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

Crohn's Disease Clinical Trial

Official title: An Open-Label, Proof of Concept Study of Vorinostat for the Treatment of Moderate-to-Severe Crohn's Disease and Maintenance Therapy With Ustekinumab

Status Recruiting

Clinical Trial 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.

Clinical Trial Description

Crohn s Disease (CD), a major sub-type of inflammatory bowel disease (IBD), is a chronic, life-long condition characterized by relapsing inflammation of the gastrointestinal (GI) tract. Despite recent advances in IBD therapeutics, a significant number of patients with CD continue to have significant symptoms.

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 regulates 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 pro-inflammatory 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 graft-vs-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 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 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 Crohn s disease most patients have alternating periods of relapse and remission with half of patients requiring surgery within 10 years of diagnosis on present maintenance therapy. Therefore, the approach to treatment must also evolve from induction control of symptoms to preventing progression of the disease with maintenance therapy. Thus, treatments that safely maintain long-term remission are essential. Treatment guidelines for Crohn s disease 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, and vedolizumab. Although TNF antagonists have significantly advanced the care of Crohn s disease, 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 IFN-g and IL-17. 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, and moderately to severely active CD.

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 Crohn s disease dosing had been established in the UNITI trial studies (up to 44 week treatment) in patients who have failed TNF antagonists or other conventional therapies. These studies demonstrated significant response rates and induction of remission rates with a positive safety profile. Studies addressing long term maintenance efficacy of ustekinumab in patients that are in remission have not been performed.

In the present protocol (Phase IV), Crohn s disease 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 followed by administration of maintenance doses of 90 mg subcutaneously (SC) every 8 weeks with participants followed over a 2-year period. ;

Related Conditions & MeSH terms

• Crohn Disease
• Crohn's Disease

• NCT number: NCT03167437
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Ivan J Fuss, M.D.
• Phone: (301) 761-7091
• Email: ifuss@niaid.nih.gov
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 30, 2017
• Completion date: June 30, 2026