A Phase III Randomized, Open-Label, Multicenter Study to Determine the
Efficacy and Safety of Durvalumab in Combination With Tremelimumab
and Enfortumab Vedotin or Durvalumab in Combination With Enfortumab
Vedotin for Perioperative Treatment in Patients Ineligible for Cisplatin or
Who Refuse Cisplatin Undergoing Radical Cystectomy for Muscle Invasive
Bladder Cancer (VOLGA)

1 Participant must be >= 18 years
2 Histologically or cytologically documented muscle-invasive TCC of the bladder
with clinical stage of T2-4aN0-N1M0
3 Medically fit for cystectomy and able to receive neoadjuvant therapy
4 ECOG performance status of 0 to 2 with no deterioration over the previous 2
weeks prior to baseline or day of first dosing.
5 Provision of the most recent tissue sample from MIBC to assess the PD L1
status/expression prior to randomization.
6 Cisplatin-ineligible, determined by protocol OR Refuse cisplatin-based
chemotherapy
7 Adequate organ and marrow function, determined by protocol
8 Minimum life expectancy of 12 weeks at randomization per the opinion of the
investigator.
9 Body weight > 30 kg.
10 Negative pregnancy test (serum) for women of childbearing potential.
11 Female participants must be 1 year post-menopausal, surgically sterile, or
using one highly effective form of birth control (a highly effective method of
contraception is defined as one that can achieve a failure rate of less than 1%
per year when used consistently and correctly.) Women of childbearing potential
must agree to use one highly effective method of birth control. They should
have been stable on their chosen method of birth control for a minimum of 3
months before entering the study to 90 days after the last dose of durvalumab,
180 days after the last dose of durvalumab + tremelimumab, or 2 months after
the last dose of EV, whichever is longer. Non sterilized male partners of a
woman of childbearing potential must use a male condom plus spermicide (condom
alone in countries where spermicides are not approved) throughout this period.
12 Non-sterilized male participants who intend to be sexually active with a
female partner of childbearing potential must be surgically sterile or using an
acceptable method of contraception (per protocol) from the time of screening
throughout the total duration of the study and the drug washout period (90 days
after the last dose of durvalumab, 180 days after the last dose of durvalumab +
tremelimumab, or 4 months after the last dose of EV, whichever is longer) to
prevent pregnancy in a partner. Male participants must not donate or bank sperm
during this same time period.
13 Capable of giving signed informed consent as described in protocol Appendix
A 3, which includes compliance with the requirements and restrictions listed in
the ICF and in the protocol.
14 Provision of signed and dated written Optional Genetic Research Information
informed consent prior to collection of sample for optional genetic research
that supports Genomic Initiative.

1 Evidence of multiple lymph node (N2+) or metastatic TCC/UC, extravesical
TCC/UC that invades the pelvic and/or abdominal wall for bladder cancer (T4b),
or primary non bladder (ie, ureter, urethral, or renal pelvis) TCC/UC of the
urothelium.
2 Nephroureterectomy required per investigator at the time of randomization for
tumor of the mid ureter, renal pelvis, or collecting system.
3 Ureterectomy required if a ureteral tumor is present proximal to common
iliacs in addition to planned cystectomy.
4 History of allogeneic organ transplantation that requires use of
immunosuppressive agents. Participants with a history of allogenic stem cell
transplantation are also excluded.
5 Active or prior documented autoimmune or inflammatory disorders (eg. Given
per protocol). The following are exceptions to this criterion:
* Participants with vitiligo or alopecia
* Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement
* Any chronic skin condition that does not require systemic therapy
* Participants without active disease in the last 5 years may be included but
only after consultation with the Study Physician
* Participants with celiac disease controlled by diet alone may be included but
only after consultation with the Study Physician
6 Uncontrolled intercurrent illness, including but not limited to, ongoing or
active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active
interstitial lung disease, serious chronic gastrointestinal conditions
associated with diarrhea, or psychiatric illness/social situations that would
limit compliance with study requirement, substantially increase risk of
incurring AEs or compromise the ability of the participant to give written
informed consent
7 Ongoing sensor or motor neuropathy of CTCAE Grade 2 or higher
8 Active keratitis or corneal ulcerations. Participants with superficial
punctate keratitis are allowed if the disorder is being adequately treated in
the opinion of the investigator.
9 History of another primary malignancy except for
* Prostate cancer of pathologic stage <= T2cN0M0 that has been previously
treated without evidence of biochemical recurrence at time of study entry and
who in the opinion of the investigator are not deemed to require active
intervention at the present time, or participants with incidental histologic
findings of prostate cancer that has not been treated prior to the study and
who do not require specific therapy for prostate cancer beyond the surgery
described in the protocol and also are considered to be at low risk for
recurrence per the investigator
* Malignancy treated with curative intent and with no known active disease >= 5
years before the first dose of IP and of low potential risk for recurrence
* Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease
* Adequately treated carcinoma in situ without evidence of disease
10 History of active primary immunodeficiency
11 Active infection including tuberculosis , hepatitis B, hepatitis C, or human
immunodeficiency virus. Participants with a past or resolved hepatitis B
infection (defined as the presence of hepatitis B core antibody [anti-HBc] and
absence of hepatitis B surface antigen) are eligible. Participants positive for
hepatitis C antibody are eligible only if polymerase chain reaction is negative
for hepatitis C RNA.
12 Mean QT interval corrected for heart rate using Fridericia*s formula (QTcF)
>= 470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
13 Known allergy or hypersensitivity to any of the study interventions or any
of the study intervention excipients
14 NYHA Class IV Heart Failure
15 Baseline hemoglobin A1C >= 8%
16 Prior exposure to immune-mediated therapy (with exclusion of
Bacillus-Calmette Guerin [BCG]), including but not limited to other
anti-CTLA-4, anti-PD-1, anti PD L1, or anti PD-L2 antibodies.
17 Receipt of live attenuated vaccine within 30 days prior to the first dose of
IP. Note: Participants, if enrolled, should not receive live vaccine whilst
receiving IP and up to 30 days after the last dose of IP.
18 Major surgical procedure (as defined by the investigator) within 28 days
prior to the first dose of IP. Note: Local surgery of isolated lesions for
palliative intent is acceptable.
19 Prior pelvic radiotherapy treatment within 6 months of randomization to
study.
20 Any prior radiotherapy for bladder cancer.
21 Current or prior use of immunosuppressive medication within 14 days before
the first dose of durvalumab or tremelimumab with exceptions described in the
protocol.
22 Any concurrent anticancer treatment. Concurrent use of hormonal therapy for
non cancer related conditions (eg, hormone replacement therapy) is allowed.
23 Participation in another clinical study with an IP administered in the last
30 days
24 Previous IP assignment in the present study (Participants in the safety
run-in will not be permitted to participate in the main study.)
25 Concurrent enrollment in another clinical study, unless it is an
observational (non interventional) clinical study or during the follow-up
period of an interventional study
26 Prior randomization or treatment in a previous durvalumab and/or
tremelimumab clinical study regardless of treatment arm assignment.
27 Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca staff and/or staff at the study site).
28 Judgment by the investigator that the participant should not participate in
the study if the participant is unlikely to comply with study procedures,
restrictions, and requirements.
29 Currently pregnant (confirmed with positive pregnancy test) or breast
feeding.