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

NCT03478956 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: CA401922017-003649-10
• Study Type: interventional
• Target: 24
• Locations: 4 countries
• Sites: 5

Brief Summary

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).

Conditions

Ulcerative Colitis; Crohn's Disease

Outcome Measures

Primary Outcomes (6)

• Maximum Serum Concentration (Cmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase

  Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

  Arm Etro Q4W: Day 1, 84 and Arm Etro Q8W: Day 1, 56

• Time to Maximum Serum Concentration (Tmax) of Etrolizumab After First and Last Dose During the Randomized Treatment Phase

  Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

  Arm Etro Q4W: Days 1, 84 and Arm Etro Q8W: Days 1, 56

• Area Under the Concentration-Time Curve Within the Last Dosing Interval (AUC-tau) of Etrolizumab During the Randomized Treatment Phase

  Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

  Arm Etro Q4W: Days 56, 84, 88, 98, 112 and Arm Etro Q8W: Day 56, 60, 70, 84, 88, 98, 112

• Elimination Half-Life (t1/2) of Etrolizumab After Last Dose During the Randomized Treatment Phase

  Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method. Non-compartmental analysis methods were employed to calculate PK parameters.

  Arm Etro Q4W: Days 84, 88, 98, 112, 126, 140, 168 and Arm Etro Q8W: Days 56, 60, 70, 84, 88, 98, 112, 126, 140, 168

• Serum Trough Concentration (Ctrough) of Etrolizumab at the End of Each Dosing Interval During the Randomized Treatment Phase

  Etrolizumab concentrations in all pharmacokinetics (PK) samples were measured using a validated assay method.

  Arm Etro Q4W: Predose on Days 28, 56, 84, 112 and Arm Etro Q8W: Predose on Days 56, 112

• Percentage of Baseline Absolute Numbers of Beta7 Receptor-Expressing Gut Homing CD3, CD4, and CD8 T Cells and CD19 B Cells With Unoccupied Beta7 Receptors in Peripheral Blood, Assessed by Flow Cytometry, During the Randomized Treatment Phase

  Target engagement of etrolizumab was assessed via measurement of Beta7 receptor occupancy on Beta7 receptor-expressing gut homing lymphocyte subsets in peripheral blood, including CD3, CD4, and CD8 T cells and CD19 B cells, using qualified flow cytometry methods. A decrease to 0% of baseline (BL) in median absolute cell counts of Beta7 receptor-expressing T and B cell subsets with unoccupied Beta7 receptors following etrolizumab treatment indicated maximal receptor occupancy by etrolizumab.

  Predose (dosing days only) at Baseline (Day 1) and on Days 4, 56, 84, 98, and 112 (Treatment Period), and Days 126, 140, and 168 (Follow-Up Period)

Secondary Outcomes (11)

• Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0), During the Randomized Treatment Phase

  From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)

• Number of Participants With Serious Infection-Related Adverse Events During the Randomized Treatment Phase

  From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)

• Number of Participants With Hypersensitivity Reactions During the Randomized Treatment Phase

  From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)

• Number of Participants With Malignancies During the Randomized Treatment Phase

  From Baseline until 12 weeks (Q4W arm only) or 16 weeks (Q8W arm only) after the last dose of study drug during the randomized treatment phase (up to 24 weeks)

• Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline During the Randomized Treatment Phase

  Predose (dosing days only) on Days 1, 28, 84, 112, and 168 (up to the end of the randomized treatment phase at Week 24)

Study Arms (2)

Etrolizumab Q4W

EXPERIMENTAL

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.

Drug: Etrolizumab

Etrolizumab Q8W

EXPERIMENTAL

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.

Drug: Etrolizumab

Interventions

Etrolizumab DRUG

Etrolizumab was administered by subcutaneous (SC) injection as described for each treatment arm.

Also known as: RG7413, RO5490261, PRO145223, rhuMAb Beta7

Etrolizumab Q4W; Etrolizumab Q8W

Eligibility Criteria

• Age: 4 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (5)

Hôpital Enfants Reine Fabiola

Brussels, 1020, Belgium

Location

Gabinet Lekarski, Bartosz Korczowski

Rzeszów, 35-302, Poland

Location

Centrum Zdrowia MDM

Warsaw, 00-189, Poland

Location

Hospital Niño Jesus; Servicio de Pediatria - Gastrenterologia y Nutricion

Madrid, 28009, Spain

Location

Royal Manchester Childrens Hospital

Manchester, M13 9WL, United Kingdom

Location

MeSH Terms

Conditions

Colitis, Ulcerative; Crohn Disease

Interventions

etrolizumab

Condition Hierarchy (Ancestors)

Colitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Inflammatory Bowel Diseases; Colonic Diseases; Intestinal Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 26, 2018
• First Posted: March 27, 2018
• Study Start: March 27, 2018
• Primary Completion: December 2, 2019
• Study Completion: September 27, 2023
• Last Updated: December 27, 2024
• Results First Posted: August 5, 2020

Record last verified: 2024-11

Locations

PL (2); ES (1); GB (1); BE (1)