High-dose Cyclophosphamide for Severe Refractory Crohn Disease

Study Overview
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Brief Summary
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This research is being done to see if people with Crohn's disease who receive high-dose cyclophosphamide have an improvement of their disease, how long the benefit may last, and how safe cyclophosphamide is. This study is for patient with medically refractory disease that is not easily amenable to surgery. Cyclophosphamide is an FDA-approved chemotherapy medication that is also frequently used to treat autoimmune illness; use of cyclophosphamide for autoimmune disease is not approved by the FDA. An autoimmune illness is when the immune system mistakenly attacks self, targeting the cells, tissues, and organs of a person's own body. There are many different autoimmune diseases and they can each affect the body is different ways. Crohn's disease is an autoimmune disease that primarily affects the small and large intestines. High dose-cyclophosphamide has been successfully used to treat Crohn's, primarily as part of a conditioning regimen for autologous stem cell transplantation. However, this therapy is limited in Crohn's because of it's serious infectious risks. This current study involves using high-dose cyclophosphamide without need for stem cell transplantation. This appears to be a safer approach in other autoimmune illnesses that have been studied.

Official Title
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High-dose Cyclophosphamide for Severe Refractory Crohn Disease

Conditions
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Crohn's Disease, Crohn Disease

Intervention / Treatment
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* Drug: High-dose Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age, males and females will be eligible Moderate to severe Crohn's Disease (CD) with CDAI > 220, in addition to evidence of ulceration on ileocolonoscopy or active disease on small bowel imaging (in patients with an ostomy, CDAI criteria do not apply) Disease progression (primary or secondary non-responder, or reaction to) to at least one anti-tumor necrosis factor (TNF) agent (infliximab, adalimumab, certolizumab pegol), and additionally had disease progression despite one of the following immunosuppressant drugs: azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, natalizumab, vedolizumab Willingness to participate in a clinical trial Approval by Enrollment Panel, who will collectively decide on the appropriateness of possible study study participants Exclusion Criteria: Pregnant or nursing women Sexually active men and women who do not agree to use effective means of birth control during treatment period Evidence of primarily fibrostenosing disease without active inflammatory disease on disease staging Co-morbid conditions including cardiac disease with an ejection fraction of < 45%, chronic renal failure with serum creatinine > 2.0, liver disease with total bilirubin > 2.0, (excluding hyperbilirubinemia secondary to Gilbert's disease) or transaminitis > 3x upper limit of normal. History of serious allergic reaction to cyclophosphamide History of malignancy in the last 5 years (excluding non-melanomatous skin cancers) Patients who are pre-terminal Toxic megacolon Active infection White blood cell count < 3000 cells/ul, platelets < 100K / ul, hemoglobin < 10.0 g/dL Any use of thiopurines, methotrexate or anti-TNF agents in the previous four weeks prior to treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose Cyclophosphamide<br>High-dose Cyclophosphamide | Drug: High-dose Cyclophosphamide<br> <br> * Other names: Revimmune™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of safety of the High-Dose Cyclophosphamide (HDC) protocol | Tablulation of serious adverse events associate with the HDC protocol | 3 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HDC-Induced Steroid-free remission | To determine if HDC therapy can induce and maintain a steroid-free clinical remission (defined as CDAI<150) at 12 and 52 weeks. Applies to patients without an existing ostomy. | 3 Years | 
| HDC-Induced Mucosal Healing | To determine if HDC therapy can induce sustained mucosal healing defined as absence of ulcers on colonoscopy | 3 Years | 
| Improvement in patient reported quality of life | To determine if HDC can lead to improvement in inflammatory bowel disease questionnaire scores at weeks 12 and 52 | 3 years | 
| Molecular Mechanisms of High-dose Cyclophosphamide (HiCy) Therapy | To investigate the molecular mechanisms by which HiCy therapy works by analyzing the effects of HiCy on the levels of serum cytokines (using multiplex ELISA), and correlate the data with clinical activity and treatment response. | 3 Years |