An Open-Label, Proof of Consent Study of Vorinostat for the Treatment of Mdoerate-to-Severe Crohn s Disease and Maintenance Therapy With Ustekinumab

Eligibility Criteria

• 1. Are 18 to 65 years of age, inclusive, at enrollment date.
• 2. Have a diagnosis of CD that has been endoscopically or radiographically confirmed. A colonoscopy will be required at baseline to document mucosal disease activity. SES-CD will be obtained with minimum score of 7.
• 3. Have active CD symptoms as defined by a CDAI score between 220 and 350 and demonstrate active symptoms as defined by continued weight loss, abdominal pain and/or diarrhea not controlled by standard therapy.
• 4. The participant must have active CD symptoms and therefore have had an inadequate response to, loss of response to, or intolerance to at least 1 of the following agent groups in control of their disease (as defined below for each individual agent group: Corticosteroids or Immunomodulators or TNF-alpha sign antagonists or Anti-integrin antibodies)
• 5. At the discretion of the PI, concomitant medications will be permitted if the following conditions are met prior to baseline assessment (Day-1):
• 6. Participants must agree to have samples of their blood and tissue stored for potential future research use.
• 7. Participants must have a primary medical care provider.
• 8. Male participants must agree to employ birth control measures to prevent pregnancy in female partners from start of treatment, and continuing through 3 months post treatment.
• 9. Females of childbearing potential must not be breast-feeding, possibly or actually pregnant, must not have had unprotected intercourse for one month prior to dosing, and must agree not to become pregnant beginning from enrollment in the study to at least 6 months after the end of treatment. Participants must remain completely abstinent of potentially reproductive sexual intercourse (e.g. due to a committed lifestyle) or to consistently use BOTH a barrier method with a spermicide (male or female condom) AND ALSO one of the below listed methods of birth control:
• 1. Continuous/daily hormonal methods including oral contraceptive pills, patch, implant/injection, etc.
• 2. Surgical sterilization of either partner, of sufficient duration to be effective, and NOT known to have failed.
• 3. Intrauterine device.
• 1. Presence of clinically significant systemic infection (e.g., chronic or acute infection, urinary tract infection, or upper respiratory tract infection) within three months of screening.
• 2. History or presence of recurrent or chronic infection (e.g., viral infection \[including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV)\], bacterial infection, systemic fungal infection, or syphilis).
• 3. Positive for tuberculosis (TB) via QuantiFERON-Gold (QFT-G). Individuals who are known to have received the tuberculosis vaccine will be administered the QFT- G. Patients can not have received tuberculosis vaccine within 12 months prior to start of study and can not receive tuberculosis vaccine while on study or within 12 months from the time of conclusion of study participation.
• 4. Has a history of active tuberculosis (TB) or a chest x-ray (CXR) with findings suggestive of old TB infection including calcified nodular lesions, apical fibrosis, or pleural scarring), acute or chronic HBV, HCV, HIV, or opportunistic infections
• 5. A conduction abnormality on baseline electrocardiogram (ECG) that in the opinion of a cardiologist, is deemed significant.
• 6. At the discretion of the principal investigator, off-label use of any small molecule therapeutics that are immune modulators (e.g., naltrexone) within 90 days of beginning screening or at any time during the 30 days of the screening window.
• 7. Presence of abnormal hematological and biochemical parameters, including:
• 1. Neutrophil count \< 1500 cells/mm3.
• 2. Hemoglobin \< 9 g/dL.
• 3. Platelet count less than or equal to 150,000 cells/mm3.
• 4. Creatinine greater than or equal to 1.2 times the upper limit of normal (ULN).
• 5. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater than or equal to 1.5 times ULN.
• 6. Prothrombin time-international normalized ratio (PT-INR) \> 1.0 ULN
• 7. Serum bilirubin level \> 1.0 times ULN.
• 8. Individuals on chronic anticoagulation medications.
• 9. Stool sample positive for GI pathogens potentially causing disease (as assessed by FilmArray GI panel for 22 viral, bacterial, and parasitic organisms that can cause infectious diarrhea \[GI pathogen panel\]). The principal investigator will consult with an infectious disease specialist to review results and decide whether treatment is warranted.
• 10. Presence of cytomegalovirus (CMV) infection as defined by positive immunohistochemical staining on tissue intestine biopsy.
• 11. History of low-grade or high-grade colonic mucosal dysplasia.
• 12. History of bowel surgery other than perianal (e.g., fistulotomy, seton placement, or abscess drainage) within 6 months prior to beginning the CDAI screening diary or drawing screening blood samples.
• 13. Presence of surgical changes to gut anatomy that preclude administration of clinical activity indices; this includes but is not limited to ileostomy, colostomy, or subtotal colectomy with ileorectal anastomosis.
• 14. Known or suspected short bowel syndrome.
• 15. Requirement of parenteral, total parenteral, elemental oral, or nasogastric nutrition.
• 16. History or current evidence of cancer, other than non-melanomatous cancer of the skin, or participants that have undergone excision of basal cell carcinoma, squamous cell carcinoma of the skin. All patients receiving ustekinumab will be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment will be followed closely.
• 17. Unwillingness or inability to comply with study requirements.
• 18. Presence of only small bowel CD that is inaccessible by standard colonoscopy for harvest of research biopsies. Individuals with only upper gastrointestinal CD or only perianal fistulizing CD are also excluded for this reason.
• 19. Refusal to abstain from using COX-2 inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) throughout the study agent administration period.
• 20. Has uncontrolled diabetes
• 21. Is taking anti-seizure medication, such as valproic acid or its derivative (i.e., Depakote)
• 22. Presence of any condition that, in the opinion of the principal investigator, contraindicates participation in this study.
• 23. Has participated in another investigational trial within 8 weeks (or 5 half-lives of any investigational study agent), whichever is greater, prior to the pre-trial (screening) visit. The window will be derived from the last date of treatment on the previous trial.