A Phase Ib Trial to Evaluate the Efficacy and Safety of Bintrafusp Alfa Monotherapy in Metastatic or Locally Advanced/Unresectable Urothelial Cancer with Disease Progression or Recurrence Following Treatment with a Platinum Agent

1. Can give signed informed consent/assent which includes compliance with the
requirements and restrictions listed in the ICF and in this protocol
2. Eighteen (18) years at the time of signing the informed consent.
3. Histologically confirmed locally advanced or metastatic or locally
advanced/unresectable urothelial carcinoma (including renal, pelvis, uterus,
urinary bladder, urethra). Mixed histologies are acceptable provided
transitional cell carcinoma is the predominant histology. a) Measurable disease
per RECIST v1.1 criteria. b) Experienced disease progression or recurrence
either (1) following platinum containing chemotherapy for metastatic or locally
advanced/unresectable urothelial cancer or (2) within 12 months from completion
of neo-adjuvant or adjuvant platinum-containing chemotherapy for localized
muscle-invasive urothelial cancer.
4. Able to provide, a tumor tissue sample collected during screening and prior
to administration of bintrafusp alfa (see SRM for details).
5. Able to provide an archival tumor sample (preferably from the most recent
biopsy). Archival material is formalin fixed tumor tissue sample from a biopsy
of a tumor lesion.
6. All prior treatment-related toxicities (defined by National Cancer Institute
Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0) must be * Grade 1
at the time of enrollment, except alopecia, grade 2 neuropathy, or asymptomatic
toxicities that are clinically stable with medical management (e.g. electrolyte
abnormalities, etc.). ECOG PS 0 or 1.
7. Adequate organ system functions as defined by the laboratory assessments
8. Life expectancy of at least 12 weeks.
9. A female is eligible if she is not pregnant or breastfeeding, and at least
one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP). OR
* If a WOCBP, use a highly effective contraceptive method (i.e., with a failure
rate of <1% per year), preferably with low user dependency, as described in the
following time periods:
o Before the first dose of the study intervention(s), if using hormonal
contraception:
* -Has completed at least one 4-week cycle of an oral contraception pill and
either had or has begun her menses.
OR
-Has used a depot contraceptive or extended-cycle oral contraceptive for least
28 days and has a documented negative pregnancy test using a highly sensitive
assay.
o During the intervention period
o After the study intervention period (i.e., after the last dose of study
intervention is administered) for at least 2 months. The Investigator evaluates
the effectiveness of the contraceptive method in relationship to the first dose
of study intervention.
Has a negative serum or highly sensitive urine pregnancy test, as required by
local regulations, within 24 hours before the first dose of study intervention.
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a
serum pregnancy test is required.
Male participants:
* Contraceptive use by men should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies.
* Male participants are eligible to participate if they agree to the following
from the time of first dose of study until 125 days after the last dose of
study treatment to allow for clearance of any altered sperm:
o Refrain from donating sperm.
PLUS, either:
* Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle (abstinent on long term and persistent basis) and agree to remain
abstinent.
OR
* Must agree to use contraception/barrier as detailed below. Agree to use a
male condom and female partner to use an additional highly effective
contraceptive method with a failure rate of <1% per year when having sexual
intercourse with a woman of childbearing potential who is not currently
pregnant.
10. Archival tumor sample high for PD-L1 by central assay.

1. Active brain and/or leptomeningeal disease that is symptomatic or requires
therapeutic intervention. Participants with asymptomatic CNS metastases who are
clinically stable as demonstrated by serial brain images and have no
requirement for corticosteroids for at least 14 days prior to enrollment are
eligible. 2. History of malignancy other than urothelial cancer within the last
3 years except for localized tumors that have been treated with curative intent
or have not required therapy in the past 2 years. (e.g., resected non-melanoma
skin cancer, etc.).
3. No more than 2 lines of systemic therapy for the treatment of meatastastic
disease. If the most recent therapy was not a platinumbased regimen, the
participant must have progressed on or after that therapy. 4. Cirrhosis or
current unstable liver or bilary disease per investigator assessment defined by
the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia,
oesophageal or gastric varices, or persistent jaundice. NOTE: Stable
non-cirrhotic chronic liver disease (including Gilbert's syndrome or
asymptomatic gallstones) is acceptable if participant otherwise meets entry
criteria.
5. Current pneumonitis or history of non-infectious pneumonitis that required
systemic immunosuppressive treatment.
6. Active autoimmune disease that required systemic immunosuppressive treatment
within the past 2 years.
7. Received prior allogeneic/autologous bone marrow or solid organ transplant.
8. Receiving systemic corticosteroids (10 mg daily oral prednisone or
equivalent) or other immunosuppressive agent within 7 days prior to study
treatment. Inhaled or topical steroids are permitted. Note: a) Physiologic
doses of corticosteroids for treatment of endocrinopathies or steroids with
minimal systemic absorption, including (e.g., topical, inhaled,
intra-articular, ophthalmic, intranasal); corticosteroids may be continued if
the participant is on a stable dose b) Steroids as premedication for
hypersensitivity reactions (e.g., CT scan premedication) are permitted.
9. Known severe hypersensitivity reactions to monoclonal antibodies or any
ingredient used in the study treatment formulation (Grade 3 NCICTCAE v5).
10. Active infection requiring systemic therapy.
11. Received any live vaccine within 30 days prior first dose of intervention.
12. Known history of positive test for human immunodeficiency virus (HIV) with
the exception of participants with CD4+ T-cell (CD4+) counts greater than or
equal to 350 cells/uL and no history of AIDS-defining opportunistic infections.
13. Active hepatitis B virus (HBV) (HBV surface antigen-positive).
14. Active hepatitis C virus (HCV) infection, or positive HCV antibody, with
the exception of participants that (1) have HCV viral load below the limits of
quantitation and (2) completed curative antiviral therapy or are receiving and
compliant with antiviral therapy
15. History or evidence of cardiac abnormalities within the 6 months prior to
first dose of intervention which include: a. Serious, uncontrolled cardiac
arrhythmia or clinically significant electrocardiogram abnormalities including
second degree (Type II) or third-degree atrioventricular block or QTc interval
> 450 msec (or QTc > 480 msec for participants with bundle branch block). b.
Cardiomyopathy, myocardial infarction, acute coronary syndromes XML File
Identifier: fLjMlVGtQpIe/E0445DzoEMLnCU= Page 13/23 (including unstable angina
pectoris), coronary angioplasty, stenting or bypass grafting c. Congestive
heart failure (Class II, III, or IV) as defined by the New York Heart
Association functional classification system d. Symptomatic pericarditis
16. Participants with history of bleeding diathesis or recent major bleeding
events considered by the Investigator as high risk for investigational drug
treatment are also excluded.
17. Any other serious or uncontrolled medical disorder that, in the opinion of
the investigator, may increase the risk associated with study participation or
study drug administration, impair the ability of the participant to receive
protocol therapy, or interfere with the interpretation of study results.
Prior/Concomitant Therapy
18. Received prior systemic anti-cancer therapy within 2 weeks prior to study
treatment.
19. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,
anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4)
antibody (including ipilimumab or any other antibody or drug specifically
targeting T-cell co-stimulation or checkpoint pathways).
20. Received prior therapy targeting TGF-* (e.g., Galunistertib, etc.).
21. Received radiation therapy (or other non-systemic disease therapy) within 2
weeks prior to study treatment.
22. Undergone major surgery within 4 weeks prior to administration of study
treatment.