A Phase I Study of Low Dose Subcutaneous Interleukin-2 (IL-2) For The Treatment of Ulcerative Colitis.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 26
- 试验地点
- 2
- 主要终点
- Number of Subjects With Serious and Non-serious Adverse Events.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-70 years.
- •A diagnosis of UC made by standard clinical, radiological, endoscopic and histological criteria.
- •Moderate to severe UC with a Mayo score of 6-
- •Failure to tolerate or failure to respond to at least one conventional therapy with the intention of inducing or maintaining remission (examples include oral corticosteroids, oral 5-aminosalicylates, azathioprine and/or 6-mercaptopurine, or a tumor necrosis factor (TNF) antagonist). Corticosteroid dependency (inability to taper oral corticosteroids without a recurrence of disease activity) is also included in this category.
- •Stable doses of concomitant medications.
- •A negative pregnancy test in the 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.
- •Ability to provide informed consent.
排除标准
- •A diagnosis of Crohn's disease or Inflammatory Bowel Disease - Unspecified (IBD-U, a diagnostic classification formerly termed "indeterminate colitis").
- •Requirement for immediate surgical, endoscopic or radiological intervention for toxic megacolon, massive hemorrhage, perforation, sepsis, or intra-abdominal or perianal abscess.
- •Ileostomy, proctocolectomy or subtotal colectomy with ileorectal anastomosis.
- •History of colorectal cancer or dysplasia.
- •Positive stool test for Clostridium difficile.
- •Current medically significant infection.
- •Significant laboratory abnormalities, including;
- •Hb < 8.0 g/dL, WBC < 2.5 x 103/mm3, Plt < 100 x 103/mm
- •Creatinine ≥ 1.5x institutional upper limit of normal (ULN).
- •Total bilirubin > 2.0 mg/dL, ALT > 2x institutional ULN, GGT > 2x institutional ULN. Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed.
- •Abnormal thyroid function tests.
- •Positive serology for HIV, hepatitis B virus (HBV) or HCV.
- •Positive screening test for tuberculosis (TB).
- •First dose of an anti-TNF medication within 4 weeks of anticipated study commencement, or a subsequent dose within 2 weeks of commencement; or ciclosporin or tacrolimus within 2 weeks of anticipated study commencement.
- •Received another investigational new drug (IND) within 5 half-lives of that agent before the planned commencement of SC IL-
- •Malignancy within the last 5 years.
- •Allergy to any component of the study drug.
- •Pregnant or lactating women.
- •Inability to comply with the study protocol or inability to give informed consent.
- •Prior exposure to IL-
- •Uncontrolled cardiac angina or symptomatic congestive cardiac failure (NYHA Class III or IV).
研究组 & 干预措施
Interleukin-2
Study drug: Interleukin-2 (aldesleukin, Proleukin, IL-2).
Each subject will receive an 8-week course of once-daily, subcutaneously administered IL-2. There will be three dose cohorts. Each subject will be recruited into a single dose cohort and receive a single dose level of IL-2 throughout the study.
The dose levels will be as follows:
- Cohort 1: 0.3x10^6 IU/m^2/day.
- Cohort 2: 1.0x10^6 IU/m^2/day.
- Cohort 3: 1.5x10^6 IU/m^2/day.
Up to 6 subjects will be recruited to each dose cohort.
Once the maximum effective dose has been identified, a further 10 subjects will receive IL-2 at the maximum effective dose.
干预措施: Interleukin-2 (aldesleukin). (Drug)
结局指标
主要结局
Number of Subjects With Serious and Non-serious Adverse Events.
时间窗: 8 weeks
Enumeration of the serious and non-serious adverse events seen in the study. Enumeration of any dose limiting toxicity seen in the study.
次要结局
- Number of Participants With Clinical Response(8 weeks.)
- Number of Participants With Clinical Remission(8 Weeks)
研究者
Scott B. Snapper, MD PHD
Associate Professor of Medicine
Boston Children's Hospital