AVELUMAB SHORT MAINTENANCE

In order to be eligible to participate in this study, a patient must meet all of the following criteria:

Patient eligibility should be reviewed and documented by an appropriate member of the
investigator’s study team before patients are included in the study.

Patients must meet all of the following inclusion criteria to be eligible for enrolment into the
study:

1. Diagnosis:
a. Histologically confirmed, unresectable locally advanced or metastatic transitional
cell carcinoma of the urothelium.
b. Documented Stage IV disease (T4b, N0, M0; any T, N1–N3, M0; any T, any N,
M1) at the start of first-line chemotherapy.
c. Measurable disease prior to the start of first-line chemotherapy by RECIST v1.1.

2. Prior first-line chemotherapy must have consisted of at least 4 cycles and no more
than 6 cycles of gemcitabine + cisplatin and/or gemcitabine + carboplatin. No other
chemotherapy regimens are allowed in this study.

3. Patients without progressive disease as per RECIST v1.1 guidelines (ie, with an
ongoing CR, PR, or SD) following completion of 4 to 6 cycles of first-line
chemotherapy.

4. Plasma samples: Provision of a baseline plasma sample is mandatory

5. Evidence of a signed and dated informed consent document indicating that the patient
(or a legally acceptable representative, as allowed by local guideline/practice) has
been informed of all pertinent aspects of the study.

6. Patients who are willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other study procedures.

7. Age; Minimum of 18 years

8. Estimated life expectancy of at least 3 months.

9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (Appendix 1).

10. Adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100 x 109/L;
c. Hemoglobin 5.6 mmol/L (may have been transfused).

11. Adequate renal function, defined as estimated creatinine clearance 30 mL/min as
calculated using the Cockcroft-Gault equation

12. Adequate liver function, including:
a. Total serum bilirubin 1.5 x upper limit of normal (ULN);
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)2.5 x ULN.

13. Serum pregnancy test (for females of childbearing potential) negative at screening.

14. Male patients able to father children and female patients of childbearing potential and
at risk for pregnancy must agree to use 2 highly effective methods of contraception
(Section 4.3.1) throughout the study and for at least 60 days after the last dose of
assigned treatment.

A potential patient who meets any of the following criteria will be excluded from participation in this study:

Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients whose disease progressed by RECIST v1.1 on or after first-line
chemotherapy for urothelial cancer.

2. Prior adjuvant or neoadjuvant therapy within 12 months of initiation of avelumab.

3. Prior immunotherapy with IL-2, IFN-ɣ.-PD-1, anti-PD-L1, anti-PD-L2,
anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.

4. Major surgery 4 weeks or major radiation therapy 2 weeks prior to initiation of avelumab. Prior palliative radiotherapy (10 fractions) to metastatic lesion(s) is permitted,
provided it has been completed at least 48 hours prior to patient initiation.

5. Patients with known symptomatic central nervous system (CNS) metastases requiring
steroids. Patients with previously diagnosed CNS metastases are eligible if they have
completed their treatment and have recovered from the acute effects of radiation
therapy or surgery prior to initiation of avelumab, have discontinued corticosteroid treatment for these metastases for at least 4 weeks, and are neurologically stable.

6. Persisting toxicity related to prior therapy NCI CTCAE v5.0 Grade >1; however,
sensory neuropathy Grade 2 is acceptable.

7. Diagnosis of any other malignancy within 5 years prior to initiation of avelumab, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the
breast or of the cervix, or low-grade (Gleason 6) prostate cancer on surveillance
without any plans for treatment intervention (eg, surgery, radiation, or castration).

8. Participation in other studies involving investigational drug(s) within 4 weeks prior to
initiation of avelumab. Observational studies are permitted.

9. Active autoimmune disease that might deteriorate when receiving an
immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo
orhyperthyroid disease not requiring immunosuppressive treatment are eligible.

10. Any of the following in the previous 6 months: myocardial infarction, severe/unstable
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure,
cerebrovascular accident, transient ischemic attack, deep vein thrombosis, or
symptomatic pulmonary embolism.

11. Active infection requiring systemic therapy.

12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade 3), any
history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of asthma
symptom control per the Global Initiative for Asthma 2015). 62

13. Known prior or suspected hypersensitivity to study drugs or any component in their
formulations.

14. Current or prior use of immunosuppressive medication within 7 days prior to
initiation of avelumab, EXCEPT the following:
a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular
injection);
b. Systemic corticosteroids at (equivalent) doses of maximum 10 mg prednisone
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).

15. Diagnosis of prior immunodeficiency or organ transplant requiring
immunosuppressive therapy, or known human immunodeficiency virus (HIV) or
acquired immunodeficiency syndrome (AIDS)-related illness.

16. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or
chronic infection.

17. Vaccination within 4 weeks of the first dose of study treatment and while on trial is
prohibited except for administration of inactivate vaccines (for example, inactivated
influenza vaccines).

18. Patients 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 patients who are Pfizer employees directly involved in the conduct of
the study.

19. Pregnant female patients; breastfeeding female patients; male patients able to father
children, and female patients of childbearing potential who are unwilling or unable to
use 2 highly effective methods of contraception as outlined in the protocol for the
duration of the study and for at least 60 days after the last dose of avelumab.

20. Other severe acute or chronic medical conditions including colitis, inflammatory
bowel disease, and pneumonitis; psychiatric condition including recent (within the
past year) or active suicidal ideation or behaviour; or laboratory abnormality that may
increase the risk associated with study participation or study treatment administration
or may interfere with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this study.