. To determine the immune-related toxicity profile of the two treatment regimens.

VIII. To determine the cardiac safety profile of the two treatment regimens.

EXPLORATORY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of paclitaxel, pertuzumab,
and trastuzumab will improve the progression-free survival and overall objective response,
assessed by investigator using immune-modified RECIST (iRECIST) criteria, relative to a
regimen of paclitaxel, pertuzumab, trastuzumab, and placebo.

II. To identify potential biomarkers that can predict benefit from the addition of
atezolizumab in patients with newly documented HER2-positive measurable metastatic breast
cancer treated with a regimen of paclitaxel, pertuzumab, and trastuzumab, and placebo.

III. To explore the toxicity profile of the two treatment regimens using patient-reported
symptomatic adverse events in addition to standard adverse event reports.

IV. To determine the feasibility and added value of frequent assessment of toxicity using
Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) with
electronic(e)PRO reporting.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on days 1 and 22,
trastuzumab IV over 30-90 minutes on days 1 and 22, paclitaxel IV over 60 minutes on days 1,
8, 15, 22, 29, and 36, and atezolizumab IV over 60 minutes on days 1 and 22. Cycles for
pertuzumab, trastuzumab and atezolizumab repeat every 6 weeks and treatment with paclitaxel
repeats every 6 weeks for up to 4 cycles in the absence of disease progression or
unacceptable toxicity. Patients may receive additional 3 cycles of paclitaxel in the absence
of progression at the investigator's discretion.

ARM II: Patients receive pertuzumab, trastuzumab, and paclitaxel as in Arm I. Patients also
receive placebo IV over 60 minutes on days 1 and 22. Cycles for pertuzumab, trastuzumab, and
placebo repeat every 6 weeks and treatment with paclitaxel repeats every 6 weeks for up to 4
cycles in the absence of disease progression or unacceptable toxicity. Patients may receive
additional 3 cycles of paclitaxel in the absence of progression at the investigator's
discretion.

After completion of study treatment, patients are followed up every 3 months for 3 years and
then every 6 months for 4 years.

Inclusion Criteria:

- The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines

- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1

- Histologically confirmed adenocarcinoma of the breast with locally recurrent,
unresectable disease or metastatic disease confirmed as described below; eligible
patients include those with either:

- De novo metastatic disease presenting without prior history of HER2-positive
breast cancer:

- Diagnosis should have been made from a biopsy of a metastatic disease site,
but biopsy from the breast primary or involved regional lymph nodes is
acceptable if biopsy of the metastatic sites was thought to carry excessive
risk for the patient

- Locally recurrent or metastatic disease following prior therapy for early breast
cancer:

- Diagnosis must have been made from the biopsy of the locally recurrent or
metastatic disease

- There must be an interval of >= 6 months between completion of
neoadjuvant/adjuvant HER2-targeted therapy and documentation of locally
recurrent or metastatic HER2-positive disease by biopsy

- Patients must have measurable disease based on RECIST 1.1, as determined by the site,
to be eligible

- The tumor specimen obtained at the time of diagnosis of locally recurrent or
metastatic disease must have been determined to be HER2-positive based on central
testing according to American Society of Clinical Oncology/College of American
Pathologists (ASCO/CAP) guidelines (Wolff 2018); HER2 status will initially be
assessed using a Food and Drug Administration (FDA)-cleared IHC assay; positive is
defined as IHC 3+ staining intensity; if HER2 IHC results are equivocal (2+), then
HER2 status will be determined using a FDA-cleared HER2 in situ hybridization (ISH)
test according to ASCO/CAP guidelines; sites can send biopsy specimens for central
testing which have been determined to be HER2-positive or initially equivocal by
either IHC or ISH on local testing

- The tumor specimen obtained at the time of diagnosis used for HER2 testing must also
have central testing for PD-L1 status; patients will be eligible irrespective of PD-L1
testing result including PD-L1 indeterminant

- The tumor specimen obtained at the time of diagnosis used for HER2 and PD-L1 testing
should also have central testing for estrogen receptor (ER) and progesterone receptor
(PgR) according to current ASCO/CAP guideline recommendations for hormone receptor
testing; patients with , 1% ER and PgR staining by IHC will be classified as negative;
if sufficient material for central confirmation of ER and PgR is unavailable, local
testing results for ER and PgR may be used for eligibility

- Localized palliative radiation therapy is allowed for symptom management if completed
>= 14 days prior to randomization

- Patients must have imaging of the chest/abdomen/pelvis, preferably with a computed
tomography (CT) scan, and a bone scan within 4 weeks prior to randomization; (NOTE: if
a patient is unable to receive CT contrast, a magnetic resonance imaging [MRI] of the
abdomen/pelvis and non-contrast chest CT should be performed; positron emission
tomography/computed tomography [PET/CT] is not an acceptable alternative)

- MRI of the brain (or contrast CT scan of the brain if patients are unable to undergo
MRI) must be obtained in patients with symptoms suggesting possible central nervous
system (CNS) metastatic disease; neuroimaging is recommended but not required in
asymptomatic patients

- Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 14 days prior to
randomization)

- Platelet count must be >= 100,000/mm^3 (within 14 days prior to randomization)

- Hemoglobin must be >= 8 g/dL (within 14 days prior to randomization)

- Total bilirubin must be =< 1.5 x upper limit of normal (ULN) for the lab or direct
bilirubin =< ULN for patients with bilirubin levels > 1.5 x ULN (within 14 days prior
to randomization)

- Aspartate aminotransferase (AST) and alanine aminotransaminase (ALT) must be =< 2.5 x
ULN for the lab or =< 5 x ULN for patients with liver metastases (within 14 days prior
to randomization)

- Serum creatinine =< 1.5 x ULN or measured or calculated creatinine clearance >= 50
mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x
ULN for the lab (within 14 days prior to randomization)

- Patients not receiving anti-coagulant therapy must have prothrombin time (PT) and
international normalized ratio (INR) =< 1.5 x ULN within 14 days prior to
randomization; for laboratories that do not report an ULN for the INR assay, use =<
1.5 as the value for the ULN; patients receiving anti-coagulants should have a
baseline INR assessed, but the value does not affect eligibility

- A serum thyroid-stimulating hormone (TSH), free T4, and AM (morning) cortisol must be
obtained within 14 days prior to randomization to obtain a baseline value and be
within normal limits for the local laboratory

- Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks
prior to randomization; (LVEF assessment performed by echocardiogram is preferred;
however, multigated acquisition scan (MUGA) scan may be substituted based on
institutional preferences); the LVEF must be >= 55% regardless of the cardiac imaging
facility's lower limit of normal

- 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 (non-hormonal or barrier method of
birth control; abstinence) prior to study entry, for the duration of study
participation, and for 5 months (150 days) after the last dose of atezolizumab/placebo
and 7 months after the last dose of trastuzumab and pertuzumab; 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

Exclusion Criteria:

- Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS
metastases are excluded, with the following exceptions:

- Patients with asymptomatic untreated CNS disease may be enrolled, provided all of
the following criteria are met:

- Evaluable or measurable disease outside the CNS

- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within
10 mm of the optic apparatus (optic nerves and chiasm)

- No history of intracranial hemorrhage or spinal cord hemorrhage

- No ongoing requirement for dexamethasone for CNS disease; patients on a
stable dose of anticonvulsants are permitted

- No neurosurgical resection or brain biopsy within 28 days prior to
randomization

- Patients with asymptomatic treated CNS metastases may be enrolled, provided all
the criteria listed above are met as well as the following:

- Radiographic demonstration of improvement upon the completion of CNS
directed therapy and no evidence of interim progression between the
completion of CNS directed therapy and the screening radiographic study

- No stereotactic radiation or whole-brain radiation within 4 weeks prior to
randomization

- Screening CNS radiographic study 4 weeks from completion of radiotherapy and
2 weeks from discontinuation of corticosteroids

- Known leptomeningeal carcinomatosis

- Patients with metastatic disease limited to the CNS

- History of systemic anti-cancer therapy (e.g., chemotherapy, targeted therapy) for
metastatic breast cancer (MBC) with the exception of administration of trastuzumab or
lapatinib concurrently with radiation therapy for brain metastases; toxicities related
to lapatinib should be =< grade 1, per the CTCAE version (v)5.0 and must have been
completed at least 2 weeks prior to randomization

- History of exposure to cumulative doses of doxorubicin greater than 360 mg per square
meter of body-surface area or its equivalent

- Prior treatment with mTOR inhibitors or CDK 4/6 inhibitors in combination with
endocrine therapy for treatment of metastatic disease

- Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including
anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

- 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

- Uncontrolled hypertension defined as sustained systolic blood pressure (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)

- History of asymptomatic LVEF decline to < 40% during or after prior HER2-targeted
therapy

- 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; or

- Symptomatic pericarditis

- History of cardiac disease

- Prior myocardial infarction documented by elevated cardiac enzymes or
persistent regional wall abnormalities on assessment of left ventricular
(LV) function;

- History of documented congestive heart failure (CHF) defined as symptomatic
heart failure with an LVEF < 40%; or

- Documented cardiomyopathy

- Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events
(CTCAE) version (v) 5.0

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

- Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
or other recombinant antibodies

- Known allergy or hypersensitivity to the components of the atezolizumab formulation or
to any of the study drugs or excipients, (e.g., Cremophor EL)

- 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%,
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

- No acute exacerbations of underlying conditions 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)

- Treatment with systemic immunosuppressive medications (including but not limited to
interferons, IL-2) within 4 weeks or 5 half-lives of the drug, whichever is longer,
prior to randomization

- Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor
necrosis [anti-TNF] factor agents) within 14 days prior to randomization or
anticipation of need for systemic immunosuppressive medications during the study;
Note: Intranasal and inhaled corticosteroids or systemic corticosteroids at doses that
do not exceed 10 mg/day of prednisone or an equivalent corticosteroid are allowed

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 2 weeks prior to randomization

- Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B
surface antigen (HBsAg) test at screening; patients with a past or resolved HBV
infection, defined as having a negative HBsAg test and a positive total hepatitis B
core antibody (HBcAb) test at screening, are eligible for the study if active HBV
infection is ruled out on the basis of HBV deoxyribonucleic acid (DNA) viral load per
local guidelines

- Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV
ribonucleic acid (RNA)

- Patients with clinically active tuberculosis

- Patients known to be human immunodeficiency virus (HIV) positive are eligible if they
meet the following criteria within 4 weeks prior to randomization:

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

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

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

- Severe infection within 4 weeks prior to randomization, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia

- Prior allogeneic stem cell or solid organ transplantation

- Symptomatic peripheral ischemia

- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis or >= grade 1 pulmonary fibrosis, per the CTCAE v5.0, on screening chest
CT scan

- Administration of a live, attenuated vaccine within 4 weeks prior to randomization or
anticipation that such vaccine will be required during the study

- Patients must agree not to receive live, attenuated influenza vaccine (e.g.,
FluMist) within 4 weeks prior to randomization, during treatment or within 5
months following the last dose of atezolizumab/placebo

- Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a diseas