To Determine the Safety of Regorafenib, Hydroxychloroquine, and Entinostat Metastatic Colorectal Cancer

Inclusion Criteria:

* Histologic or cytologic confirmation of metastatic colorectal cancer
* Measurable disease based on modified RECIST 1.1 criteria
* Patients should have received adequate therapy with prior 5-fluorouracil, oxaliplatin, and irinotecan, unless contra-indicated, not tolerated or declined.
* No prior therapy with regorafenib or other anti-angiogenic tyrosine kinase inhibitor
* No prior or current therapy with an HDAC inhibitor
* Age 18 years or older
* ECOG performance status of 0 or 1
* If a female of childbearing potential, has a negative serum blood pregnancy test during screening and a negative urine pregnancy test within 3 days prior to receiving the first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required. If a patient is of childbearing potential the patient must agree to use effective contraception (see Appendix C for acceptable methods) during the study and for 120 days after the last dose of study drug. Non-childbearing potential is defined as (by other than medical reasons):
* ≥45 years of age and has not had menses for \>2 years
* Amenorrheic for \<2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation
* Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the patient must be willing to use 2 adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last dose of study drug
* If male, agrees to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug
* Life expectancy of greater than 3 months
* Patients must have the ability to understand and the willingness to sign a written informed consent document.
* Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements within 4 weeks of starting treatment

  * Absolute neutrophil count \>1,500 per uL
  * Hemoglobin \> 9 g/dL
  * Platelets \>100,000 per uL
  * Creatinine \< 1.5 x ULN OR Creatinine clearance (CrCl) \> 60 by Cockcroft-Gault Equation if Creatinine \>1.5
  * AST and ALT \< 2.5 x ULN (\< 5 x ULN if documented liver metastases)
  * Total bilirubin \<1.5 ULN OR direct bilirubin \< ULN if total bilirubin \> 1.5 x ULN
  * INR \< 2.0
* Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy to Grade \<1 (except alopecia or neuropathy). If patient underwent major surgery or radiation therapy of \>30 Gy, they must have recovered from the toxicity and/or complications from the intervention.

Exclusion Criteria

* History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to:

  1. Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a QTc interval \> 470 msec.
  2. Uncontrolled hypertension or diabetes mellitus.
  3. Another known malignancy that is progressing or requires active treatment.
  4. Any prior history of other cancer within the prior 5 years with the exception of adequately treated basal cell carcinoma or cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ or melanoma in situ).
  5. Active infection requiring systemic therapy
  6. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
* Allergy to benzamide, inactive components of entinostat, or any of the other administered therapies
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
* Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study drug.
* If female, is pregnant or breastfeeding.
* Known G6PD deficiency, severe psoriasis, porphyria, macular degeneration, or severe diabetic retinopathy due to greater potential HCQ toxicity
* Patients with pre-existing hypertension should be on a stable antihypertensive regimen and have a blood pressure ≤ 150/100 mmHg at the time of enrollment.
* Evidence or history of bleeding diathesis. Any hemorrhage or bleeding event of CTCAE grade 3 or higher within 4 weeks of start of study medication
* Non-healing wound, ulcer, or bone fracture
* Patients using warfarin are excluded. Patients using other oral or parenteral anticoagulation are not excluded provided they are on a stable dose of anticoagulant but must undergo more frequent platelet count monitoring.