Background:

Crohn s disease (CD) is an inflammatory bowel disease. It causes inflammation of the gut. Symptoms may include diarrhea, abdominal pain, fatigue, weight loss and malnutrition. CD has no cure, but symptoms can sometimes be controlled with medicine. Researchers want to see if it is safe to treat CD with the medicine vorinostat. It is thought that vorinostat may reduce the inflammation process of CD. This may then help to relieve symptoms of CD. Participants who respond to Vorinostat will be invited to an extension phase of treatment with Vorinostat and possibly a maintenance treatment using Ustekinumab.

Objectives:

To see if vorinostat is safe for people with moderate-to-severe CD. To see if it is safe for people with moderate-to-sever CD to receive maintenance therapy using Ustekinumab after successful treatment of Vorinostat.

Eligibility:

Adults 18-65 with moderate-to-severe CD that medicine is not controlling.

Design:

Phase I is screening. It may last 120 days. Participants will have:

Physical exam

Medical history

Tests of blood, urine, and stool samples

Heart test

Questionnaires

Tuberculosis skin test

They may have a colonoscopy and lymphapheresis collection. These will be explained in a separate consent.

They will keep a diary of symptoms.

Phase II is treatment using Vorinostat. It will take 12-13 weeks. Participants will take the study drug by mouth twice daily for 12 weeks. They will get a weekly phone call to talk about how the drug makes them feel. They will have blood taken regularly. Every 4 weeks, they will have a check-up that will repeat some screening tests.

Phase III extension treatment of Vorinostat for an additional 6 months for those who respond to vorinostat and it is safe for them to continue treatment. Participants will continue to receive weekly calls to talk about how the drug makes them feel. They will have blood taken regularly. Every 3 months, they will have a check-up that will repeat some screening tests.

Phase IV: is maintenance therapy for 2 years with Ustekinumab. Participants will receive a one time loading dose of ustekinumab, and then will receive the approved maintenance dose once every 8 weeks, at which time they will return to the NIH Clinical Center for evaluation. The participant will get a phone call 3 days after each dose and again 2 weeks later to see how the drug makes them feel. After two years of receiving treatment with ustekinumab the participant will have an end of study visit, where some of the screening tests, including a colonoscopy, will be repeated.

Inflammatory bowel disease (IBD), comprised of Crohn s disease and Ulcerative colitis, are chronic, life-long conditions characterized by relapsing inflammation of the gastrointestinal (GI) tract. Despite recent advances in IBD therapeutics, a significant number of patients with IBD continue to have significant symptoms.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency, due to a mutation in one of the 5 genes encoding the phagocyte NADPH oxidase, and inability to generate reactive oxygen species (ROS) and in turn leads to dysregulated inflammation as ROS production is required for normal innate immune function but also plays a role in regulating inflammation Almost 50% of individuals with CGD develop intestinal inflammation, ranging from mild dysmotility to severe IBD.

In prior studies, it has been demonstrated that epigenetic modifications of the genome are associated with and may contribute to the pathogenesis of various disease entities. One type of epigenetic modification involves acetylation and deacetylation of histones, mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs). Acetylation and deacetylation of histones regulate the affinity of histones for DNA, thus modulating the accessibility of transcription factors to gene promoters and enhancer sites. Of interest in this context is evidence that epigenetic modifications brought about by HDAC inhibitors (HDACi), i.e., agents that cause hyperacetylation of histones, can limit the course of gastrointestinal inflammation. One naturally occurring HDAC inhibitor, the bacterial product butyrate, has been shown to have effects on gene transcription that regulate potentially deleterious pro-inflammatory responses to microbiota in the gut environment. It has been shown that treatment of dendritic cells and macrophages with butyrate leads to down-regulation of lipopolysaccharide induced proinflammatory mediators such as nitric oxide, IL-6 and IL-12. In addition, butyrate has been shown to enhance the differentiation of intestinal Foxp3-positive T cells (T regulatory T cell (Treg) development that then modulates GI inflammation and contributes to mucosal homeostasis.

Along the same lines, another HDAC inhibitor, vorinostat, has been shown to ameliorate graftvs-host disease (GVHD) affecting the GI tract in patients undergoing allogeneic bone marrow transplantation. This anti-inflammatory effect was also attributable to increased Treg activity, suggesting that vorinostat, like butyrate, decreases inflammation by enhancing the activity of cells with the capacity to down-regulate immune responses. The effect of vorinostat on Treg cell expansion in this study was particularly notable because it suggested that Treg cell numbers can be increased by agents that have an intrinsic effect on the transcription of key Treg cell transcription factors. On this basis, treatment of patients with inflammatory and autoimmune diseases by influencing Treg cell numbers may be a more effective than alternative existing methods of inducing Treg cell expansion such as administration of purified Tregs.

In this protocol we propose a proof-of-concept clinical trial to study the safety and efficacy of vorinostat (100 mg PO BID for 36 weeks) in treating 20 individuals with moderate-to-severe CD, UC, or CGD colitis who have not been controlled by standard maintenance therapy. This will be accomplished in Phase II (12 weeks of treatment) and Phase III (36 weeks of treatment). We will assess the effectiveness of vorinostat by evaluating changes in symptom scores, endoscopic/histologic findings, and immunologic/laboratory parameters. The participant will return to the NIH Clinical Center (CC) after starting treatment on week 4, week 8, and week 24 for assessment of safety labs and testing of clinical response. On Week 12 and week 36 participants will return to the NIH CC for assessment of safety labs and testing of clinical and immunologic response.

In IBD, 10-15 % of patients require surgery within 10 years of diagnosis with about 20-30% of patients ultimately requiring surgery due to failure of medical management . Therefore, the approach to treatment must also evolve from induction control of symptoms to preventing progression of the disease with maintenance therapy. Thus, the current paradigm has moved beyond treatment of just clinical symptoms to address inflammatory activity early on in the disease process and effectively down-modulate these pathways before irreversible intestinal damage and disability occur. The treatment goal is for patients to achieve a clinical response of symptoms but also subsequent development of clinical remission with the long term goal of optimizing treatment to have patients achieve a sustained clinical remission with endoscopic mucosal healing (STRIDE Committee).

Thus, treatments that safely maintain long-term remission are essential. Treatment guidelines for CD and UC recommend maintenance therapy after remission is achieved, particularly for moderate-to-high risk patients. Potential benefits include reduction in hospitalization and surgery and improved quality of life. Long-term efficacy has been studied with azathioprine/mercaptopurine, methotrexate tumor necrosis factor (TNF) antagonists, vedolizumab. Although TNF antagonists have significantly advanced the care of CD and UC, their efficacy is limited and the development of anti-drug antibodies is associated with loss of response in maintenance therapy. In addition, potential significant side effects of maintenance treatments include bone marrow suppression, malignancy, and serious infections. Therefore, a need exists for safer agents that have demonstrated improved long-term maintenance efficacy.

The gut inflammation complicating Crohn s disease has been characterized as a T helper type 1 (Th1)/T helper type 17 (Th17) inflammatory response, with excess IL-12, IL-23 cytokine production leading to the generation of excessive IFNgamma and IL-17. In comparison, the intestinal inflammation observed in UC can be characterized as a mixed T helper 2/Th17/Th1 response with predominately excess IL-13 and IL-17 excess but IFN-gamma can also be observed albeit decreased in levels opposite to CD patients.

Intestinal inflammation observed in CGD colitis is typically chronic, relapsing, and difficult to manage. CGD colitis has some degree of association with CD and UC, as it is characterized by an increased secretion of inflammatory cytokines such as IFNgamma, IL-17 and IL-6. Glucocorticoids can be effective but often require addition of steroid-sparing agents such as purine antimetabolites, 5-aminosalicylates or other immunomodulators such as methotrexate cyclosporine, (Rosh et al. 1995), anakinra (Hahn et al. 2015), vedolizumab, and anti TNF alpha agents all with limited success. Most important, although decreased inflammatory responses can be observed with anti-TNF alpha therapy it is not without risk in these patients as TNFblockade therapy has led to life threatening infections.

Ustekinumab, a monoclonal antibody to the p40 subunit of IL-12 and IL-23, is currently FDA approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderately to severely active CD and ulcerative colitis

Prior clinical trials have demonstrated long-term efficacy and safety profile of ustekinumab in psoriasis. Similarly, the long-term efficacy and safety of ustekinumab in CD dosing had been established in the UNITI trial studies (up to 44 week treatment) in patients who have failed TNF antagonists or other conventional therapy. These studies demonstrated significant response rates and induction of remission rates with a positive safety profile. In a phase 3 trial of IL-12 p40 monoclonal antibody in patients with moderate-to-severe UC, ustekinumab was found to be effective than placebo in achieving induction of clinical remission at 8 weeks. This effect was also observed in patients with or without previous treatment failure with other biologic agents. Studies addressing long term maintenance efficacy of ustekinumab in patients that are in remission are limited.

In a prior retrospective review of CGD patients that received ustekinumab for CGD colitis at the NIH, nine patients were summarized. Six patients were reported with a clinical response and four patients achieved clinical remission. No long-term maintenance efficacy studies have been performed.

In the present protocol (Phase IV), CD, UC, or CGD colitis patients that have achieved either a defined clinical response or are in remission with vorinostat will then be enrolled to receive long term maintenance treatment with ustekinumab. Participants will receive a weight-based IV loading dose of ustekinumab (see section 5.5) followed by administration of maintenance doses of 90 mg subcutaneously (SC) every 8 weeks with participants followed over a 2-year period.

• INCLUSION CRITERIA:

Individuals with moderate-to-severe CD, UC, and CGD colitis who are not controlled by and refractory to standard therapy will be eligible for inclusion into this study if they meet the following criteria:

1. Are 18 to 65 years of age, inclusive, at enrollment date.

2. Have a diagnosis of CD, UC, or CGD colitis that has been endoscopically or radiographically confirmed. A colonoscopy will be required at baseline to document mucosal disease activity. SES-CD for CD and CGD colitis will be obtained with minimum score of 7 and MES for UC patients will be obtained with minimum score of 2.

3. Have active CD symptoms as defined by a CDAI score between 220 and 350, UC symptoms defined by a Mayo score of 6 to 10 (moderate) or 10 to 12 (severe), or CGD colitis symptoms defined as an HBI score of 8-16 (moderate) or > 16 (severe), 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 and UC symptoms (as noted above) 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 antagonists or Anti-integrin antibodies or JAK inhibitors or IL-12p19 (IL-23) antagonists). No specific induction therapy or long-term treatment for CGD colitis patients has been defined; therefore all symptomatic patients will be evaluated for inclusion on individual basis.

   a. Corticosteroids

   i. Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone >=30 mg PO once daily (QD) for 2 weeks or intravenously (IV) for 1 week OR

   ii. One failed attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg PO QD or to taper to below a dose of 9 mg of budesonide

   OR

   iii. History of intolerance of corticosteroids at the discretion of the principal investigator (PI) (including but not limited to Cushing s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, or infection)

   b. Immunomodulators

   i. Signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of oral azathioprine (AZA) (>= 2.5 mg/kg/Day) or 6-MP (>= 1.5 mg/kg/Day) OR

   ii. Signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of MTX (>= 25 mg/week) OR

   iii. History of intolerance of at least one immunomodulator (including but not limited to nausea/vomiting leading to discontinuation, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, thiopurine methyltransferase genetic mutation, or serious infection)

   c. TNF-alpha antagonists with signs and symptoms of persistently active disease despite a history of receiving infliximab, adalimumab, or certolizumab at a dose approved for the treatment of CD or UC and:

   i. Patient had an inadequate response after completing the full induction regimen, per approved product labeling

   ii. Responded initially but then lost response with continued therapy

   iii. Patient had a significant adverse event response which precluded further use including but not exclusion of infusion reaction, serum sickness and/or lupus-like rash.

   d. Anti-integrin antibodies:

   with signs and symptoms of persistently active disease despite a history of receiving an anti-integrin antibody agent (natalizumab or vedolizumab) at a dose approved for the treatment of CD or UC and:

   i. Patient had an inadequate response after completing the full induction regimen, per approved product labeling

   ii. Responded initially but then lost response with continued therapy

   iii. Patient had a significant adverse event response which precluded further use including but not exclusion of infusion reaction, serum sickness and/or lupus-like reaction.

   e. JAK inhibitor:

   with signs and symptoms of persistently active disease despite a history of receiving a JAK inhibitor (tofacitinib and ruxolitinib) at a dose approved for the treatment of CD or UC and:

   i. Patient had an inadequate response after completing the full induction regimen, per approved product labeling

   ii. Responded initially but then lost response with continued therapy

   iii. Patient had a significant adverse event response which precluded further use including but not exclusion of infusion reaction, serum sickness and/or lupus-like reaction.

   f. Anti-IL-12 p19 (IL-23) antibodies:

   with signs and symptoms of persistently active disease despite a history of receiving an anti-IL-12p19 (IL-23) antibody agent (Skyrizi and Tremfya) at a dose approved for the treatment of CD or UC and:

   i. Patient had an inadequate response after completing the full induction regimen, per approved product labeling

   ii. Responded initially but then lost response with continued therapy

   iii. Patient had a significant adverse event response which precluded further use including but not exclusion of infusion reaction, serum sickness and/or lupus-like reaction.

5. At the discretion of the PI, concomitant medications will be permitted if the following conditions are met prior to baseline assessment (Day-1):

   a. 5-aminosalicylic acid (ASA)-based compounds are permissible if:

   i. Oral 5-ASA-based compounds must be at a stable dose for at least 3 weeks prior to baseline or

   ii. Recently discontinued oral 5-ASA-based compounds must have been discontinued at least 3 weeks prior to baseline or

   iii. Rectal 5-ASA-based compounds are not permissible during the study and must have been discontinued at least 3 weeks prior to baseline.

   b. Corticosteroids (e.g., prednisone, budesonide) are permissible if:

   i. Oral corticosteroids must be at a prednisone-equivalent dose of <= 40 mg/day, or 9 mg/day of budesonide, and have been at a stable dose for at least 3 weeks prior to baseline or

   ii. Discontinuation of oral corticosteroids must have been completed at least

3 weeks prior to baseline or

iii. Parenteral (subcutaneous, intramuscular, or IV) or rectal corticosteroids are not permitted during the study and must not have been used within a 3- week period prior to baseline

c. CD, UC, or CGD colitis-specific antibiotics are permissible if using an antibiotic for treatment of CD,UC, or CGD colitis (i.e., metronidazole, ciprofloxacin, rifaximin, ampicillin, sulfonamide and tetracycline)

i. Participants must have been using the antibiotic for at least 3 weeks before baseline at a stable dose or

ii. If not currently using a CD, UC, or CGD colitis-specific antibiotic, the stop date must have been at least 3 weeks prior to baseline.

d. Immunomodulators are permissible if:

i. Participants receiving chronic (i.e., >= 12 weeks) treatment with AZA, 6- MP, or MTX prior to baseline must be on a stable dose for at least 6-8 weeks prior to baseline and must continue on this same dose during the study. OR

ii. Participants who have discontinued therapy with AZA, 6-MP, or MTX must have stopped the medication at least 4 weeks prior to baseline. OR

iii. Participants must not have received therapy with other known immunomodulators (e.g. cyclosporine, tacrolimus, sirolimus, pentoxifylline, or mycophenolate mofetil) or experimental agents (e.g. granulocyte- or macrophage colony stimulating factor) for at least 8 weeks or 5 half-lives of agent from baseline, whichever is longer.

e. The use of Anti-TNF, Anti-integrin, JAK inhibitors, Anti-IL-12p19 (IL-23) therapy or other biological therapy listed below will not be permitted and the following washout period will be required in order for participant to be eligible:

i. Three months washout prior to baseline for certolizumab or natalizumab.

ii. Two months washout prior to baseline for adalimumab, infliximab, and vedolizumab, tofacitinib, ruxolitinib, Skyrizi and Tremfya.

iii. 8-week washout prior to baseline for cyclosporine, pimecrolimus, tacrolimus, and any other systemic immunosuppressant.

6. Participants must have a primary medical care provider.

7. 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.

8. 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.

   EXCLUSION CRITERIA:

   Individuals who meet ANY of the following criteria will be excluded from participation in this

   study:

   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 cannot have received tuberculosis vaccine within 12 months prior to start of study and cannot 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 last 30-days of the screening window.

   7. Presence of abnormal hematological and biochemical parameters, including:

      • Neutrophil count < 1500 cells/mm3
      • Hemoglobin < 9 g/dL
      • Platelet count <= 150,000 cells/mm3
      • Creatinine >= 1.2 times the upper limit of normal (ULN)
      • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >= 1.5 times

      ULN

      • Prothrombin time-international normalized ratio (PT-INR) > 1.0 ULN
      • 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, Mayo scoring, or Harvey Bradshaw index 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 disease that is inaccessible by standard colonoscopy for harvest of research biopsies. Individuals with only upper gastrointestinal disease or only perianal fistulizing disease 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.