Vorinostat Plus Hydroxychloroquine Versus Regorafenib in Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Vorinostat; Hydroxychloroquine; Regorafenib
Intervention description: 400mg by mouth daily; 600mg by mouth daily; 160 mg by mouth daily
Intervention MeSH terms: Hydroxychloroquine; Vorinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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