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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Ulcerative Colitis	Drug: MDX-1100 (anti-CXCL10 human monoclonal antibody)	Phase 1

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	24 participants
Allocation:	Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I, Multicenter, Dose-escalation Study of MDX-1100 (Anti-CXCL10 Human Monoclonal Antibody) in Patients With Active Ulcerative Colitis
Study Start Date :	January 2006
Actual Primary Completion Date :	January 2008
Actual Study Completion Date :	January 2008

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1; patients will receive active MDX-1100	Drug: MDX-1100 (anti-CXCL10 human monoclonal antibody); Patients will receive a single dose of MDX-1100 at 0.3, 1.0, 3.0 or 10 mg/kg as a 60 minute intravenous infusion. Patients who respond to treatment may receive up to an additional 3 doses of MDX-1100.

Outcome Measures

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Primary Outcome Measures :

1. incidence and severity of treatment-emergent adverse events [ Time Frame: events will be followed to resolution ]

Secondary Outcome Measures :

1. vital sign measurements [ Time Frame: study duration - each visit ]
2. clinical laboratory tests [ Time Frame: study duration - each visit ]
3. immunogenicity assessment [ Time Frame: dosing and follow up phases ]
4. physical examinations [ Time Frame: study duration - each visit ]
5. Electrocardiograph [ Time Frame: periodically through study duration ]
6. pharmacokinetic sampling [ Time Frame: during dosing phase ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• signed informed consent and HIPAA
• must be 18 years or older
• patients with active ulcerative colitis with a UCDAI greater than or equal to 4 and less than or equal to 9.
• certain medications initiated at specific schedules prior to study drug administration may be enrolled.
• must meet screening laboratory values
• women of childbearing potential must be using effective contraception for at least 1 month prior to study entry and agree to continue contraception for the duration of their participation in the study, and
• Sexually active male patients must use a barrier method of contraception during the course of the study.

Exclusion Criteria:

• History of colectomy, partial colectomy, current ostomy, or pouchitis
• Presence of Cushing's Syndrome
• Toxic megacolon or fulminant disease likely to require colectomy
• Prior treatment with any monoclonal antibody or immunoglobulin-based fusion proteins 8 weeks or less prior to treatment with MDX-1100
• Any experimental treatment 4 weeks or less prior to treatment with MDX-1100
• Primary or secondary immunodeficiency
• Any history of malignancy, excluding adequately treated and cured basal or squamous cell carcinoma of the skin, or cervical carcinoma in situ
• Active major psychiatric disease(stable depression receiving appropriate medical management will be permitted)
• Evidence of acute or chronic infection or neoplasm on Screening chest radiography
• Current treatment for TB or positive PPD without prophylaxis
• Herpes zoster 3 months or less prior to screening
• Clinically significant cardiac disease requiring medication, unstable angina, myocardial infarction within 6 months, or congestive heart failure
• Active infectious disease requiring i.v. antibiotics within the past 4 weeks or oral antibiotics at the time of enrollment
• Arrhythmia requiring active therapy, with the exception of clinically insignificant extrasystoles, or minor conduction abnormalities
• History of cerebrovascular disease requiring medication/treatment
• Anticoagulation therapy or a known bleeding disorder
• Seizure disorder requiring active therapy
• Known drug or alcohol abuse
• Positive tests for HIV, HBV, or HCV
• Pregnant or nursing
• Any underlying medical condition that in the Investigator's opinion will make the administration of study drug hazardous to the patient or would obscure the interpretation of adverse events, or
• Inability or unwillingness to return for Follow-up visits

Contacts and Locations

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Locations

United States, California
Cedars-Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Florida
DMI Health Care Group, Inc.
Largo, Florida, United States, 33773
United States, Maryland
Metropolitan Gastroenterology Group, PC
Chevy Chase, Maryland, United States, 20815
United States, New Jersey
University of Medicine and Dentistry of New Jersery (UMDNJ)
New Brunswick, New Jersey, United States, 08903
United States, New York
Mount Sinai School of Medicine
New York, New York, United States, 10029

Sponsors and Collaborators

Bristol-Myers Squibb

Investigators

Study Director:	Bristol-Myers Squibb	Bristol-Myers Squibb

More Information

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Additional Information:

For FDA Safety Alerts and Recalls refer to the following link www.fda.gov/MEDWATCH/safety.htm 

Responsible Party:	Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT00295282 History of Changes
Other Study ID Numbers:	MDX1100-01; IM129-001 ( Other Identifier: BMS )
First Posted:	February 23, 2006
Last Update Posted:	April 23, 2010
Last Verified:	April 2010

Keywords provided by Bristol-Myers Squibb:

Ulcerative Colitis; UC; Colitis

Additional relevant MeSH terms:

Colitis; Ulcer; Colitis, Ulcerative; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases	Pathologic Processes; Inflammatory Bowel Diseases; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs