A Dose-Escalation Study of MDX-1100 in Patients With Active Ulcerative Colitis

Overview

This is a Phase I dose-escalation study of MDX-1100. patients with ulcerative colitis will be enrolled into one of four dose cohorts, to receive of MDX-1100 at 0.3, 1.0, 3.0 or 10mg/kg. Three to six patients will be enrolled at each dose level, starting at the lowest dose level, for a maximum of 24 patients to be enrolled into the study. The study is designed to establish the safety and tolerability of single doses of MDX-1100 administered in dose-escalating cohorts to patients with ulcerative colitis. Other study objectives include characterizing a pharmacokinetic profile and pharmacodynamic effects of MDX-1100 and determination of immunogenic response to MDX-1100.

The primary objectives of this study is to establish the safety and tolerability of single doses of MDX-1100 administered in dose-escalating cohorts to patients with active ulcerative colitis (UC). The secondary objectives include: 1. to characterize the pharmacokinetic profile of MDX-1100, 2. to determine the pharmacodynamic effects of MDX-1100 on CXCL10-related surrogate markers, 3. to obtain preliminary evidence as assessed by the Ulcerative Colitis Disease Activity Index (DAI), 4. to determine the immunogenic response to MDX-1100, and 5. determine the safety and efficacy of repeat doses in patients who respond to a single dose of MDX-1100. This is a Phase I, multicenter, dose-escalation study of MDX-1100 (anti-CXCL10 human monoclonal antibody) in patients with UC, as defined by standard clinical, endoscopic and histological criteria and a DAI greater than or equal to 4 and less than or equal to 9. Three to six patients will be entered into each of 4 cohorts (0.3, 1.0, 3.0 or 10mg/kg). Starting with the lowest dose cohort (0.3mg/kg), patients will be administered a single dose of MDX-1100 at Day 1 and will be followed until 70 days from the last dose. Dose escalation may proceed when the third patient in the cohort has reached Day 29 and if no dose-limiting toxicities (DLTs) have occurred. Dose escalation may proceed when the sixth patient reaches Day 29 and \<2 DLTs have occurred in the cohort. Dose escalation will continue until the last cohort is enrolled or the maximum tolerated dose (MTD) is defined. Patients who respond to the initial dose, as defined by a decrease in the UC disease activity index (UCDAI) by greater than or equal to 3 points at Day 29 compared to baseline, will be offered the option of receiving up to 3 additional doses of MDX-1100 at their originally assigned dose level. Re-dosing will be permitted at the time of disease flare which is defined as a worsening of the modified UCDAI of greater than or equal to 2 compared to the prior nadir. In order to obtain PK data, the first re-dose may not be administered until Day 43 and all subsequent doses may be great than or equal to 28 days apart. A response in the repeat dosing phase will be defined as a decrease in the mUCDAI of greater than or equal to 2 as compared to the previous baseline mUCDAI. For the second infusion, the comparison will use the mUCDAI calculated at Day 29 or subsequent nadir. The study will terminate approximately 70 days after the last patient has received the last dose of MDX-1100. It is anticipated that the maximum total time on study for any patient will be less than 1 year.