Entinostat, Nivolumab, and Ipilimumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Locally Advanced or Metastatic HER2-Negative Breast Cancer

Inclusion Criteria:

• Dose escalation: patients must have histologically or cytologically confirmed solidtumor malignancy that is metastatic or unresectable and for whom either standardcurative or palliative measures do not exist or are no longer effective, or for whomanti-PD-L1/cytotoxic T-lymphocyte antigen (CTLA)-4 is appropriate

• Dose expansion: patients must have histologically or cytologically confirmedinvasive adenocarcinoma of the breast (human epidermal growth factor receptor 2 [HER2]-negative) that is locally advanced/metastatic and has progressed despitestandard therapy; at least 1 prior chemotherapy regimen in the metastatic setting,and two lines of hormonal therapy (administered in the adjuvant or metastaticsetting) for patients with hormone receptor-positive disease; NOTE: HER2-negativitywill be defined per American Society of Clinical Oncology (ASCO)-College of AmericanPathologists (CAP) guidelines; patients whose tumors have HER2 immunohistochemistry (IHC) 3+, in situ hybridization (ISH) >= 2.0, or average HER2 copy number >= 6.0signals per cell are not eligible

• Age ≥ 18 years.

• NOTE: Because no dosing or adverse event data are currently available on theuse of these agents in patients <18 years of age, children are excluded fromthis study, but will be eligible for future pediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)

• Life expectancy of greater than 12 weeks

• Hemoglobin (HgB) >= 9.0 g/dL

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); an exception tothis may be allowed for participants with Gilbert's syndrome with documentedapproval by the protocol chair

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN

• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/minusing the modified Cockcroft-Gault formula

• Negative (serum or urine) pregnancy test, for women of childbearing potential only

• Patients must have measurable or evaluable/non-measurable disease per ResponseEvaluation Criteria in Solid Tumors (RECIST) 1.1; patients with bone only diseaseare not eligible due to difficulties in obtaining serial bone biopsies forcorrelative analyses; NOTE: for patients with metastatic disease in the liver, tumorburden should not be deemed significant (e.g., to no more than 30% of total livervolume as assessed by local review/investigator)

• Adequate pulmonary function as assessed by oxygen saturation >= 90% when ambulatingand not requiring supplemental oxygen

• Patient must have an accessible non-bone tumor lesion from which serial core biopsyspecimen can be obtained; NOTE: if baseline biopsy is attempted and is unsuccessful (e.g., patient intolerance, inadequate tissue), the patient will still be consideredeligible for the study; if core biopsy is not possible, other methods may beapproved in advance by the protocol chair/designee

• The effects of nivolumab, ipilimumab and entinostat on the developing human fetusare unknown; for this reason and because other therapeutic agents used in this trialare known to be teratogenic, women of child-bearing potential (WOCBP) and men mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry and for the duration of study participation; WOCBPmust have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L orequivalent units of human chorionic gonadotropin [HCG]) at baseline; women must notbe breastfeeding; women who are not of childbearing potential (i.e., who arepostmenopausal or surgically sterile as well as azoospermic men) do not requirecontraception; NOTE: A WOCBP is defined as any female who has experienced menarcheand who has not undergone surgical sterilization (hysterectomy or bilateraloophorectomy) or who is not postmenopausal; menopause is defined clinically as 12months of amenorrhea in a woman over 45 in the absence of other biological orphysiological causes

• Willingness to provide tissue and blood samples for mandatory translational research

• Willingness to return to the enrolling institution for follow-up

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Patients who have had chemotherapy or other systemic therapy or radiotherapy, orthose who have not recovered from adverse events due to prior administered agents asfollows:

• Chemotherapy < 3 weeks prior to registration

• Hormone therapy < 2 weeks prior to registration

• Targeted therapy (other than below) < 2 weeks prior to registration (e.g.,tyrosine kinase inhibitors)

• Trastuzumab < 6 weeks prior to registration

• Bevacizumab < 6 weeks prior to registration

• Nitrosoureas/mitomycin C < 6 weeks prior to registration

• Radiotherapy < 3 weeks prior to registration (NOTE: a previously irradiatedlesion may not be used as a target lesion unless there is evidence ofpost-radiation progression)

• Surgery < 3 weeks prior to registration

• Other approved or investigational agents < 3 weeks prior to registration unlessotherwise noted by the protocol chair

• Patients who have received prior epigenetic (e.g., histone deacetylase [HDAC]inhibitors such as entinostat, panobinostat, vorinostat, romidepsin ordemethylating agents such as 5-azacitidine or decitabine) immunomodulatory orother checkpoint inhibitors should only be considered after discussion with theprotocol chair

• Those who have not recovered from acute adverse events to grade < 2 or baselinedue to agents administered, with exception of alopecia, unless approved by theprotocol chair

• Known sensitivity to or history of allergic reactions attributed to compounds ofsimilar chemical or biologic composition entinostat, nivolumab, or ipilimumab;history of severe hypersensitivity reaction to any monoclonal antibody

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding systemic corticosteroids, should be excluded; these include but are notlimited to patients with a history of immune related neurologic disease, multiplesclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome,myasthenia gravis, systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD),Crohn's, ulcerative colitis, autoimmune hepatitis, and patients with a history oftoxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded; patients with vitiligo, endocrine deficiencies includingthyroiditis managed with replacement hormones including physiologic corticosteroidsare eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren'ssyndrome and psoriasis controlled with topical medication and patients with positiveserology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should beevaluated for the presence of target organ involvement and potential need forsystemic treatment but should otherwise be eligible

• NOTE: patients are permitted to enroll if they have vitiligo, type I diabetesmellitus, residual hypothyroidism due to autoimmune condition only requiring hormonereplacement, psoriasis not requiring systemic treatment, or conditions not expectedto recur in the absence of an external trigger (precipitating event)

• Subjects with interstitial lung disease that is symptomatic or may interfere withthe detection or management of suspected drug-related pulmonary toxicity; NOTE:subjects must have baseline oxygen/saturation level requirements as above

• Patients with active or untreated brain metastases or leptomeningeal metastases areexcluded from this clinical trial because of their poor prognosis and because theyoften develop progressive neurologic dysfunction that would confound the evaluationof neurologic and other adverse events; NOTE: Patients with previously treated brainmetastases must have stable neurologic status and magnetic resonance imaging (MRI)imaging following local therapy (surgery or radiation) for at least 4 weeks, with norequirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/dayprednisone equivalents) for at least 2 weeks prior to study drug administration (stable low dose dexamethasone allowed at discretion of protocol chair)

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that in the judgment of theinvestigator would limit compliance with study requirements

• Pregnant women are excluded from this study because the agents have the potentialfor teratogenic or abortifacient effects; because there is an unknown but potentialrisk for adverse events in nursing infants secondary to treatment of the mother,breastfeeding should be discontinued

• Known human immunodeficiency virus (HIV)-positive patients on combinationantiretroviral therapy are ineligible; patients who have a positive test forhepatitis B virus surface antigen (HBV sAg) or hepatitis C antibody (HCVAb)/ribonucleic acid (RNA) (HCV RNA) indicating acute or chronic infection are alsoineligible (baseline testing required); these are because of the potential forpharmacokinetic interactions with the study agents; in addition, these patients areat increased risk of lethal infections when treated with marrow-suppressive therapy;appropriate studies will be undertaken in patients receiving combinationantiretroviral therapy when indicated

• Patients should be excluded if they have a condition requiring systemic treatmentwith either corticosteroids (> 10 mg daily prednisone equivalents) or otherimmunosuppressive medications within 14 days of study drug administration; inhaledor topical steroids and adrenal replacement doses =< 10 mg daily prednisoneequivalents are permitted in the absence of active autoimmune disease; patients arepermitted to use topical, ocular, intra-articular, intranasal, and inhalationalcorticosteroids (with minimal systemic absorption); physiologic replacement doses ofsystemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents;a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) orfor treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivityreaction caused by contact allergen) is permitted

• Patients requiring concurrent administration of valproic acid are also excluded

• Patients who have had evidence of active or acute diverticulitis, intra-abdominalabscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which areknown risk factors for bowel perforation should be evaluated for the potential needfor additional treatment before coming on study

• Another active malignancy =< 3 years prior to registration with the exception ofnon-melanotic skin cancer or carcinoma-in-situ of any type; NOTE: if there is ahistory of prior malignancy, they must not be receiving other specific treatment fortheir cancer; any malignancy considered to be indolent and that has never requiredtherapy may allowed at the discretion of the protocol chair