Phase I/II Trial of Regorafenib, Hydroxychloroquine, and Entinostat in 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.