Study of MLN0002 Following Multiple Intravenous Doses in Patients With Ulcerative Colitis

• To assess the safety and tolerability of a range of multiple IV doses of MLN0002 [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  Adverse events, vital signs, standard laboratory tests, 12-lead electrocardiograms (ECGs), progressive multifocal leukoencephalopathy (PML) checklist evaluations, lymphocyte subsets, assessment for human anti-human antibodies (HAHA) and physical examinations
• To define the multiple-dose pharmacokinetics (PK) of MLN0002 for a range of IV doses [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To characterize the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of MLN0002 over a range of multiple IV doses [ Time Frame: Days 1-4, 8, 15, 29, 43, 57, 71, 85-87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, 253 ] [ Designated as safety issue: No ]
  For patients participating in the Reduced Sampling Schedule, samples will not be taken on Days 2-4 or 86-89
• To describe the extent and duration of MLN0002 binding to α4β7 receptors on peripheral blood lymphocytes following a range of multiple IV doses [ Time Frame: Days 1-4, 8, 15, 29, 43, 57, 71, 85-87, 89, 92, 99, 113, 127, 141, 155, 169, 183, 197, 211, 225, 239, 253 ] [ Designated as safety issue: No ]
  For patients participating in the Reduced Sampling Schedule, samples will not be taken on Days 2-4 or 86-89

This is a phase 2, randomized, placebo-controlled, double-blind trial to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple intravenous (IV) doses of MLN0002 or placebo in patients with active ulcerative colitis (UC).

• Drug: vedolizumab (MLN0002)
  Patients will receive MLN0002 at a dose of 2 mg/kg, 6 mg/kg or 10 mg/kg administered intravenously on Days 1, 15, 29 and 85. Treatment will be followed by an observation period until day 253. Patients will either rollover into the phase 2, open-label, long-term safety study (C13004) or be followed off study with telephone contact at 6-month intervals for 2 years after the last administration of the study drug.
• Drug: Placebo
  Patients will receive a normal saline solution administered intravenously on Days 1, 15, 29 and 85. Treatment will be followed by an observation period until day 253. Patients will either rollover into the phase 2, open-label, long-term safety study (C13004) or be followed off study with telephone contact at 6-month intervals for 2 years after the last administration of the study drug.

• Experimental: MLN0002
  Intervention: Drug: vedolizumab (MLN0002)
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled in the study.

• Males or non-pregnant, non-lactating females voluntarily able to give informed consent
• All patients must agree to use 2 effective forms of contraception from screening to the end of the Observation Phase
• Negative surveillance colonoscopy within the last 6 months if indicated by standard clinical practice guidelines

• Confirmed and active ulcerative colitis (UC)

  • Partial Mayo Score 1 - 7
  • Disease involvement extending proximal to the rectum
• May be receiving a therapeutic dose of conventional therapies for UC as defined by the protocol

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study.

• Patients who require ulcerative colitis (UC) surgical intervention or for whom surgical intervention is anticipated during the study
• Patients who fail to meet laboratory values as specified in the protocol or have a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist during the screening period
• Low-grade dysplasia, high-grade dysplasia, dysplasia-associated lesion or mass, or colorectal cancer
• Treatment with cyclosporine, FK506 (tacrolimus) or infliximab within 60 days prior to study
• Patients receiving any of the following within 14-days prior to the study: antibiotics for treatment of irritable bowel syndrome, heparin or warfarin, narcotics, tube feeding, defined formula diets or parenteral alimentation
• Colostomy, fistulae or known fixed symptomatic stenosis of the intestine
• Immunologic or ischemic intestinal condition
• Toxic megacolon
• Chronic hepatitis B or C or human immunodeficiency virus (HIV) infection
• Any vaccinations within 30 days prior to study drug administration
• History of imaging abnormalities, multiple sclerosis (MS), brain tumor or neurodegenerative disease
• Significantly impaired liver or renal function
• Current or recent history of alcohol dependence
• Current use of illicit drugs
• Active or recent serious infections or serious underlying disease as specified in protocol
• Active psychiatric problems that might interfere with compliance to study
• Previous exposure to MLN0002
• Participated in an investigational study within 30 days prior to study drug administration or received treatment with an investigational monoclonal antibody within the last 6 months