Hydroxychloroquine Sulfate, Everolimus, or the Combination in Preventing Recurrence in Patients with Breast Cancer

Inclusion Criteria

• Histologically-confirmed, primary, invasive breast cancer diagnosed within 5 years of study entry
• Qualifying risk status, at diagnosis utilizing receptor testing by American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, meeting one of the following: * Histologically positive axillary lymph nodes * Primary tumor that is estrogen receptor (ER)/progesterone receptor (PR)/Her2 negative * Primary tumor that is ER+/Her2 negative/lymph node negative with Breast Cancer Recurrence Score of >= 25 per the Genomic Health Oncotype diagnosis (DX) breast cancer test * Evidence of residual disease in the breast on pathological assessment after neoadjuvant chemotherapy
• Patients must have completed all primary therapy (definitive surgery, (neo)adjuvant chemotherapy adjuvant radiation and/or Her2-directed therapy) for the index malignancy at least 4 weeks prior to study entry; all prior treatment-related toxicity must be resolved prior to study enrollment; concurrent receipt of adjuvant endocrine and bone modifying agents is allowed per standard of care guidelines
• Bone marrow aspirate after completion of therapy demonstrates detectable DTCs (via IHC)
• No evidence of recurrent local or distant breast cancer by physical examination, blood tests (complete blood count [CBC], liver function tests [LFTs], alkaline phosphatase [alk phos]), or symptom-directed imaging, per National Comprehensive Cancer Network (NCCN) guidelines
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• No contraindications to the study medications or uncontrolled medical illness
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin (Hb) > 9 g/dL
• Serum bilirubin =< 1.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) =< 2.5 x ULN
• Aspartate aminotransferase (AST) =< 2.5 x ULN
• International Normalized Ratio (INR) =< 1.5
• Anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of anticoagulant for > 2 weeks at time of randomization; for patients on therapeutic anti-coagulants, medication must be clinically held peri-procedure (bone marrow aspirate) per standard clinical management
• Adequate renal function: serum creatinine =< 2.0 x ULN or creatinine clearance (CrCl) >= 30mL/min obtained within 28 days prior to registration; a calculated creatinine clearance by Cockcroft-Gault formula is acceptable in lieu of a measured value
• 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
• Ability to provide informed consent

Exclusion Criteria

• Concurrent enrollment on another investigational therapy
• Prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
• Known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients
• Patients receiving chronic, high dose systemic treatment with corticosteroids defined as: chronic use of cortisone > 50mg; hydrocortisone > 40mg, prednisone > 10mg, methylprednisone > 8mg or dexamethasone > 1.5mg; or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study including: * Symptomatic congestive heart failure of New York heart Association class III or IV * Unstable angina pectoris, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease * Severely impaired lung function with a previously documented spirometry and Carbon Monoxide Diffusing Capability Test (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air * Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN * Active (acute or chronic) or uncontrolled severe infections * Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis * A known history of human immunodeficiency virus (HIV) seropositivity as reported by the patient * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of EVE (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) * Patients with an active, bleeding diathesis * Active or latent, untreated hepatitis B or C; a detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients; hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) ribonucleic acid (RNA) polymerase chain reaction (PCR) testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection
• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; if barrier contraceptives are being used, these must be continued throughout the trial and for 8 weeks after stopping study drug, by both sexes; hormonal contraceptives are not acceptable as a sole method of contraception; (women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of EVE)