Phase 2 Study of Neoadjuvant Immune Checkpoint Inhibitors in Urothelial Cancer
Phase 2 Study of Neoadjuvant Immune Checkpoint Inhibitors in Urothelial Cancer
This study is being carried out to see if the drug atezolizumab can reduce the size of
 tumours in patients with types of urothelial cancer before surgery. Atezolizumab is designed
 to stop a protein called PD-L1 (programmed death-ligand 1) being expressed on the cancer,
 allowing the immune system to recognise the tumour cells as foreign bodies and attack them.
 Atezolizumab has been shown to have activity in urothelial cancer which has spread.

 There two cohorts for this trial. One cohort will investigate the most common histological
 type of urothelial cancer (transitional cell carcinoma) outside the bladder, for example in
 the upper urinary tract. The other cohort will investigate rarer histological subtypes (such
 as such as squamous cell or adenocarcinoma) of urothelial cancer throughout the entire
 urinary system.

 This study will be recruiting patients from hospitals in the UK, France and Spain. If a
 patient is eligible for the study and decides to take part, they will receive up to two
 3-weekly cycles of atezolizumab. 4-8 weeks after being enrolled, the patient will have an
 operation to remove the bladder (cystectomy) or the kidney, ureter and part of the bladder
 (nephroureterectomy or distal ureteral resection) as per normal practice. Following surgery,
 they will attend three hospital visits (4,12 and 24 weeks after surgery) and their disease
 progress/survival will be followed over the next 2 years. The clinical team will compare the
 patient's tumour tissue samples,scan results and blood results from before and after
 treatment with atezolizumab in order to see how well the drug works and if it is safe. Many
 of the procedures involved in this study are offered as standard care and participation in
 this trial will not delay surgery.
Screening (up to 28 days before day 1 of treatment):

 Written informed consent will be obtained before potential participants undergo any study
 specific procedures. Each potential participant will undergo screening during the 28 days
 prior to recruitment in the study to confirm eligibility. Clinical data obtained as part of
 their standard care prior to consent may be used to confirm eligibility if they fall within
 the protocol specified timelines. Screening will involve standard of care and study specific
 assessments.

 Standard care assessments:

 -  Medical history

 -  Demographics

 -  Physical Examination

 -  Weight

 -  Height

 -  Vital signs

 -  An assessment of how easily patients can carry out their daily activities (ECOG
 performance score)

 -  An assessment of the patient's fitness for surgery

 -  Questions about what medicines including over the counter and herbal medicines the
 potential participant is taking

 Study specific assessments to be carried out once the potential participant has consented to
 the study:

 -  Blood samples will be taken for routine biochemistry, haematology, coagulation tests,
 thyroid function testing, and hepatitis/HIV serology testing

 -  Urine sample for routine urinalysis testing

 -  Women of childbearing potential will be asked to take a pregnancy test

 -  An ECG to confirm cardiac function

 -  A CT scan or MRI of the disease area

 -  Blood sample (approximately 20ml/4 teaspoons) and urine sample (approximately 50ml) for
 research purposes

 -  An archival FFPE tumour sample will also be collected as part of patient's normal
 clinical care

 Treatment period:

 Eligible participants will undergo two cycle of atezolizumab treatment (1200 mg administered
 by IV infusion every 3 weeks (21 days ±3 days for Cycle 2)). At each cycle, patients will
 undergo the following assessments:

 -  Physical Examination

 -  Weight

 -  Vital signs

 -  ECOG performance score

 -  Blood samples will be taken for biochemistry and haematology blood tests

 -  Urine sample for routine urinalysis testing

 -  Signs and symptoms (side effects) or other adverse events they may be experiencing and
 any medications being taken

 -  Blood sample (approximately 20ml/4 teaspoons) and urine sample (approximately 50ml) for
 research purposes

 Surgery:

 There must be a minimum of 5 days between the last atezolizumab infusion and surgery.
 Patients will undergo a pre-surgery visit, at which they will undergo the following
 assessments:

 -  Physical Examination

 -  Weight

 -  Vital signs

 -  ECOG performance score

 -  An assessment of the patient's fitness for surgery

 -  A CT scan or MRI of the disease area

 -  Signs and symptoms (side effects) or other adverse events they may be experiencing and
 any medications being taken

 -  Blood sample (approximately 20ml/4 teaspoons) and urine sample (approximately 50ml) for
 research purposes

 An FFPE excision sample will be collected after the tumour has been surgically excised and
 pathologically examined.

 Post-surgery visits:

 Patients will undergo follow-up visits at 4 weeks,12 weeks, and 24 weeks after surgery.
 Patients who do not undergo radical surgery will attend safety follow up visits from the date
 the decision was made to cancel surgery. At these visits, they will undergo the following
 assessments:

 -  Physical Examination (4 week visit only)

 -  Weight (4 week visit only)

 -  Vital signs (4 week visit only)

 -  ECOG performance score (4 week visit only)

 -  Blood samples will be taken for routine biochemistry, haematology, coagulation tests (4
 week visit only),and thyroid function testing (12 & 24 week visits only)

 -  Signs and symptoms (side effects) or other adverse events they may be experiencing and
 any medications being taken

 -  Clavien-Dindo assessment of any surgical complications will be carried out as per normal
 hospital practice (4 & 12 week visits only)

 -  Blood sample (approximately 20ml/4 teaspoons) and urine sample (approximately 50ml) for
 research purposes

 -  Survival, disease status and new anti-cancer treatment information (12 & 24 week visits
 only)

 Patients will be followed up at 1 year and 2 years after surgery for details on survival,
 disease status and new anti-cancer treatment information. This will be conducted via
 telephone or review of patient medical notes on site.
Inclusion Criteria:

 Cohort-Specific Inclusion Criteria • Bladder cohort: Histopathologically confirmed
 carcinoma of the urothelium (T1 high grade -T4a) in the bladder with mixed or rare
 histological subtypes such as squamous cell or adenocarcinoma. Patients with mixed
 histologies are required to have a dominant non- transitional cell pattern.

 • UTUC cohort:

 Histopathologically confirmed,high grade or high risk upper urinary tract urothelial
 carcinoma (renal pelvis and ureter). This cohort includes all patients with upper tract
 malignancy who in the opinion of the investigators qualify for radical surgery
 (nephroureterectomy or distal ureter resection). Urothelial carcinoma of the upper urinary
 tract qualifies as high-risk disease if any of the below factors are present:

 -  Hydronephrosis

 -  Tumour size >2cm on cross sectional imaging

 -  High grade cytology

 -  High grade biopsy

 -  Multifocal disease

 -  Variant histology

 -  Previous radical cystectomy for urothelial cancer of the bladder

 All patients undergoing radical surgery with curative intent in the opinion of the
 investigator are eligible. Radical surgical interventions include nephroureterectomy or
 distal ureteral resection.

 General inclusion criteria:

 1. Willing and able to provide written informed consent

 2. Ability to comply with the protocol

 3. Age ≥ 18 years

 4. Residual disease after TURBT or URS (surgical opinion, endoscopy or radiological
 presence).

 5. Fit and planned for radical surgery with curative intent in the opinion of the
 investigator (according to local guidelines).

 6. N0 or M0 disease CT or MRI (within 4 weeks of registration)

 7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an
 associated pathology report that are determined to be available and sufficient for
 central testing.

 8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant
 cisplatin-based therapy is not appropriate.

 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

 10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of
 childbearing potential.

 11. For female patients of childbearing potential to use a highly effecting form(s) of
 contraception (i.e. one that results in a low failure rate [<1% per year] when used
 consistently and correctly) and to continue its use for 90 days after the last dose of
 atezolizumab.

 12. Adequate hematologic and end-organ function within 4 weeks prior to the first study
 treatment defined by the following:

 1. ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within
 2 weeks prior to Cycle 1, Day 1)

 2. WBC counts > 2500/μL

 3. Lymphocyte count ≥ 500/μL

 4. Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1,
 Day 1)

 5. Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic
 treatment to meet this criterion).

 6. AST or ALT,and alkaline phosphatase ≤ 2.5 times the institutional upper limit of
 normal (ULN) (patients with known Gilbert disease who have serum bilirubin level
 ≤ 3 × the institutional ULN may be enrolled).

 7. INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are
 not receiving therapeutic anticoagulation; patients receiving therapeutic
 anticoagulation should be on a stable dose.

 8. Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)

 Exclusion Criteria:

 1. Pregnant and lactating female patients.

 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for
 a major surgical procedure during the course of the study other than for diagnosis.

 3. Previously intravenous chemotherapy for urothelial cancer.

 4. Patients with prior allogeneic stem cell or solid organ transplantation.

 5. Prior treatment with CD137 agonists,anti-CTLA-4,anti-programmed death-1 (PD-1),or
 anti-PD-L1 therapeutic antibody or pathway-targeting agents.

 6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The
 use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids
 (i.e.,for adrenal insufficiency), and mineralocorticoids (e.g. fludrocortisone) is
 allowed.

 7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to
 enrolment (Patients receiving prophylactic antibiotics (e.g.,for prevention of a
 urinary tract infection or chronic obstructive pulmonary disease) are eligible).

 8. Administration of a live,attenuated vaccine within 4 weeks prior to enrolment or
 anticipation that such a live,attenuated vaccine will be required during the study.

 9. Treatment with systemic immunostimulatory agents (including but not limited to
 interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug,
 whichever is shorter, prior to enrolment.

 10. Treatment with any other investigational agent or participation in another clinical
 trial with therapeutic intent within 4 weeks prior to enrolment.

 11. Evidence of significant uncontrolled concomitant disease that could affect compliance
 with the protocol or interpretation of results, including significant liver disease
 (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava
 syndrome).

 12. Malignancies other than UC within 5 years prior to Cycle 1,Day 1,with the exception of
 those with a negligible risk of metastasis or death and treated with expected curative
 outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous
 cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent)
 or localized prostate cancer treated with curative intent and absence of
 prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤
 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).

 13. Severe infections within 4 weeks prior to enrolment in the study including but not
 limited to hospitalization for complications of infection, bacteraemia,or severe
 pneumonia.

 14. Significant cardiovascular disease, such as New York Heart Association cardiac disease
 (Class II or greater), myocardial infarction within 3 months prior to enrolment,
 unstable arrhythmias, or unstable angina.

 15. History of idiopathic pulmonary fibrosis (including pneumonitis),drug-induced
 pneumonitis, organizing pneumonia (i.e.,bronchiolitis obliterans, cryptogenic
 organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
 (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).

 16. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes
 controlled on a stable insulin regimen are eligible.

 17. Patients with active hepatitis infection (defined as having a positive hepatitis B
 surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past
 hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a
 negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc]
 antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody
 are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

 18. Positive test for HIV

 19. Patients with active tuberculosis

 20. History of gastrointestinal disorders (medical disorders or extensive surgery) which
 may interfere with the absorption of the study drug.

 21. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected
 serum calcium > the institutional ULN) or symptomatic hypercalcemia requiring
 continued use of bisphosphonate therapy or denosumab. Patients who are receiving
 bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do
 not have a history of clinically significant hypercalcemia are eligible. Patients who
 are receiving denosumab prior to enrollment must be willing and eligible to receive a
 bisphosphonate instead while on study.

 22. History of autoimmune disease including but not limited to myasthenia gravis,
 myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
 inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
 syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
 multiple sclerosis, vasculitis, or glomerulonephritis.

 23. Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose
 of thyroid-replacement hormone.

 24. History of severe allergic, anaphylactic,or other hypersensitivity reactions to
 chimeric or humanized antibodies or fusion proteins

 25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
 ovary cells or any component of the atezolizumab formulation