Azacitidine and/or Romidepsin with Pembrolizumab in Treating Patients with Microsatellite Stable Metastatic Colorectal Cancer

Inclusion Criteria

• Have histologically confirmed microsatellite stable metastatic colorectal cancer and have received at least one line of treatment for metastatic colorectal cancer including fluoropyrimidines, oxaliplatin and/or irinotecan
• Be willing and able to provide written informed consent/assent for the trial
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Have biopsiable disease; if biopsy is attempted and unsuccessful (the patient undergoes an invasive procedure), the patient may still be treated
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale at study entry
• Absolute neutrophil count (ANC) >= 1,500/mcL (within 7 days of treatment initiation)
• Platelets >= 100,000/mcL (within 7 days of treatment initiation)
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 7 days of treatment initiation)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance rate [CrCl]) (within 7 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 7 days of treatment initiation)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (within 7 days of treatment initiation)
• Albumin > 3.0 gm/dL (within 7 days of treatment initiation)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 7 days of treatment initiation)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 7 days of treatment initiation)
• Female subject of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
• In patients with liver metastases, there should be < 50% involvement of the liver
• Patients must have had =< 3 prior therapies in the metastatic setting (not including chemotherapy given as maintenance therapy)

Exclusion Criteria

• Has primary refractory disease (this is, those whose tumors have progressed at the first restaging during first line therapy)
• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks (6 weeks for nitrosureas or mitomycin C) prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy and be at least 28 days from surgery
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study; any autoimmune diagnoses not listed here must be approved by the protocol chair
• Has a history of (non-infectious) pneumonitis that required steroids or any current pneumonitis
• Has an active infection requiring systemic therapy
• Any clinical or radiological ascites or pleural effusions
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has received prior therapy with an anti-PD-1, anti-programmed cell death ligand 1 (PD-L1), anti- programmed cell death 1 ligand 2 (PD-L2), anti-cluster of differentiation (CD)137, anti-tumor necrosis factor receptor superfamily member 4 (OX-40), anti-CD40, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways); prior therapies with other immunomodulatory agents must be reviewed by the principal investigator (PI) and may be cause for ineligibility
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days prior to the first dose of trial treatment
• Any known cardiac abnormalities such as: * Congenital long QT syndrome * Corrected QT (QTc) interval >= 485 milliseconds; * Myocardial infarction within 6 months of cycle 1 day 1 (C1D1); subjects with a history of myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate; * Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min) trial treatments * Symptomatic coronary artery disease (CAD), e.g., angina; in any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present; * An ECG recorded at screening showing evidence of cardiac ischemia (ST depression, depression of >= 2 mm, measured from isoelectric line to the ST segment); if in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present; * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 40% by multi gated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI); * A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsade de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD); * Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes; * Uncontrolled hypertension, i.e., blood pressure (BP) of >= 160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria; or * Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers) * Patients taking drugs leading to significant QT prolongation