Low Dose IL-2 for Ulcerative Colitis
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Study type: Interventional
Phase: Phase 1

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 ulcerative colitis.
    

Detailed description: 
      Interleukin-2 (IL-2) is a T cell growth factor. IL-2 is currently licensed for the treatment
      of metastatic renal cell carcinoma and metastatic melanoma, where it promotes the expansion
      of anti-cancer cytotoxic T cells and natural killer (NK) cells. However at low doses
      (100-times lower than those used in cancer therapy), IL-2 promotes the selective expansion of
      regulatory T cells (Tregs): an immune modulating subset of CD4+ lymphocytes.

      A recent phase 1 clinical trial from our collaborators at the Dana Farber Cancer Institute
      showed that low-dose IL-2 selectively expands Tregs in patients with treatment-resistant
      Graft vs. Host Disease (GvHD), and that low-dose IL-2 is safe in this condition. A detailed
      immunological analysis of samples from this study showed that low-dose IL-2 treatment was
      associated with increased Treg proliferation, increased de novo thymic generation of Tregs,
      and a resolution of defects in intracellular signalling and apoptosis seen in Tregs in
      chronic GvHD. A recent phase 1 study from another group showed that low-dose IL-2 is safe in
      the treatment of HCV-associated vasculitis. Low-dose IL-2 has also been shown to be
      well-tolerated in subjects with HIV.

      Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Evidence from
      pre-clinical models of intestinal inflammation, and also from patients with monogenetic
      defects in Treg function, suggests that Tregs play a role in the prevention of inflammation
      in the intestine.

      The treatment (or intervention) in this study is a once-daily, subcutaneous injection of
      IL-2, for a total of 8 weeks. The first 2 doses of the study drug will be administered by
      research nurses at Boston Children's Hospital. Further doses will be self-administered, at
      home. Training will be provided for correct self-administration.

      This is a 3+3 dose escalation study of IL-2 in moderate-to-severe UC. This study design is
      powered to identify the MED of low-dose IL-2 in UC. Once the MED is identified, a further 10
      subjects will receive IL-2 at that dose. Recruitment of between 2 and 28 patients is planned.
      The maximum tolerated dose (MED) is the highest tolerated dose level at which a minimum of 6
      subjects have been evaluated, with fewer than 2 evaluable subjects in 6 experiencing a dose
      limiting toxicity (DLT); i.e. DLT in >1/6 evaluable subjects. In addition to the above at
      least 1 patient should meet the criteria for response or remission for it to be considered
      the MED.

      Dose levels are based on the experience of our collaborators in GvHD. In addition to
      determining the MED, this study will determine if low-dose IL-2 is safe and well-tolerated in
      patients with moderate-to-severe ulcerative colitis. A detailed immunological analysis of
      samples obtained from this study will determine if low-dose IL-2 expands Tregs in vivo, in
      patients with moderate-to-severe UC. Immunological changes will then be correlated with
      clinical response.

      The study will take place at Boston Children's Hospital. The study will involve 10 study
      visits. Most of the study visits involve blood tests. A flexible sigmoidoscopy or colonoscopy
      will be performed as part of the screening process. A flexible sigmoidoscopy will also be
      performed on completion of therapy, to determine clinical response.

      The first two subjects to receive the study drug will be admitted overnight following the
      first dose. Subsequent doses will be administered on an out-patient basis. All other subjects
      will receive IL-2 on an out-patient basis.

      Responders (with an acceptable side-effect profile) will be allowed to continue the study
      drug for at least 1 year. Compensation will be provided for participants.
    

Intervention name(s): Interleukin-2 (aldesleukin).
Intervention type(s): Drug
Intervention description(s): Description of intervention is covered in "Arm", above.
Other intervention name(s): Proleukin.
Intervention MeSH terms: Aldesleukin; Interleukin-2
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Ulcerative colitis; Inflammatory bowel disease; Interleukin 2; Interleukin-2; IL-2; Regulatory T Cells; Tregs; T-Lymphocytes, Regulatory