Liposomal Doxorubicin, Bevacizumab, and Everolimus in Patients With Locally Advanced TNBC With Tumors Predicted Insensitive to Standard Chemotherapy; A Moonshot Initiative
Condition: Invasive Breast Carcinoma; Triple-Negative Breast Carcinoma
MeSH terms: Carcinoma; Breast Neoplasms
Intervention: Bevacizumab; Everolimus; Laboratory Biomarker Analysis; Pegylated Liposomal Doxorubicin Hydrochloride
Intervention description: Given IV; Given PO; Correlative studies; Given IV
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Doxorubicin; Liposomal doxorubicin; Everolimus; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well pegylated liposomal doxorubicin, bevacizumab, and
      everolimus work in treating patients with triple-negative breast cancer with tumors predicted
      insensitive to standard chemotherapy. Drugs used in chemotherapy, such as pegylated liposomal
      doxorubicin, work in different ways to stop the growth of tumor cells by stopping them from
      dividing. Bevacizumab may stop or slow breast cancer by blocking the growth of new blood
      vessels necessary for tumor growth. Everolimus may stop the growth of tumor cells by blocking
      some of the enzymes needed for cell growth. Giving pegylated liposomal doxorubicin together
      with bevacizumab and everolimus may kill more tumor cells.
    

Eligibility criteria:

        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; the tumor must have evidence of mesenchymal differentiation defined as
             metaplastic breast cancer, or vimentin >= 50% by IHC

          -  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 the following:

               -  Placement of an intrauterine device (IUD) or intrauterine system (IUS);

               -  Barrier methods of contraception: condom or occlusive cap (diaphragm or
                  cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository;

               -  Total abstinence or;

               -  Male/female sterilization.

               -  Note: Women are considered post-menopausal and not of child-bearing potential if
                  they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
                  clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
                  had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
                  ligation at least six weeks prior to treatment; in the case of oophorectomy
                  alone, only when the reproductive status of the woman has been confirmed by
                  follow up hormone level assessment is she considered not of child-bearing
                  potential

          -  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