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

Study Overview
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Brief Summary
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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).

Official Title
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A Phase I, Open-Label, Randomized, Pharmacokinetic, Pharmacodynamic, And Safety Study Of Etrolizumab Followed By Open-Label Extension And Safety Monitoring In Pediatric Patients From 4 Years To Less Than 18 Years Of Age With Moderate To Severe Ulcerative Colitis Or Moderate To Severe Crohn's Disease

Conditions
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Ulcerative Colitis, Crohn's Disease

Intervention / Treatment
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* Drug: Etrolizumab


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etrolizumab Q4W<br>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<br>* Etrolizumab was administered by subcutaneous (SC) injection as described for each treatment arm.<br>* Other names: rhuMAb Beta7;|
| Experimental: Etrolizumab Q8W<br>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<br>* Etrolizumab was administered by subcutaneous (SC) injection as described for each treatment arm.<br>* Other names: rhuMAb Beta7;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Predose (dosing days only) on Days 1, 4, 28, 56, (and Days 60 and 70 for Q8W arm only), 84, 88, 98, 112, 126, 140, and 168 | 
| 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. | Predose (dosing days only) on Days 1, 4, 28, 56, (and Days 60 and 70 for Q8W arm only), 84, 88, 98, 112, 126, 140, and 168 | 
| 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. | Predose (dosing days only) on Days 1, 4, 28, 56, (and Days 60 and 70 for Q8W arm only), 84, 88, 98, 112, 126, 140, and 168 | 
| 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. | Predose (dosing days only) on Days 1, 4, 28, 56, (and Days 60 and 70 for Q8W arm only), 84, 88, 98, 112, 126, 140, and 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. | Predose on Days 28 (Q4W arm only), 56, and 84 (Q4W arm only), and Day 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | 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 by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase | Serious infection-related AEs were graded for severity per the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | 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 by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase | Hypersensitivity reactions were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | 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 by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0, During the Randomized Treatment Phase | Malignancies were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | 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 | Participants were considered to be etrolizumab anti-drug antibody (ADA) positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (i.e., treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment-enhanced ADA positive); these ADA positive responses are summarized together (induced + enhanced) in the 'treatment-emergent ADA positive' category. Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (i.e., treatment-emergent ADA negative), or if they are ADA positive at baseline but did not have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment unaffected). | Predose (dosing days only) on Days 1, 28, 84, 112, and 168 (up to the end of the randomized treatment phase at Week 24) | 
| Long-Term Safety of Etrolizumab: Number of Participants With Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0 | All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline until study discontinuation (up to 8.5 years) | 
| Long-Term Safety of Etrolizumab: Number of Participants With Serious Infection-Related Adverse Events by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0 | Serious infection-related AEs were graded for severity per the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline until study discontinuation (up to 8.5 years) | 
| Long-Term Safety of Etrolizumab: Number of Participants With Hypersensitivity Reactions by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0 | Hypersensitivity reactions were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline until study discontinuation (up to 8.5 years) | 
| Long-Term Safety of Etrolizumab: Number of Participants With Malignancies by Highest Severity Grade, Assessed According to NCI-CTCAE v4.0 | Malignancies were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline until study discontinuation (up to 8.5 years) | 
| Long-Term Safety of Etrolizumab: Number of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Post-Baseline | Participants were considered to be etrolizumab anti-drug antibody (ADA) positive if they were ADA negative or had missing data at Baseline (BL) but developed an ADA response following study drug exposure (i.e., treatment-induced ADA positive), or if they were ADA positive at baseline and the titer of one or more postbaseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment-enhanced ADA positive); these ADA positive responses are summarized together (induced + enhanced) in the 'treatment-emergent ADA positive' category. Participants were considered to be ADA negative if they were ADA negative or had missing data at Baseline (BL) and all postbaseline samples were negative (i.e., treatment-emergent ADA negative), or if they are ADA positive at baseline but did not have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the titer of the baseline sample (i.e., treatment unaffected). | Predose (dosing days only) at Baseline (Day 1), Days 28, 84, and 112, Weeks 24, 36, 72, and 120, and every 12 weeks thereafter for up to 6.5 years | 
| Number of Participants With Confirmed Progressive Multifocal Leukoencephalopathy (PML) During the Post-Treatment PML Monitoring Phase | The 104-week safety surveillance PML-monitoring phase (no etrolizumab treatment) will consist of telephone calls approximately every 6 months with administration of the protocol's PML Subjective Checklist. If there are any signs or symptoms suggestive of PML identified on this subjective checklist during the telephone call, the participant will be asked to come into the clinic for a neurologic examination. The protocol's PML Algorithm will be followed for any suspected case of PML, and any confirmed case of PML will be reported as a serious adverse event. | Approximately every 6 months from last dose of study drug until the end of the PML monitoring phase (up to 104 weeks) |