This will be a randomized phase II clinical trial of patients with histologic documentation of metastatic colorectal cancer, who have received local and currently approved standard therapies, excluding RGF.

The investigators will give VOR 400 mg PO daily and HCQ 600 mg PO daily in 4-week cycles. Patients will require imaging up to 6 weeks prior to enrollment and will be assessed for measureable evidence of mCRC. This will be a randomized, controlled phase II clinical trial of patients with histological documentation of metastatic colorectal cancer, who have received locally and currently approved standard therapies, excluding RGF. Patients will be randomized 1:1 to RGF or VOR/HCQ (see schema below). Also, crossover is optional after first progression on the initial therapy, and based on physician discretion and in the best interest of the patient. If crossover is not done, then the patient will be off study and can go on to receive other treatments.

Inclusion Criteria:

• Histological documentation of metastatic colorectal cancer (mCRC)
• ECOG performance status of 0-2
• Radiographical documentation of metastatic disease with imaging up to 6 weeks prior to enrollment
• Patients with mCRC must have been previously treated with irinotecan and/or oxaliplatin and/or VEGF/EGFR therapy or intolerant to these agents
• Documentation of K-Ras mutational status
• Adequate hematologic, renal and liver function (i.e. absolute neutrophil count > 1000/mm3, platelets > 75,000/mm3); creatinine < 2 times the upper limits of normal (ULN) total bilirubin < 1.5 mg/dl, ALT and AST< 3 times above the ULN, ALT and AST can be < 5 times ULN if patients have hepatic involvement.
• Able to provide written informed consent
• Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative pregnancy test within 72 hours prior to receiving the investigational product
• Tumor blocks available from previous surgery/biopsy, or if not available, patients willing to have biopsy

Exclusion Criteria:

• Patients receiving prior therapy with RGF, VOR, and/or HCQ
• Patients with uncontrolled brain metastases. Patients with brain metastases must be asymptomatic and off corticosteroids for at least one week
• Due to risk of disease exacerbation, patients with porphyria are not eligible
• Due to risk of disease exacerbation, patients with psoriasis are ineligible unless the disease is well controlled, and they are under the care of a specialist for the disorder who agrees to monitor the patient for exacerbations
• Patients with previously documented macular degeneration or diabetic retinopathy
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. For targeted therapies, patients will need to clear for 5 half-lives
• Patients may not be receiving any other investigational agents
• Patients should not have taken valproic acid or another histone deacetylase inhibitor for at least 2 weeks prior to enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to VOR or HCQ
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Major surgery or significant traumatic injury occurring within 21 days prior to treatment
• QTc > 500 ms at baseline (average of 3 determinations at 10 minutes interval)
• Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease. Patients with NG-tube, J-tube, or G-tube will not be allowed to participate
• Pregnant women are excluded from this study because vorinostat has the potential for teratogenic or abortifacient effects. For this reason, women of childbearing potential and men must also agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation
• Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with vorinostat, breastfeeding should be discontinued
• Informed Consent - No study specific procedures will be performed without a written and signed informed consent document. Patients who do not demonstrate the ability to understand or the willingness to sign the written informed consent document will be excluded from study entry

Data collected from baseline up to 22 months.