A Phase I Study of Etrolizumab Followed by Open-Label Extension and Safety Monitoring in Pediatric Patients With Moderate to Severe Ulcerative Colitis or Moderate to Severe Crohn's Disease (FENNEL)

Roche

Status and phase: Terminated; Phase 1

Conditions: Ulcerative Colitis; Crohn's Disease

Treatments: Drug: Etrolizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03478956

2017-003649-10 (EudraCT Number)

CA40192

Details and patient eligibility

About

This study will evaluate pharmacokinetics, pharmacodynamics and safety of etrolizumab in pediatric patients of 4 to <18 years of age with moderate to severe ulcerative colitis (UC) or with moderate to severe Crohn's disease (CD).

Enrollment: 24 patients

Sex: All

Ages: 4 to 17 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age of 4 years to <18 years at the time of signing the Informed Consent Form.
• Weight of 13 kilograms (kg) or more
• Diagnosis of ulcerative colitis (UC) or Crohn's Disease (CD) confirmed by biopsy and established for ≥3 months (i.e., after first diagnosis by a physician according to American College of Gastroenterology [ACG] guidelines) prior to screening
• Inadequate response, loss of response or intolerance to prior immunosuppressants and/or corticosteroid treatment and/or anti-tumor necrosis factor (TNF) therapy
• For postpubertal females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for at least 24 weeks after the last dose of etrolizumab.
• For male patients: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion criteria

• Pregnant or lactating
• Lack of peripheral venous access
• Congenital or acquired immune deficiency
• Neurological conditions or diseases that may interfere with monitoring for progressive multifocal leukoencephalopathy (PML)
• History of demyelinating disease
• History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening

Exclusion Criteria Related to Inflammatory Bowel Disease:

• Prior extensive colonic resection, subtotal or total colectomy, or planned surgery
• Past or present ileostomy or colostomy
• Diagnosis of indeterminate colitis
• Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
• Diagnosis of toxic megacolon within 12 months of initial screening visit
• Abdominal abscess
• A history or current evidence of colonic mucosal dysplasia
• Patients with fixed symptomatic stenosis of the intestine
• Patients with history or evidence of adenomatous colonic polyps that have not been removed

Exclusion Criteria Related to Ulcerative Colitis:

• Severe extensive colitis per investigator judgment that colectomy is imminent

Exclusion Criteria Related to Crohn's Disease:

• Sinus tract with evidence for infection (e.g., purulent discharge) in the clinical judgment of the investigator
• Short-bowel syndrome
• Evidence of abdominal or perianal abscess
• Expected to require surgery to manage CD-related complications during the study

Exclusion Criteria Related to Prior or Concomitant Therapy:

• Any prior treatment with anti-integrin agents (including natalizumab, vedolizumab, and efalizumab), ustekinumab, anti-adhesion molecules (e.g., anti-MAdCAM-1), or rituximab
• Use of IV steroids within 30 days prior to screening with the exception of a single administration of IV steroid
• Use of agents that deplete B or T cells (e.g., alemtuzumab or visilizumab) within 12 months prior to Day 1, with the exception of AZA and 6-MP
• Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks prior to Day 1
• Use of other biologics (e.g. anti-TNF) within 8 weeks before dosing (unless drug level is below detectability before completion of the 8-week interval)
• Chronic nonsteroidal anti-inflammatory drug (NSAID) use
• Patients who are currently using anticoagulants
• Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to Day 1
• Received any investigational treatment including investigational vaccines within 12 weeks prior to Day 1 of the study or 5 half-lives of the investigational product, whichever is greater
• History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L-histidine, L-arginine, succinic acid, polysorbate 20)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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24 participants in 2 patient groups

Etrolizumab Q4W

Experimental group

Description:

Etrolizumab 1.5 milligrams per kilogram of body weight (mg/kg) was administered by subcutaneous (SC) injection once every 4 weeks (Q4W) for a total of 4 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

Treatment:

Drug: Etrolizumab

Etrolizumab Q8W

Experimental group

Description:

Etrolizumab 3.0 mg/kg was administered by subcutaneous (SC) injection once every 8 weeks (Q8W) for a total of 2 doses over the course of the 24-week randomized treatment phase (16-week treatment period plus 8-week safety follow-up). Participants were then given the option to participate in the 312-week open-label extension (OLE) treatment phase with etrolizumab 1.5 mg/kg SC Q4W followed by the 104-week safety surveillance phase (no etrolizumab treatment) to monitor for progressive multifocal leukoencephalopathy (PML). All participants who chose not to enter the OLE phase after the 24-week randomized treatment phase entered the 104-week PML monitoring phase.

Treatment:

Drug: Etrolizumab