A Single Arm Phase 2 Trial of Atezolizumab with Sacituzumab Govitecan to Prevent Recurrence in Triple Negative Breast Cancer (ASPRIA)

The purpose of this study is to determine if a combination of two drugs ipatasertib and
atezolizumab works as a treatment for residual cancer in the breast or lymph nodes and have
circulating tumor DNA in the blood.

This research study involves the following investigational drugs:

- Sacituzumab govitecan

- Atezolizumab

Inclusion Criteria:

- Pathologically confirmed residual invasive breast cancer, in the breast and/or lymph
node(s), following neoadjuvant chemotherapy. In the absence of residual invasive
disease in the breast, lymph node must contain at least 2mm of invasive disease.

- HER2 negative in primary tumor pre-treatment by local pathology assessed according to
current ASCO/CAP guidelines:

- In situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe
average HER2 gene copy number < 4 signals/cell), OR

- Immunohistochemistry (IHC) 0 or IHC 1+.

- NOTE: If more than one test result is available and not all results meet the
inclusion criterion definition, all results should be discussed with the
Principal Investigator to establish eligibility

- ER and PR negative in primary tumor pre-treatment defined as < 10% of cells expressing
hormonal receptors via IHC analysis by local laboratory assessment.

- Patients must have received neoadjuvant chemotherapy prior to breast surgery.

- Patients must be within 4 months of completion of all locoregional therapy (either
last surgery or last dose of radiation, whichever is later) . Definitive breast
surgery must have been performed and includes lumpectomy or mastectomy with
pathologically clear margins (i.e. no ink on tumor). For patients undergoing
lumpectomy, this must be followed by whole breast irradiation. Definitive surgery also
includes axillary surgery, either sentinel lymph node biopsy or axillary lymph node
dissection at the discretion of the attending surgeon.

- Evidence of ctDNA in blood sample collected after completion of all local and systemic
neoadjuvant therapy (preoperative chemotherapy, surgery and radiation), confirmed by
central testing. Detection of any tumor specific mutations (TSMs) within the sample
will be considered positive for purposes of study eligibility.

- Concurrent receipt of bone modifying agents (bisphosphonates or rank-ligand
inhibitors)is allowed.

- Prior treatment with an immune checkpoint inhibitor in the neoadjuvant setting is
permitted.

- ECOG Performance Status of 0 or 1

- Men and women, age ≥ 18 years

- Adequate hematologic and organ function defined by the following:

- ANC ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support

- WBC count ≥ 2.5 × 109/L (2500/μL)

- Absolute Lymphocyte count ≥ 0.5 × 109/L (500/μL)

- Platelet count ≥ 100 × 109/L (100,000/μL)

- Hemoglobin ≥ 90 g/L (9.0 g/dL), with or without transfusion

- AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 × institutional upper limit of
normal (ULN).

- Serum bilirubin ≤ 1.5 × institutional ULN with the following exception:

- Patients with known Gilbert syndrome: serum bilirubin level ≤ 3 ×
institutional ULN

- Serum creatinine < 1.5 x institutional ULN

- Creatinine clearance ≥30 mL/min as assessed by the Cockcroft-Gault equation

- Serum albumin ≥ 25 g/L (2.5 g/dL)

- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 ×
institutional ULN

- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

- Women of childbearing potential (pre-menopausal) must have a negative serum or urine
pregnancy test within 7 days prior to start of therapy. A woman is defined as
premenopausal if she is less than 12 months from last menstrual period with no
identified cause other than menopause (medication induced amenorrhea is not
acceptable). Pregnancy test is not required in women who are surgically sterile via
bilateral salpingooophorectomy or hysterectomy.

- Women of childbearing potential and men must agree to use adequate contraception for
the duration of protocol treatment and for 6 months after last dose of atezolizumab
and 6 months after last dose of sacituzumab govitecan, whichever is later. Hormonal
contraceptives are not acceptable (see section 5.6).

- Ability to understand and the willingness to sign a written informed consent document.
Non-English speakers are eligible to participate but will be excluded from
surveys/questionnaires unless the participant has a proxy available for translation.

Exclusion Criteria:

- Prior therapy with sacituzumab govitecan, irinotecan, or any topoisomerase
I-containing antibody-drug conjugates at any time for early stage disease.

- Receipt of adjuvant chemotherapy (all chemotherapy prior to registration must have
occurred in the preoperative setting)

- Prior hypersensitivity to atezolizumab or the excipients of atezolizumab or
sacituzumab govitecan

- Clinical or radiographic evidence of metastatic disease

- Residual DCIS or LCIS alone without invasive cancer OR pT0N0i and pT0N1mic residual
disease

- Concurrent enrollment on another investigational therapy trial

- Prior treatment-related toxicity must be resolved to ≤ Grade 1 prior to study
enrollment with the exception of alopecia and peripheral neuropathy, prior to study
enrollment.

- Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
study

- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.

- Intercurrent illness including, but not limited to: ongoing or active infection
requiring systemic therapy, active tuberculosis, serious liver disease such as
cirrhosis, active bleeding diathesis, uncontrolled Type I or Type II diabetes
mellitus, Grade ≥ 2 uncontrolled or untreated hypercholesterolemia,
Hypertriglyceridemia or hypercalcemia

- Cardiovascular disease including: congestive heart failure of New York Heart
Association Class III or IV, myocardial infarction (<6 months prior to enrollment)
unstable angina pectoris, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease, in the opinion of the investigator

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

- Active (acute or chronic) autoimmune disease of any type except hypothyroidism on a
thyroid-replacement hormone, celiac disease, or well-controlled psoriasis, eczema,
lichen simplex chronicus or vitiligo.

- Impairment of gastrointestinal function or active gastrointestinal disease that may
significantly alter the absorption of the study agents (e.g., ulcerative disease,
uncontrolled nausea(> grade 2), vomiting (> grade 2), diarrhea (> grade 2),
malabsorption syndrome or small bowel resection).

- Congenital long QT syndrome or screening QT interval corrected through use of
Fridericia's formula >480 ms.

- Participants known to be positive for the human immunodeficiency virus (HIV),
Hepatitis B antigen (HepBsAg), or Hepatitis C virus (HCV) RNA are ineligible.

- History of prior invasive breast cancer in either breast.

- Participants with history of prior malignancy other than breast cancer are eligible if
they have been disease-free for at least 5 years prior to enrollment with the
exception of patients with thyroid cancer that has been definitively treated without
spread to regional lymph nodes.

- Treatment with strong strong UGT1A1 inhibitor or inducer within 4 weeks or 5
drug-elimination half-lives, whichever is longer, prior to initiation of study drug.

- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment, or anticipation of need for such a vaccine while on protocol treatment

- Known allergy or hypersensitivity to any of the study drugs or any of their
excipients, including chimeric or humanized antibodies or fusion proteins and Chinese
hamster ovary cell products or recombinant human antibodies

- Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study
treatment, or anticipation of need for systemic immunosuppressive medication during
the course of the study, with the following exceptions:

- Patients who received acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible. o Patients who received
mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic
obstructive pulmonary disease or asthma, or low-dose corticosteroids for
orthostatic hypotension or adrenal insufficiency are eligible for the study.

- Pregnant women are excluded from this study because the effects of sacituzumab
govitecan and atezolizumab on a developing fetus are unknown. Breastfeeding should be
discontinued prior to entry onto the study and for one month following the last dose
of sacituzumab govitecan.