ETRO: GA29102

Principal Investigator: John  Valentine
Keywords: Ulcerative Colitis , Etrolizumab Department: Gastroenterology
IRB Number: 00075857 Co Investigator:  
Specialty: Gastroenterology
Sub Specialties: Inflammatory Bowel Disease/Crohn's/Ulcerative Colitis
Recruitment Status: Recruiting

Contact Information

Heather Munk
heather.munk@hsc.utah.edu
801-587-9092

Brief Summary

STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT

Although there are therapeutic options including anti-TNF agents, a significant proportion of patients with UC will not experience a durable clinical benefit with those treatment options. Furthermore, adverse events associated with anti-TNFs include elevated rates of serious bacterial infection, including TB, and (more rarely) lymphoma and demyelination (Chang and Lichtenstein 2006). No currently available therapy achieves sustained remission in more than 10%30% of patients with IBD who have chronic disease (Hanauer et al. 2002; Sandborn et al. 2005). As noted above, etrolizumab distinguishes itself from other anti-integrins on the basis of gut selectivity combined with a potential dual mechanism of action. It binds αEβ7 in addition to α4β7 and so regulates retention as well as trafficking leucocyte/lymphocyte in the intestinal mucosa.

A global Phase II multicenter study (Study ABS4986g; EUCALYPTUS) designed to determine the exposure-response relationship and to further characterize the safety and tolerability of etrolizumab in treatment of adult patients with moderate to severely active UC patients has been completed. Patients were randomized in a 1:1:1 ratio to receive 100 mg etrolizumab SC (0.7 mL of 150 mg/mL solution via vial and syringe, with an intended nominal dose of 100 mg) at Weeks 0, 4, and 8 or 420 mg SC at Week 0 (loading dose [LD]) followed by 300 mg SC (three injections of 0.7 mL of 150 mg/mL solution via vial and syringe, with an intended nominal dose of 300 mg) at Weeks 2, 4, and 8 (40 patients per dose arm) versus matching placebo SC (40 patients per arm).

The primary objective of the study was to obtain evidence of clinical efficacy of etrolizumab as measured by induction of clinical remission (Mayo Clinic Score [MCS] 2 and no individual subscore > 1) at Week 10 (2 weeks after the final dose).

In EUCALYPTUS, etrolizumab showed clinically meaningful efficacy for both doses relative to placebo for the primary endpoint: the proportion of patients in clinical remission at Week 10 was 20.5% in the 100-mg dose group and 10.3% in the 300-mg + LD group versus 0% in the placebo group (p = 0.004 and p = 0.048, respectively). In the TNF-naive subgroup, clinical remission at Week 10 was observed in 43.8% versus 0% of patients in the 100 mg etrolizumab versus placebo group, and in 25% of 300 mg+ LD group.

In summary, favorable safety (see Section 1.2) and efficacy data were observed in the Phase II EUCALYPTUS study and in the OLE study (SPRUCE). Overall, etrolizumab showed compelling efficacy compared with placebo and there were no clinically significant safety signals. Additionally, etrolizumab distinguishes itself from vedolizumab by blocking αEβ7 in addition to α4β7, which is involved in lymphocyte retention and may contribute to its efficacy and/or safety profile. Etrolizumab is a gut-selective anti-trafficking agent and does not bind to α4β1 (target for natalizumab), which regulates trafficking to both mucosal and non-mucosal tissues, including the CNS. Although natalizumab has been associated with an increased risk of PML, no events of PML to date have been reported during 2-year PML extensive monitoring in the Phase II study, EUCALYPTUS, and OLE SPRUCE study.

Please refer to the most recent etrolizumab Investigator’s Brochure for additional details on clinical and nonclinical studies.

OBJECTIVES

EFFICACY OBJECTIVES

The primary efficacy objective for this study is as follows:

To evaluate the efficacy of etrolizumab (105 mg SC every 4 weeks [Q4W]) compared with placebo for maintenance of remission at Week 62 for randomized patients in remission at Week 10, as determined by the MCS

The secondary efficacy objectives for this study are as follows:

To evaluate maintenance of clinical remission at Week 62 for randomized patients in clinical remission at Week 10

To evaluate clinical remission at Week 62

To evaluate clinical response at Week 62

To evaluate improvement in endoscopic appearance of the mucosa at Week 62

To evaluate endoscopic remission at Week 62

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroid for at least 24 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate corticosteroid-free remission at Week 62 (off corticosteroid for at least 24 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate histologic remission at Week 62

To evaluate change from baseline to Week 62 in UC bowel movement signs and symptoms, as assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) measure

To evaluate change from baseline to Week 62 in UC abdominal symptoms, as assessed by the UC-PRO/SS measure

To evaluate change from baseline to Week 62 in patient-reported health-related QOL, as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)

The exploratory efficacy objectives for this study are as follows:

To evaluate corticosteroid-free clinical remission at Week 62 (off corticosteroid for at least 12 weeks prior to Week 62) in patients who were receiving corticosteroids at baseline

To evaluate change in health utilities, as assessed by the EuroQoL Five-Dimension Questionnaire (EQ-5D), from Week 10 to Week 62

To evaluate improvement in endoscopic appearance of mucosa at Week 10 

To evaluate improvement in histologic score at Week 62

To evaluate endoscopic remission at Baseline

To evaluate the frequency and duration of hospitalizations from Week 10 to Week 62

SAFETY OBJECTIVES

The safety objectives for this study are as follows:

To evaluate the overall safety and tolerability of etrolizumab over a period of 62 weeks

To evaluate the incidence and severity of infection-related adverse events

To evaluate the incidence of malignancies

To evaluate the incidence and severity of hypersensitivity reactions

To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs)

PHARMACOKINETIC OBJECTIVES

The pharmacokinetic (PK) assessment will be performed in all patients during the Induction Phase and in all patients who were randomized into the Maintenance Phase.

The PK objectives for this study are as follows:

To evaluate etrolizumab serum concentration at the time of primary endpoint evaluation (Week 62) and predose concentration at the steady state during the maintenance dosing period

To evaluate the interindividual variability and potential covariate effects on etrolizumab serum exposure

EXPLORATORY PHARMACODYNAMIC AND DIAGNOSTIC OBJECTIVES

The exploratory pharmacodynamics (PD) and diagnostic objectives for this study are as

follows:

To evaluate the relationship between baseline colonic mucosal biomarkers and/or peripheral blood and response to study drug, including but not limited to the αE integrin

To evaluate the levels of biomarkers in colonic tissue and/or peripheral blood during the treatment period, including but not limited to the αE integrin

To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood following study treatment or placebo

Inclusion Criteria

Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent

1880 years of age, inclusive

Diagnosis of UC established at least 6 months prior to Day 1 by clinical and endoscopic evidence. This diagnosis should be corroborated by histopathology conducted at any time prior to screening and documented by a histopathology report. (Note: histopathology may be performed at screening if no prior report is readily available.)

Moderately to severely active UC as determined by a MCS of 612 with an endoscopic subscore 2, as determined by the central reading procedure described in Section 4.5.1.4, a rectal bleeding subscore 1, and a stool frequency subscore 1 within 14 days of Day 1. See also Section 4.5.2.1 for additional information regarding this time window.

Evidence of UC extending a minimum of 20 cm from the anal verge as determined by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed between 4 and 10 days prior to Day 1. See also Section 4.5.2.1 for additional information regarding this time window.

Naive to treatment with any anti-TNF therapy

Patients must have had an inadequate response, loss of response, or intolerance to prior immunosuppressant and/or corticosteroid treatment.

Inadequate response to, loss of response to, or intolerance to prior immunosuppressant treatment is defined as 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 (1.5 mg/kg) or 6-MP (0.75 mg/kg) and/or MTX (15 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 abnormalities, lymphopenia, TPMT genetic mutation, infection) within the previous 5 years Inadequate response, loss of response, 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

Any ongoing UC therapy must be at stable doses:

May be receiving oral 5-ASA compounds provided that the dose has been stable for 4 weeks immediately prior to Day 1 May be receiving oral corticosteroid therapy (prednisone at a stable dose of 30 mg a day, or equivalent steroid) provided that the dose has been stable for  4 weeks immediately prior to Day 1 if corticosteroids have just been initiated or for the 2 weeks immediately prior to Day 1 if corticosteroids are being tapered

May be receiving budesonide MMX therapy at a stable dose of up to 9 mg a day for 4 weeks prior to Day 1

May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii), provided that the dose has been stable for 2 weeks immediately prior to Day 1

May be receiving AZA, 6-MP, or MTX, provided that the dose has been stable for 8 weeks immediately prior to Day 1

For women who are not postmenopausal (at least 12 months of non-therapy-induced amenorrhea) or surgically sterile (e.g., absence of ovaries and/or uterus): agreement to remain abstinent or use a highly effective method of contraception (e.g., combined oral contraceptive pill or transdermal patch, spermicide and barrier (condomes), intrauterine device, implants for contraception, injections for contraception (with prolonged release), hormonal vaginal device, sterilization, or surgical tubal ligation for the duration of the study (i.e., during the treatment period and for at least 24 weeks after the last dose of study drug (see Appendix 3).

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: 

With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 24 weeks after the last dose of the study drug to avoid exposing the embryo to study drug. Men must refrain from donating sperm during this same period. 

The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Must have received a colonoscopy within the past year or be willing to undergo a colonoscopy in lieu of a flexible sigmoidoscopy at screening. This colonoscopy must:

Confirm disease extent (defined as 1) left-sided colitis [up to the splenic flexure], 2) extensive colitis [beyond the splenic flexure but not involving the entire colon], and 3) pancolitis; see Section 4.5.1.4)

Include removal of any adenomatous polyps

Document evidence of surveillance for dysplasia for all patients with left-sided colitis of > 12 years’ duration and total/extensive colitis of > 8 years duration

 

Exclusion Criteria

Patients who meet any of the following criteria will be excluded from study entry:

Exclusion Criteria Related to Inflammatory Bowel Disease

Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC

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

Any diagnosis of Crohn’s disease

Past or present fistula or abdominal abscess

A history or current evidence of colonic mucosal dysplasia

Patients with any stricture (stenosis) of the colon

Patients with history or evidence of adenomatous colonic polyps that have not been removed

Exclusion Criteria Related to Prior or Concomitant Therapy

Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, vedolizumab, and efalizumab)

Any prior treatment with 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

Chronic nonsteroidal anti-inflammatory drug (NSAID) use. (Note: occasional use of NSAIDs and acetaminophen [e.g., headache, arthritis, myalgias, or menstrual cramps] and aspirin up to 325 mg daily is permitted.)

Patients who are currently using anticoagulants including but not limited to warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban. (Note that antiplatelet agents such as aspirin up to 325 mg daily or clopidogrel are permitted.)

Patients who have received treatment with corticosteroid enemas/suppositories and/or topical (rectal) 5-ASA preparations within 2 weeks prior to Day 1

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)

Patients administered tube feeding, defined formula diets, or parenteral alimentation/nutrition who have not discontinued these treatments 3 weeks prior to Day 1

Exclusion Criteria Related to General Safety

Pregnant or lactating

Lack of peripheral venous access

Hospitalized (other than for elective reasons) within 4 weeks prior to screening and during screening

Inability to comply with study protocol, in the opinion of the investigator

Significant uncontrolled co-morbidity, such as cardiac (e.g., moderate to severe heart failure New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders (excluding UC)

Neurological conditions or diseases that may interfere with monitoring for PML

History of demyelinating disease

Clinically significant abnormalities on screening neurologic examination (PML Objective Checklist)

Clinically significant abnormalities on the screening PML Subjective Checklist

History of alcohol, drug, or chemical abuse 6 months prior to screening

Conditions other than UC that could require treatment with > 10 mg/day of prednisone (or equivalent) during the course of the study

History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening with the following caveats:

Local basal or squamous cell carcinoma of the skin that has been excised and is considered cured is not exclusionary. A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell carcinoma, or Kaposi sarcoma is exclusionary irrespective of the duration of time before screening.

History of a cervical smear indicating the presence of adenocarcinoma in situ (AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia (CIN) of Grade > 1 is exclusionary, irrespective of the duration of time before screening.

Exclusion Criteria Related to Infection Risk

Congenital or acquired immune deficiency

• Patients must undergo screening for HIV and test positive for preliminary confirmatory tests

Positive hepatitis C virus antibody test result, unless the patient (1) has undetectable HCV RNA levels for > 6 months after completing a successful course of HCV anti-viral treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV antibody positivity with a history of undetectable HCV RNA and undetectable HCV RNA at screening in the absence of history of HCV anti-viral treatment. 

Patients must undergo screening for hepatitis B virus (HBV). This includes testing for HBsAg (HBV surface antigen), anti-HBc total (HBV core antibody total), and HBV DNA (patients who test negative for these tests are eligible for this study):

Patients who test positive for surface antigen (HBsAg +) are not eligible for this study, regardless of the results of other hepatitis B tests.

Patients who test positive only for core antibody (anti-HBc +) must undergo further testing for hepatitis B DNA (HBV DNA test).

If the HBV DNA test is positive, the patient is not eligible for this study.

In the event the HBV DNA test cannot be performed, the patient is not eligible for this study.

If the HBV DNA test is negative, the patient is eligible for this study. These patients will undergo periodic monitoring for HBV DNA during the study.

Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) within 60 days prior to Day 1 or other intestinal pathogens (as assessed by stool culture and ova and parasite evaluation) within 30 days prior to Day 1

Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on the investigator’s judgment) within 60 days prior to Day 1. Laboratory confirmation of CMV from colon biopsy sample is required during screening evaluation only if clinical suspicion is high and to determine the need for CMV treatment.

History of active or latent TB, regardless of treatment history (see Section 4.5.1.5) Patients with a history of active or latent TB (based on a positive screening assay, either purified protein derivative [PPD] skin test or QuantiFERON®TB Gold test, see below) are not eligible for this study.

Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of Day 1 suspicious for pulmonary TB are not eligible for this study.

History of recurrent opportunistic infections and/or history of severe disseminated viral infections (e.g., herpes)

Any serious opportunistic infection within the last 6 months

Any current or recent signs or symptoms (within 4 weeks before screening and during screening) of infection, except for the following:

Minor infections (e.g., common cold) that have, in the investigator’s judgment, completely resolved prior to Day 1 Fungal infections of the nail beds

Oral or vaginal candidiasis that has resolved with or without treatment prior to Day 1

Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks prior to screening

Received a live attenuated vaccine within 4 weeks prior to Day 1

History of organ transplant

Exclusion Criteria Related to Laboratory Values (at Screening)

Serum creatinine > 2 × upper limit of normal (ULN)

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN, or alkaline phosphatase > 3× ULN, or total bilirubin > 2.5 × ULN (unconjugated hyperbilirubinemia that is associated with known Gilbert's syndrome is not an exclusion criterion)

Platelet count < 100,000/μL

Hemoglobin < 8 g/dL

Absolute neutrophil count < 1500/μL

Absolute lymphocyte count < 500/μL