Atezolizumab + Stereotactic Radiation in Triple-negative Breast Cancer and Brain Metastasis

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

The FDA (the U.S. Food and Drug Administration) has not approved atezolizumab for this
specific disease but it has been approved for other uses.

Atezolizumab is a protein that affects the immune system by blocking the PD-L1 pathway. The
PD-L1 pathway controls the body's natural immune response, but tumors can interrupt this
pathway and partially resist or escape the immune system. By blocking the PD-L1 pathway,
Atezolizumab may help the immune system identify and catch tumor cells.

Stereotactic radiosurgery (SRS) is a standard procedure used to treat patients with cancer in
the brain. SRS uses many precisely focused radiation beams to treat tumors. It is not surgery
in the traditional sense because there's no incision. Instead, SRS uses 3-D imaging to target
high doses of radiation to the affected area with minimal impact on the surrounding healthy
tissue. Like other forms of radiation, SRS works by damaging the DNA of the targeted (tumor)
cells. The affected cells then lose the ability to reproduce, which causes tumors to shrink.

When given separately, atezolizumab and SRS, work in different ways to help stop cancer cells
from growing and spreading. However, it is not known if giving atezolizumab and SRS at the
same time will have a better effect than giving each treatment on its own. It is hoped that
SRS treatment will damage cancer cells and make them more visible to the immune system.

The researchers conducting this study are testing to see whether giving SRS with atezolizumab
may boost the body's immune response to cancer, and therefore improve upon the effects of
either SRS or atezolizumab given alone.

In this research study, the investigators will measure the length of time that the
participant receive this study intervention without the disease getting worse. The
investigators will also look at how well the disease responds to atezolizumab and SRS as well
as the safety of the combination.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed Stage IV invasive
breast cancer. Participants without pathologic or cytologic confirmation of metastatic
disease should have unequivocal evidence of metastasis from physical examination or
radiologic evaluation.

- Either the primary tumor and/or metastatic tumor must be triple-negative as defined
below:

- Hormone receptor status: the invasive tumor must be ER- and PR-negative, or
staining present in <1% by immunohistochemistry (IHC)

- HER2 status: the invasive tumor must be Human Epidermal Growth Factor Receptor 2
Negative (HER2-negative) by the ASCO CAP guidelines

- In cases where both primary tumor and metastatic sample(s) have been tested for ER,
PR, and HER2, the triple-negative status of the most recent sample should be used.

- Participants must have a diagnosis of brain metastases for which SRS is indicated, as
determined by a radiation oncologist.

- The contrast-enhancing intraparenchymal brain metastases(s) must be well circumscribed
and must have a maximum diameter of ≤ 3.0 cm in any direction on the enhanced scan.

- Participants must not have more than 5 new or progressive lesions in the brain
requiring SRS treatment (greater than 5 total brain lesions are allowed as long as no
more than 5 lesions require SRS treatment).

- Participants must have measurable extracranial disease as defined by RECIST 1.1.

- Participants must be willing to undergo a research biopsy at baseline and at Cycle 2
Day 1 if extracranial metastases are safely accessible. Participants for whom biopsies
cannot be safely performed must be willing to submit an archival primary and/or
metastatic specimen. The biopsies may be waived with prior PI approval for the first 6
participants enrolled to the safety run in phase.

- Prior systemic therapy:

- Participants must have discontinued systemic therapy at least 14 days prior to
initiating protocol therapy.

- There is no limit to the number of prior lines of systemic therapy. Participants
who have not received any systemic therapy for metastatic disease are also
eligible.

- Participants may initiate or continue bisphosphonate therapy on study.

- Prior local therapy:

- Prior surgery, whole brain radiation or SRS is allowed as long as the most recent
brain progression is amenable to SRS treatment.

- Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1
severity or lower, except for stable sensory neuropathy (≤ Grade 2 allowed) and
alopecia (of any grade).

- Participant is ≥18 years old.

- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

- Stable dose of dexamethasone 2mg or less for at least 7 days prior to initiation of
treatment

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,000/μl

- platelets ≥75,000/μl

- hemoglobin ≥9 g/dL

- total bilirubin ≤1.5mg/dL (≤2.0 in patients with known Gilberts syndrome)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. ≤5.0 × institutional ULN for
patients with documented liver metastases.

- albumin >2.5mg/dL

- serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min

- Female subjects of childbearing potential must have a negative serum or urine
pregnancy test within 8 days of initiating protocol therapy.

- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use 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 treatment. A woman is considered to be of childbearing potential if she
is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of
amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive
methods with a failure rate of < 1% per year include bilateral tubal ligation, male
sterilization, established, proper use of hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception. The effects of atezolizumab on
the developing human fetus are unknown and radiotherapy has known teratogenic effects
so women of child-bearing potential and men must agree to use adequate contraception
(barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation and 4 months after completion of atezolizumab
administration.

- The subject is capable of understanding and complying with the protocol and has signed
the informed consent document

Exclusion Criteria:

- CNS complications for whom urgent neurosurgical intervention is indicated (e.g.,
resection, shunt placement).

- Known leptomeningeal or brainstem metastases. The presence of leptomeningeal
enhancement alone, without associated clinical manifestations and/or positive CSF
cytology, will not be constituted as known leptomeningeal metastases.

- Treatment with high dose systemic corticosteroids defined as dexamethasone >2mg/day or
bioequivalent within 7 days of initiating therapy.

- Patients unable to undergo gadolinium contrast-enhanced MRI or receive IV contrast for
any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme
obesity, hypersensitity).

- Participants who are receiving any other investigational agents.

- Previous treatment with any anti-PD-1, PD-L1, or PD-L2 agent.

- Subjects with a history of hypersensitivity to compounds of similar biologic
composition to atezolizumab or any constituent of the product

- The participant has an uncontrolled intercurrent illness, including, but not limited
to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac
arrhythmia, congestive heart failure-New York Heart Association Class III or IV,
active ischemic heart disease, myocardial infarction within the previous six months,
uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the
previous 6 months, severe malnutrition or psychiatric illness/social situations that
would limit compliance with study requirements.

- Participant has a medical condition that requires chronic systemic steroid therapy or
on any other form of immunosuppressive medication. For example, patients with
autoimmune disease that requires systemic steroids or immunosuppression agents should
be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.

- Has evidence of active, noninfectious pneumonitis that requires treatment with
steroids.

- Has a history of interstitial lung disease.

- The participant is known to be positive for the human immunodeficiency virus (HIV),
HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with
atezolizumab.

- Individuals with a history of different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 3 years or are deemed by the principal
investigator to be at low risk for recurrence of that malignancy.

- Has received a live vaccine within 28 days of planned start of study therapy.

- The participant is pregnant or breast-feeding.