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

• Status: Recruiting
• Trial end date: 2022-06-30
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Treatments: Ustekinumab; Vorinostat

Criteria

• INCLUSION 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)

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 greater than or equal to 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) (greater than or equal to 2.5 mg/kg/Day) or 6-MP (greater than or equal to 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 (greater than or equal to 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 sign 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 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 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 less than or equal to 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-specific antibiotics are permissible if using an antibiotic for treatment of CD ( a CD-specific antibiotic 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-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., greater than or equal to 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 and Anti-integrin 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.

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

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.

EXCLUSION CRITERIA:

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.