Liposomal Doxorubicin, Bevacizumab, and Everolimus in Patients With Locally Advanced TNBC With Tumors Predicted Insensitive to Standard Chemotherapy; A Moonshot Initiative

PRIMARY OBJECTIVES:

I. Determine excellent clinical response rates (pathologic complete response [pCR]/residual
cancer burden [RCB]-0 or minimal residual disease [RCB-I]) in patients with
anthracycline-based chemotherapy insensitive, localized triple-negative breast cancer (TNBC)
who receive 4 cycles of pegylated liposomal doxorubicin hydrochloride, bevacizumab, and
everolimus (DAE) following anthracycline-based chemotherapy in the neoadjuvant setting.

SECONDARY OBJECTIVES:

I. Determine response rate after 4 cycles of DAE using radiographic imaging. II. Correlate
pathologic response with vimentin expression as measured by immunohistochemistry (IHC).

III. Determine toxicity associated 4 cycles of DAE in the neoadjuvant setting. IV. Compare
pathologic response rates to 4 cycles of DAE in mesenchymal tumors versus (vs.)
non-mesenchymal tumors.

V. Compare pathologic response rates in mesenchymal tumors to 4 cycles of DAE vs. 12 weeks of
weekly paclitaxel.

VI. Determine pathologic response rates for all patients who discontinue study drug due to
toxicity.

TERTIARY OBJECTIVES:

I. Determine the correlation between vimentin expression by IHC and the presence of
mesenchymal gene signatures at the time of initial tumor biopsy prior to neoadjuvant
chemotherapy (NACT).

II. Determine rates of pCR in patients with mesenchymal tumors identified by gene signatures
and compare to pCR rates in non-mesenchymal tumors.

OUTLINE:

Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over about
3 hours on day 1, bevacizumab IV over 90 minutes on day 1, and everolimus orally (PO) daily.
Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity. Patients will not receive bevacizumab during course 4 of therapy.
Patients then undergo surgery.

After completion of study treatment, patients are followed up at 2-3 weeks.

Inclusion Criteria:

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Confirmed invasive triple-negative breast cancer defined as estrogen receptor (ER) <
10%; progesterone receptor (PR) < 10% by immunohistochemistry (IHC) and human
epidermal growth factor receptor 2 (HER2) 0-1+ (by IHC), or 2+ (fluorescence in situ
hybridization [FISH] < 2, gene copy number < 4)

- Primary tumor sample collected before NACT started and

- Undergone molecular testing for integral biomarkers including immunohistochemical
staining for vimentin

- Received at least one dose of an anthracycline-based NACT; patients are eligible if
therapy was discontinued due to disease progression or therapy intolerance

- At least 1.0 cm of measurable residual disease after neoadjuvant anthracycline-based
chemotherapy

- Baseline multi-gated acquisition (MUGA) scan or echocardiogram showing left
ventricular ejection fraction (LVEF) >= 50% at least 6 weeks prior to initiation of
NACT

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Hemoglobin (Hb) > 9 g/dL

- Total serum bilirubin =< 2.0 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper
limit of normal (ULN) (=< 5 x ULN in patients with liver metastases)

- International normalized ratio (INR) =< 2

- Serum creatinine =< 1.5 x ULN

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L, AND fasting triglycerides =<
2.5 x ULN; NOTE: In case one or both of these thresholds are exceeded, the patient can
only be included after initiation of appropriate lipid lowering medication

- Signed informed consent obtained prior to any screening procedures

Exclusion Criteria:

- Pregnant or lactating woman

- Presence of metastatic disease

- Prior therapy with bevacizumab, liposomal doxorubicin, or everolimus

- Prior radiation therapy of the primary breast carcinoma or axillary lymph nodes

- Patients who have a history of another primary malignancy, with the exceptions of:
non-melanoma skin cancer, and carcinoma in situ of the cervix, uterus, or breast from
which the patient has been disease free for =< 3 years

- Prior cumulative dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of
greater than 640 mg/m^2

- Any serious medical illness, other than treated by this study, which would limit
survival to less than 1 month or psychiatric illness which would limit informed
consent

- Patients with history of serious cardiac events defined as: New York Heart Association
class 3 or 4 heart failure, history of myocardial infarction, unstable angina, or
cardiovascular accident (CVA) within 6 months of protocol registration; history of PR
prolongation or atrioventricular (AV) block

- Known intolerance or hypersensitivity to rapamycin analogs (e.g. sirolimus,
temsirolimus)

- Known impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral everolimus

- Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) > 8% despite
adequate therapy; patients with a known history of impaired fasting glucose or
diabetes mellitus (DM) may be included, however blood glucose and antidiabetic
treatment must be monitored closely throughout the trial and adjusted as necessary

- Patients who have any severe and/or uncontrolled medical conditions such as: a.
serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac
disease b. active (acute or chronic) or uncontrolled severe infection, liver disease
such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e.
quantifiable hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive
surface antigen of the hepatitis B virus [HBsAg], quantifiable hepatitis C virus
[HCV]-ribonucleic acid [RNA]), c. known severely impaired lung function (spirometry
and Diffusing capacity of the lungs for carbon monoxide [DLCO] 50% or less of normal
and oxygen (O2) saturation 88% or less at rest on room air), d. active, bleeding
diathesis; e. Moderate or severe hepatic impairment (Child-Pugh B or C)

- Chronic treatment with corticosteroids or other immunosuppressive agents; topical or
inhaled corticosteroids are allowed

- Known history of human immunodeficiency virus (HIV) seropositivity

- Patients who have received live attenuated vaccines within 1 week of start of
everolimus and during the study; patient should also avoid close contact with others
who have received live attenuated vaccines; examples of live attenuated vaccines
include intranasal influenza, measles, mumps, rubella, oral polio, bacillus
Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines

- Patients with a history of non-compliance to medical regimens or who are considered
potentially unreliable or will not be able to complete the entire study

- Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing

- Women of child-bearing potential (WOCBP), defined as all women physiologically capable
of becoming pregnant, must use highly effective methods of contraception during the
study and 8 weeks after; highly effective contraception methods include combination of
any two of those listed in the protocol

- Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment