Inclusion Criteria:
- Participants can give signed informed consent/assent which includes compliance with
the requirements and restrictions listed in the informed consent form (ICF).
- At least eighteen years of age at the time of signing the informed consent.
- Participants with histologically confirmed locally advanced or metastatic or locally
advanced/unresectable urothelial carcinoma (including renal, pelvis, ureter, urinary
bladder, urethra). Mixed histologies are acceptable provided transitional cell
carcinoma is the predominant histology. 1. Measurable disease per RECIST v 1.1
criteria; and 2. Experienced PD or recurrence either following platinum containing
chemotherapy for metastatic or locally advanced/unresectable urothelial cancer or
within 12 months from completion of neo-adjuvant or adjuvant platinum-containing
chemotherapy for localized muscle-invasive urothelial cancer.
- Able to provide, a tumor tissue sample collected during screening and prior to
administration of bintrafusp alfa.
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
- Participants with adequate organ system functions as defined follows: Absolute
neutrophil count (ANC) >=1.5*10^9 cells per liter (cells/L); Hemoglobin >=9.0 grams
per deciliter (g/dL); Platelets >=100*10^9 cells/L; international normalized ratio
(INR) or prothrombin time (PT) <=1.5*Upper limit of normal (ULN); Albumin >=2.5 g/dL;
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) <=2.5*ULN or
<=5*ULN for participants with documented liver metastases; Total bilirubin <=1.5*ULN
(Isolated bilirubin >1.5*ULN is acceptable if bilirubin is fractionated and direct
bilirubin <35 percent); calculated creatinine clearance (CrCI) >=30 milliliter per
minute (mL/min) and Ejection Fraction >=50 percent.
- Life expectancy of at least 12 weeks.
- 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, for the following time periods: Before
the first dose of the study interventions, 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; during the intervention period; and 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.
- Participant 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.
- The Investigator reviews the medical history, menstrual history, and recent sexual
activity to decrease the risk for inclusion of a female with an early undetected
pregnancy.
- 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: Refrain from donating sperm; Be
abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on long term and persistent basis) and agree to remain abstinent or 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.
- Archival tumor sample high for Programmed Death-Ligand 1 (PD-L1) by central assay.
Exclusion Criteria:
- Active brain and/or leptomeningeal disease that is symptomatic or requires therapeutic
intervention. Participants with asymptomatic central nervous system (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.
- 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).
- No more than 2 lines of systemic therapy for the treatment of metastastic disease. If
the most recent therapy was not a platinum-based regimen, the participant must have
progressed on or after that therapy.
- Cirrhosis or current unstable liver or biliary disease per investigator assessment
defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia,
esophageal or gastric varices, or persistent jaundice.
- Current pneumonitis or history of non-infectious pneumonitis that required systemic
immunosuppressive treatment.
- Active autoimmune disease that required systemic immunosuppressive treatment within
the past 2 years.
- Received prior allogeneic/autologous bone marrow or solid organ transplant.
- 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.
- Known severe hypersensitivity reactions to monoclonal antibodies or any ingredient
used in the study treatment formulation (Grade >=3 NCI-CTCAE v 5.0).
- Active infection requiring systemic therapy.
- Received any live vaccine within 30 days prior first dose of intervention.
- Known history of positive test for human immunodeficiency virus (HIV) with the
exception of participants with cluster of differentiation 4 (CD4) + T-cell (CD4+)
counts >=350 cells per microliter (cells /uL) and no history of acquired
immunodeficiency syndrome (AIDS)-defining opportunistic infections.
- Active hepatitis B virus (HBV) (HBV surface antigen-positive).
- 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.
- 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 QTcF interval >450 millisecond (msec)
(or QTcF >480 msec for participants with bundle branch block); b. Cardiomyopathy,
myocardial infarction, acute coronary syndromes (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; and d. Symptomatic pericarditis.
- 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.
- 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.
- Received prior systemic anti-cancer therapy within 2 weeks prior to study treatment.
- Received prior therapy with an anti- programmed death 1 (PD-1), anti-PD-L1,
anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
antibody (including ipilimumab or any other antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways).
- Received prior therapy targeting transforming growth factor (TGF) beta - (e.g.,
Galunistertib).
- Received radiation therapy (or other non-systemic disease therapy) within 2 weeks
prior to study treatment.
- Undergone major surgery within 4 weeks prior to administration of study treatment.
- Residual toxicities attributed to prior anti-cancer therapy that are clinically
significant or unmanaged and >Grade 1 or previous baseline other than neuropathy
(<=Grade 2), alopecia, and fatigue.
- The participant has participated in a clinical trial and has received an
investigational product within the following time period prior to the first dosing day
in the current study: 30 days, 5 half-lives or twice the duration of the biological
effect of the investigational product (whichever is longer).
- Exposure to more than 2 investigational anti-cancer medicinal products within 12
months prior to the first dosing day.
- Is known to abuse alcohol or drugs.
- Has any psychiatric condition that would prohibit the understanding or rendering of
informed consent or consistent participation in study procedures.
- Has legal incapacity or limited legal capacity.
