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

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:;1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.;2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.;3. Male and/or female subjects between *18 and *75 years of age at the time of informed consent.;4. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and until the Week 26 visit (or 98 days after the last dose of IP).;Women of childbearing potential (WOCBP) will be eligible for this study provided these women use two highly effective
methods of contraception throughout the study and until the Week 26 visit (or 98 days after the last dose of IP), as outlined in Section 4.3. ;Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria):;* Have undergone a documented hysterectomy and/or bilateral oophorectomy;;* Have medically confirmed ovarian failure; or;Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state.;5. A diagnosis of UC for *4 months. A biopsy report must be available to confirm the histological diagnosis in the subject*s source documentation. In addition, a report documenting disease duration and extent of disease (eg, proctosigmoiditis, left-sided colitis, and pancolitis) based upon prior endoscopy must also be available in source documentation.;6. Subjects with moderate to severe active UC as defined (via screening colonoscopy) by a total Mayo score of *6, with a rectal bleeding subscore of *1 and an endoscopic subscore of *2 on the Mayo.;7. Active disease beyond the rectum (>15 cm of active disease at the screening colonoscopy).;8. Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for UC:;* Steroids;;* Immunosuppressants (AZA [azathioprine], 6-MP, or MTX [methotrexate]);;* Anti-TNF inhibitors (eg, infliximab, adalimumab, or golimumab);;* Anti-integrin inhibitors (eg, vedolizumab).;For subjects in The Netherlands: Subjects must have inadequate response to, loss of response to, or intolerance to at least one biological therapy, such as an anti-TNF inhibitor.;Note: The information below is provided as guidance. Local standards of care, as well as investigator assessment should be considered.;Inadequate response to, loss of response to, or intolerance to corticosteroid treatment is defined as one or more of the following:;* Steroid refractory: persistent symptoms of active disease despite treatment with at least one 4-week induction regimen that included a dose of *30 mg prednisone (oral) daily for at least 2 weeks or IV for at least 1 week within the previous
5 years;;* Steroid dependent: two failed attempts to taper steroids below a dose equivalent to 10 mg prednisone (oral) daily;;* Steroid intolerant: history of intolerance to corticosteroids (including but not limited to Cushing*s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) within the previous 5 years.;Inadequate response to, loss of response to, or intolerance to prior immunosuppressant treatment is defined by one or more of the following:;* Persistent signs and symptoms of active disease despite a history of at least one 12-week regimen of oral AZA (*2-2.5 mg/kg/day) or 6-MP (*1-1.5 mg/kg/day) and/or MTX (*25 mg/week) within the previous 5 years;;* History of intolerance to AZA, 6-MP, or MTX (including but not limited to nausea/vomiting, abdominal pain, pancreatitis, LFT [liver function testing] abnormalities, lymphopenia, TPMT [thiopurine methyltransferase] genetic mutation, infection) within the previous 5 years.;Inadequate response to, loss of response to, or intolerance to prior anti-TNF inhibitors and anti-integrin inhibitors is defined as one or more of the following:;* Persistent signs and symptoms of active disease despite at least one 8-week regimen of infliximab (3 intravenous doses *5 mg/kg), or adalimumab (subcutaneous doses of 160 mg at Week 0 and 80 mg at Week 2 followed by a dose of *40 mg every 2 weeks), or golimumab (subcutaneous doses of 200 mg at Week 0 and 100 mg at Week 2, followed by 50 mg or 100 mg every 4 weeks), or vedolizumab (intravenous doses of 300 mg at Weeks 0, 2, and 6).;Note: There is no specific requirement for a subject to *washout* of a current treatment and no patient should be actively removed from prohibited medications in order to meet study inclusion/exclusion criteria.;9. Subjects currently receiving the following treatment for UC are eligible provided they have been on stable doses as described below:;* Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline. If oral 5-ASA treatment has been recently discontinued, it must have been stopped for at least 2 weeks prior to total Mayo score screening procedures.;* Oral corticosteroids (prednisone equivalent up to 20 mg/day; budesonide up to
9 mg/day) stable dose for at least 2 weeks prior to baseline. If oral corticosteroids have been recently discontinued, they must have been stopped at least 2 weeks prior to total Mayo score screening procedures. Decreases in steroid use due to AEs are allowed.;* 6-MP or AZA (*2.5 mg/kg) stable dose for 8 weeks prior to baseline. Decreases due to AEs are permitted.

Subjects with any of the following characteristics/conditions will not be included in the study:;1. Subjects with a diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, microscopic colitis or CD. Subjects with clinical findings suggestive of CD (eg, fistulae, granulomas on biopsy) are also excluded.;2. Subjects with an imminent need for surgery or with elective surgery scheduled to occur during the study.;3. Subjects with colonic dysplasia or neoplasia.;4. Subjects with toxic megacolon.;5. Subjects with primary sclerosing cholangitis.;6. Subjects with known colonic stricture.;7. Subjects with history of colonic or small bowel stoma.;8. Subjects with a history of colonic or small bowel obstruction or resection.;9. Abnormal findings on the chest x-ray film performed routinely before initiating a new biologic therapy, such as presence of tuberculosis (TB), general infections, heart failure, or malignancy. Chest x-ray examination may be performed up to 12 weeks prior to screening. Documentation of the official reading must be located and available in the source documentation.;10. Any current evidence of untreated latent or active TB infection, evidence of prior or currently active TB by chest x-ray, residing with or frequent close contact with individual(s) with active TB. Subjects who have a positive Mantoux (PPD)
tuberculin skin test or a positive Interferon Gamma Release Assay (IGRA to be tested
at the site*s local lab where feasible) during screening or within 12 weeks prior to randomization. The following are acceptable assays: QuantiFERON*-TB Gold test (QFT-G), QuantiFERON*-TB Gold In-Tube test (QFT-GIT) and T-SPOT*-TB test during screening or within 12 weeks prior to screening.;* A positive Mantoux tuberculin skin test is defined as *5 mm of induration (or as defined by country specific or local standards) at 48-72 hours without consideration of prior Bacillus Calmette-Guerin (BCG) vaccination. Documentation of the dose and product used for the Mantoux tuberculin test as well as the official test reading must be obtained and available in the subject*s source documentation.;* An IGRA is preferred for subjects with a prior BCG vaccination (to be tested by a site*s local lab where feasible), but may be used for any subject. Documentation of IGRA product used and the test result must be in the subject*s source documentation.;* If results of the IGRA are indeterminate, the test may be repeated, and if a negative result is obtained, enrollment may proceed. A positive test on repeat is exclusionary.;* Subjects with repeat indeterminate IGRA results may be enrolled after consultation with pulmonary or infectious disease specialist that determines low risk of infection (ie, subject would be acceptable for immunosuppressant
(eg, anti-TNF) treatment without additional action).;* Subjects with adequately treated latent tuberculosis infection may be enrolled regardless of Mantoux or IGRA results.;11. Presence of active enteric infections (positive stool culture and sensitivity). The presence of Clostridium difficile or pseudomembranous colitis. Known active invasive fungal infections such as histoplasmosis or parasitic infections. Subjects with clinically significant underlying disease that could predispose the subjects to infections. A history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks before Day 1. Pyoderma gangrenosum is allowed.;12. Known history of human immunodeficiency virus (HIV) based on documented history with positive serological test, or positive HIV serologic test at screening, tested at the site*s local lab. (Note: a documented negative HIV test within 1 year of screening is acceptable and does not need to be repeated).;13. Presence of transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.;14. Significant concurrent medical condition as judged by the investigator at the time of screening or baseline visit, including but not limited to the following:
* Any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary,
immunologic [eg, Felty*s syndrome], or local active infection/infectious illness) that, in the investigator*s judgment will substantially increase the risk to the subject if he or she participates in the study.;* 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) and any history of cerebrovascular disease within 24 weeks before screening.;* Subjects with current, or a history of QT prolongation would be excluded.;* Class III or Class IV heart failure.;15. Prior evidence of liver injury or toxicity due to methotrexate.;16. Abnormality in hematology and/or chemistry profiles during screening:;* Positive hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb; also referred to as anti-HBc), and/or hepatitis C antibody (HCVAb) with confirmation by hepatitis C virus ribonucleic acid (HCV RNA).;* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
*1.5 times the upper limit of normal (ULN).;* Total bilirubin level *1.5 times the ULN.;* Hemoglobin level *80 g/L (8.0 g/dL).;* Platelet count *100 x 109/L (100,000 cells/mm3) or *1000 x 109/L (1,000,000 cells/mm3).
* White blood cell (WBC) count *3.5 x 109/L (3500 cells/ mm3).
* Absolute neutrophil count (ANC) <2000 cells/mm3.
* Serum creatinine level *177 *mol/L (2 mg/dL).;* Glycosylated hemoglobin (HbA1C) >10%.
Screening laboratory tests if considered by the investigator to be transient and inconsistent with the subject*s clinical condition may be repeated once during the screening period for confirmation.;17. Subjects receiving the following therapies within the designated time period or are expected to receive any of these therapies during the study period:;* >9 mg/day of oral budesonide or >20 mg/day of prednisone or equivalent oral systemic corticosteroid dose 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 below:;* Infliximab within 8 weeks prior to baseline.;* Adalimumab within 8 weeks prior to baseline.;* Golimumab within 8 weeks prior to baseline.;* Anti-integrin inhibitors (eg, vedolizumab) within 12 weeks prior to baseline.;* Other investigational procedure(s) or product(s), such as immunosuppressants used in transplantation (eg, mycophenolate mofetil, cyclosporine, rapamycin, or tacrolimus) or live (attenuated) vaccine within 30 days prior to baseline.;18. Current or history within 2 years of serious psychiatric disease or alcohol or drug abuse.;19. Subjects who are investigational site staff members directly involved in the conduct
of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.;20. Participation in other studies involving investigational drug(s) within 30 days, or 5 half-lives of IP (whichever is greater), prior to baseline and/or during study participation.;21. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.;22. Pregnant female subjects; breastfeeding female subjects; male subjects with partners currently pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and until the Week 26 visit (or 98 days after the last dose of IP) or longer based on the compound*s half-life characteristics.