Safety, Efficacy, and Tolerability Study of PF-06480605 in Subjects With Moderate to Severe Ulcerative Colitis.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and efficacy of PF-06480605 in subjects with moderate to severe ulcerative colitis.

Detailed Description
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This is a Phase 2a, single arm, two-stage study in subjects with moderate to severe ulcerative colitis. Subjects will receive 500 mg of PF-06480605 intravenously every 2 weeks for a total of 7 doses. Blood, stool, and tissue samples will be collected at various time points throughout the study to evaluate safety, tolerability, efficacy, pharmacokinetics, and immunogenicity. Duration of participation for subjects will be approximately 8 months.

Official Title
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A PHASE 2A, MULTICENTER, SINGLE ARM, OPEN- LABEL, TWO-STAGE, STUDY TO EVALUATE THE EFFICACY, SAFETY, TOLERABILITY AND PHARMACOKINETICS OF PF-06480605 IN SUBJECTS WITH MODERATE TO SEVERE ULCERATIVE COLITIS

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Drug: PF-06480605


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between ≥ 18 and ≤ 75 years of age at the time of informed consent Male subjects able to father children and female subjects of childbearing potential must agree to use two highly effective methods of contraception throughout the study and until the Week 26 visit Diagnosis of ulcerative colitis for ≥ 4 months Subjects with moderate to severe active ulcerative colitis as defined by screening colonoscopy with total Mayo score of ≥ 6, with rectal bleeding subscore of ≥ 1, and an endoscopic subscore of ≥ 2 on the Mayo Active disease beyond the rectum (> 15 cm of active disease at the screening colonoscopy) Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for ulcerative colitis such as: Steroids; Immunosuppressants (AZA, 6-MP, or MTX); Anti -TNF inhibitors (eg, infliximab, adalimumab, or golimumab); Anti-integrin inhibitors (eg, vedolizumab). Subjects currently receiving the following treatment are eligible provided they have been on stable doses of Oral 5-ASA or sulfasalazine for at least 4 weeks prior to baseline; oral corticosteroids stable dose for at least 2 weeks prior to baseline; 6-MP or AZA stable dose for 8 weeks prior to baseline. Exclusion Criteria: Diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, microscopic colitis or Crohn's Disease. Subjects with clinical findings suggestive of Crohn's disease (eg, fistulae, granulomas on biopsy) are also excluded. Subjects with colonic dysplasia or neoplasia, toxic megacolon, primary sclerosing cholangitis, known colonic stricture, history of colonic or small bowel stoma, history of colonic or small bowel obstruction or resection Presence of active enteric infections (positive stool culture and sensitivity) Known history of HIV based on documented history with positive serological test, or positive HIV serologic test at screening Presence of a transplanted organ Cancer or history of cancer or lymphoproliferative disease within the previous 5 years (other than resected cutaneous basal cell or squamous cell carcinoma that has been treated with no evidence of recurrence); Acute coronary syndrome (eg., myocardial infarction, unstable angina pectoris); Any history of cerebrovascular disease within 24 weeks before screening; Subject with current or a history of QT prolongation Class III or Class IV heart failure Prior evidence of liver injury or toxicity due to methotrexate Abnormality in hematology and/or chemistry profiles during screening (as detailed in the protocol) Subjects receiving the following therapies within the designated time period: > 9 mg/day of oral budesonide or >20 mg/day prednisone or equivalent within 2 weeks prior to baseline IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline Biologics including anti-TNF inhibitors as described: Infliximab, Adalimumab, or Golimumab within 8 weeks prior to baseline Anti-integrin inhibitors (eg, vedolizumab) within 12 weeks prior to baseline Other investigational procedures or products, or live attenuated vaccine within 30 days prior to baseline. Current or history (within 2 years) of serious psychiatric disease or alcohol or drug abuse

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06480605<br>PF-06480605 500 mg IV Q2W X 7 doses | Drug: PF-06480605<br>* PF-06480605 500 mg IV Q2W x 7 Doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events, Serious Adverse Events, and Who Withdrew Due to Adverse Events | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious AE (SAE) was any untoward medical occurrence at any dose that (1) resulted in death; (2) was life-threatening (immediate risk of death); (3) required inpatient hospitalization or prolongation of existing hospitalization; (4) resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); (5) resulted in congenital anomaly/birth defect. A treatment-emergent AE (TEAE) was defined as an event that emerged during treatment having been absent pre-treatment, or worsened relative to the pre-treatment state. Causality to study treatment was determined by the investigator. | Day 1 up to final onsite visit (Week 26) | 
| Number of Participants With Laboratory Abnormalities | The following parameters were evaluated: hematology (hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular volume, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, and prothrombin time), clinical chemistry (bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, protein, albumin, blood urea nitrogen, creatinine, urate, sodium, potassium, chloride, calcium, glucose, and creatine kinase), and urinalysis (urine glucose, ketones, urine protein, urine hemoglobin, nitrite, leukocyte esterase, urine erythrocytes, urine leukocytes, hyaline casts, and bacteria). | Day 1 up to final onsite visit (Week 26) | 
| Number of Participants With Vital Signs Data Meeting Pre-specified Criteria | Vital signs evaluation included sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse rate. Sitting blood pressure was measured with the participant's arm supported at the level of the heart, and recorded to the nearest millimeters of mercury (mm Hg). The same size BP cuff which had been properly sized and calibrated was used to measure BP each time. Number of participants with vital signs data meeting pre-specified criteria is presented. | Baseline up to final onsite visit (Week 26) | 
| Number of Participants With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria | All scheduled 12-lead ECGs were performed after the participant had rested quietly for at least 10 minutes in a supine position. Number of participants with ECG data meeting pre-specified criteria is presented. | Baseline up to final onsite visit (Week 26) | 
| Percentage of Participants Achieving Endoscopic Improvement at Week 14, Based on Uniformly Minimum-Variance Unbiased Estimator (UMVUE) - Per Protocol Analysis Set | Endoscopic improvement at Week 14 was defined as Mayo endoscopic sub-score of 0 or 1, and without friability. The Mayo scoring system was used to assess ulcerative colitis activity, and it ranges from 0 to 12, calculated as sum of 4 sub-scores, with higher scores indicating more severe disease. The 4 sub-scores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2=3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, mild friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease). | Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Remission at Week 14 - Full Analysis Set | Remission: total Mayo score <=2 with no individual subscore >1. Mayo scoring system was used to assess ulcerative colitis activity (range: 0 to 12, calculated as sum of 4 subscores, higher scores indicating more severe disease). The 4 subscores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on modified endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, no friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease). | Week 14 | 
| Percentage of Participants Achieving Remission at Week 14 - Per Protocol Analysis Set | Remission: total Mayo score <=2 with no individual subscore >1. Mayo scoring system was used to assess ulcerative colitis activity (range: 0 to 12, calculated as sum of 4 subscores, higher scores indicating more severe disease). The 4 subscores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on modified endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, no friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease). | Week 14 | 
| Percentage of Participants Achieving Endoscopic Remission at Week 14 - Full Analysis Set | Endoscopic remission at Week 14 was defined as Mayo endoscopic sub-score of 0. The Mayo scoring system was used to assess ulcerative colitis activity, and it ranges from 0 to 12, calculated as sum of 4 sub-scores, with higher scores indicating more severe disease. The 4 sub-scores are stool frequency (0=normal number of stools; 1=1 to 2 stools more than normal; 2= 3 to 4 stools more than normal; 3= 5 or more stools more than normal); rectal bleeding (0=no blood seen; 1=streaks of blood with stools less than half the time; 2=obvious blood with stool most of the time; 3=blood alone passes); findings on endoscopy (0=normal or inactive disease; 1=mild disease [erythema, decreased vascular pattern, mild friability]; 2=moderate disease [marked erythema, lack of vascular pattern, friability, erosions]; 3=severe disease [spontaneous bleeding, ulceration]); and physician's global assessment (0=normal; 1=mild disease; 2=moderate disease; 3=severe disease). | Week 14 | 
| Maximum Serum Concentration (Cmax) of PF-06480605 | Maximum serum concentration (Cmax) of PF-06480605 was observed directly from data. | 30 minutes pre-dose and 1 hour post-dose on Day 85 | 
| Average Serum Concentration (Cav) of PF-06480605 | Average serum concentration (Cav) of PF-06480605 was calculated as AUCtau/tau, where tau was the dosing interval (tau=14 days), and AUCtau was the area under the concentration-time profile from time 0 to time tau. | 30 minutes pre-dose and 1 hour post-dose on Day 85 | 
| Lowest Serum Concentration (Cmin) of PF-06480605 | Lowest serum concentration (Cmin) of PF-06480605 was observed directly from data. | 30 minutes pre-dose and 1 hour post-dose on Day 85 | 
| Area Under the Concentration-time Profile From Time Zero to Time Tau (AUCtau) of PF-06480605 | AUCtau of PF-06480605 was calculated using linear/log trapezoidal method; tau was the dosing interval (=14 days). | 30 minutes pre-dose and 1 hour post-dose on Day 85 | 
| Percentage of Participants Who Developed Anti-drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) | Serum samples were analyzed using a new ADA assay with acid pre-treatment followed by a more drug-tolerant cell-based NAb assay. For ADA assay with acid pre-treatment, the sample was deemed positive if log titer >=1.30; for cell-based NAb assay, the sample was deemed positive if log titer >=0.699. | Day 1 up to final onsite visit (Week 26) | 
| Change From Baseline in Fecal Calprotectin | Fecal calprotectin has been used to detect intestinal inflammation (colitis or enteritis) and can serve as a biomarker for inflammatory bowel diseases. Elevated fecal calprotectin levels indicate migration of neutrophils into the intestinal mucosa, which occurs during intestinal inflammation. | Baseline, Weeks 2, 8, 12 and 26 | 
| Change From Baseline in High Sensitivity C-reactive Protein (HsCRP) | HsCRP is used mainly as a marker of inflammation. | Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, and 26 | 
| Change From Baseline in Serum Total Soluable Tumor Necrosis Factor-like Ligand 1A (sTL1A) | TL1A is a member of the tumor necrosis factor (TNF) family of cytokines. The investigational product of this study PF-06480605 is a fully human neutralizing antibody against TL1A. | Baseline, Weeks 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, and 26 |