Low Dose IL-2 for the Treatment of Crohn's Disease

Crohn Disease Clinical Trial

Official title:

Low Dose IL-2 for the Treatment of Crohn's Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04263831
• Other study ID #: IRB-P00032653
• Secondary ID: R01DK126448
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 11, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: April 2024
• Source: Boston Children's Hospital
• Contact: Jennifer J Mitri
• Phone: 617-525-7322
• Email: jjmitri[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety and maximum effective dose (MED) of Interleukin-2 in subjects with moderate-to-severe crohn's disease.

Description:

Despite recent advances in treatment, a significant proportion of patients with Crohn's disease have suboptimal responses to medical therapy, leaving an urgent need to identify new therapies. One promising new approach to trea t IBD is through the manipulation of regulatory T cells (Tregs). Tregs are an immune modulating subset of CD4+ lymphocytes that antagonize the activation and effector function of multiple immune cell types and promote tolerance to self-antigens. Adoptively transferred Tregs are effective in murine models of IBD. An alternative approach to disease management through Treg manipulation is to increase Treg numbers in vivo. Interleukin-2 (IL-2, Proleukin®) is a T cell growth factor. IL-2 is currently licensed for the treatment of metastatic renal cell carcinoma and metastatic melanoma. At low doses, IL-2 promotes the selective activation and expansion of Tregs in humans. Tregs constitutively express CD25, a component of the high-affinity IL-2R, while CD25 is only transiently expressed by activated conventional T effector cells. Low-dose (LD) IL-2 selectively expands Tregs in humans and is safe in chronic GvHD and other phase 1 and 2 clinical trials.

This is a phase 1b/2a clinical trial to assess the safety and the efficacy of LD SC IL-2 for the treatment of CD utilizing daily sc LD IL-2 for 8 weeks in CD patients to determine the maximum effective dose (MED) and safety profile, and to assess a signal of efficacy. We aim to determine in CD patients whether sc LD IL-2 modulates peripheral blood and lamina propria Tregs in vivo and correlates with clinical outcome. We will perform deep immunophenotyping in CD patients treated with LD IL-2 and comprehensively assess the effects of LD IL-2 on CD4+ Tregs and other immune cells in both peripheral and mucosal compartments, and correlate changes in immune phenotype with clinical outcome. Overall this trial is designed to determine the MED and safety profile of LD IL-2 in CD, to obtain a signal of efficacy, and to assess mechanistic underpinnings.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Age 18-80 years. Maximum age limit for subjects recruited at BCH will be 30 years.

2. A diagnosis of CD made by standard clinical, radiological, endoscopic and histological criteria.

a. A subset of patients with Ileostomies or colostomies will be permitted.

3. Adult subjects with moderate-to-severe CD (CDAI score 220-450)

a. a modified CDAI will be used to assess patients with ileostomies/colostomies. Number of liquid stools per day will be substituted for number of bag empties per day.

4. Evidence of endoscopic inflammation accessible via ileocolonoscopy or ileoscopy

1. Simple Endoscopic Score for CD (SES-CD) = 6 or = 4 for isolated ileal disease

2. patients with ileostomies will be assessed as patients with isolated ileal disease via SES-CD.

5. Failure to tolerate or failure to respond to at least one conventional therapy with the intention of inducing or maintaining remission (including but not limited to oral corticosteroids, oral 5-aminosalicylates, azathioprine and/or 6-mercaptopurine, TNF alpha antagonist, anti-integrins, ustekinumab). Corticosteroid dependency (inability to taper oral corticosteroids without a recurrence of disease activity) is also included in this category.

6. Stable doses of concomitant medications, as defined in Section 5

7. A negative pregnancy test within 2 weeks prior to anticipated commencement of the study drug, in female subjects of child-bearing age. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.

8. The ability of adult participants who are able to make their own healthcare decisions to provide informed consent or the ability of a legal guardian to provide consent if the participant has mild intellectual disability and cannot consent for him or herself. In the event that a legal guardian provides consent, the study participant must be able to demonstrate an understanding of the study at his or her comprehension level and must have the ability to give verbal assent. The legal guardian must be able to provide documentation of court appointed guardianship.

Exclusion Criteria:

1. A diagnosis of ulcerative colitis or indeterminate colitis.

2. Requirement for immediate surgical, endoscopic or radiological intervention for perforation, sepsis, or intra-abdominal or perianal abscess.

3. History of colorectal cancer or dysplasia.

4. Positive stool test for Clostridium difficile via GDH/EIA two step testing method. PCR only testing will not be accepted. If patient is GDH positive and EIA negative, enrollment will be permitted.

5. Current medically significant infection.

6. Significant laboratory abnormalities;

1. Hb < 7.0 g/dL, WBC < 2.5 x 103/mm3, Plt < 50 x 103/mm3.

2. Creatinine = 2x institutional ULN.

3. Total bilirubin > 2.0 mg/dL, ALT > 2x institutional ULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed.

4. Abnormal thyroid function tests.

7. Positive serology for HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV).

8. Positive screening test for tuberculosis (TB).

9. Treatment with any biologic medication within 4 weeks of first study drug dose (baseline) (see below section on washouts)

10. Received another IND within 5 half-lives of that agent baseline.

11. Malignancy within the last 5 years, excluding non-melanoma skin cancer.

12. Allergy to any component of the study drug.

13. Pregnant or lactating women.

14. Inability to comply with the study protocol or inability of the subject or the subject's legal guardian to provide informed consent.

15. Prior exposure to IL-2.

16. Uncontrolled cardiac angina or symptomatic congestive cardiac failure (NYHA Class III or IV).

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Drug:
• Interleukin-2 (aldesleukin).
Description of intervention is covered in "Arm", above.

Locations

Country	Name	City	State
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Mount Sinai	New York	New York

Sponsors (3)

Lead Sponsor	Collaborator
Boston Children's Hospital	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (5)

Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, Armand P, Cutler C, Ho VT, Treister NS, Bienfang DC, Prasad S, Tzachanis D, Joyce RM, Avigan DE, Antin JH, Ritz J, Soiffer RJ. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011 Dec 1;365(22):2055-66. doi: 10.1056/NEJMoa1108188. — View Citation

Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y, Murase K, Cutler C, Ho VT, Alyea EP, Armand P, Blazar BR, Antin JH, Soiffer RJ, Ritz J. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013 Apr 3;5(179):179ra43. doi: 10.1126/scitranslmed.3005265. — View Citation

Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-76. doi: 10.1056/NEJMoa050516. Erratum In: N Engl J Med. 2006 May 18;354(20):2200. — View Citation

Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011 Dec 1;365(22):2067-77. doi: 10.1056/NEJMoa1105143. Erratum In: N Engl J Med. 2014 Feb 20;370(8):786. — View Citation

Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987 Dec 24;317(26):1625-9. doi: 10.1056/NEJM198712243172603. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subjects with serious and non-serious adverse events.	Enumeration of the serious and non-serious adverse events seen in the study. Enumeration of any dose limiting toxicity seen in the study.	8 weeks
Primary	Maximum effective dose	Identification of the dose cohort at which the MED occurs.	8 weeks
Secondary	Clinical Response	This is a composite endpoint. CDAI scores will be used to assess clinical activity. Moderate to severe CD, denoted by a CDAI score 220-450, is an inclusion criterion.; Definition of Clinical Response. CDAI-100 response (=100-point decrease in the CDAI score) at week 8 Composite Outcome: Clinical response and at least a 50% decrease in fecal calprotectin or CRP	8 weeks
Secondary	Immunological Response	Enumeration of the number of subjects with a change in the absolute number of immune cells in the peripheral blood and lamina propria of subjects during the 8 weeks of treatment, and during the 4 weeks following cessation of treatment.	12 weeks