| Eligibility |
Inclusion Criteria:
1. Male or female subjects = 18 years old.
2. Written informed consent approved by the Independent Ethics Committee (IEC), prior to
the performance of any trial activities.
3. Patients with histologically documented, locally advanced (T4B, any N; or any T, N2-3)
or metastatic urothelial carcinoma (M1, Stage IV)*.
*Also termed transitional cell carcinoma (TCC) or Urothelial Cell Carcinoma (UCC) of
the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra).
4. Patients should not be eligible (unfit) for full dose of cisplatin, in the
investigator's judgement, based on:
a. Age older than 70 years. b. Eastern Cooperative Oncology Group (ECOG) Performance
status (PS) 2 or Karnofsky PS of 60 - 70% (only 15 patients will be included with ECOG
2). c. Measured creatinine clearance (ClCr) > 30 and < 60 mL/min by the
Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for
the determination of creatinine clearance:
Males:
Creatinine Clearance (CL) (mL/min) = Weight (kg) × (140 - Age) 72 x serum creatinine
(mg/dL)
Females:
Creatinine CL (mL/min) =
Weight (kg) × (140 - Age) ×0.85 72 x serum creatinine (mg/dL) d. Any other reason the
physician considers but should specify in the Case Report Form (CRF) and discussed
with the PI.
5. At least one measurable lesion through radiographic tumor evaluation (CT scan or
magnetic resonance imaging/MRI) as defined by RECIST version 1.1, that has not been
previously irradiated within 4 weeks prior to the study enrolment.
6. Patients with an archival or de novo tumor biopsy (representative formalin-fixed
paraffin-embedded (FFPE) paraffin block obtained within 6 months prior to inclusion)
with an associated pathology report, for testing of PD-L1 expression prior to study
enrollment. Samples in unstained slides could be acceptable (at least 15 slides).
7. Patients with adequate normal organ and marrow function as defined below:
1. Haemoglobin = 9.0 g/dL.
2. Absolute neutrophil count (ANC) > 1500 per mm
3. Platelet count = 100,000 per mm
4. Serum bilirubin = 1.5 X institutional upper limit of normal (ULN) unless liver
metastases are present, in which case it must be = 2X ULN. This will not apply to
patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of
haemolysis or hepatic pathology); however, they will be allowed only in
consultation with their physician.
5. Serum transaminases (ALT, AST and GGT) = 2.5X institutional upper limit of normal
unless liver metastases are present, in which case it must be = 3X ULN.
8. No major active bleeding.
9. Female subjects of childbearing potential (not surgically sterile or at least 2 years
postmenopausal) must provide a negative urine pregnancy test at screening, and use a
medically accepted double barrier method of contraception. In addition, they must
agree to continue the use of this double barrier method for the duration of the study
and for 6 months after participation in the study.
10. Males should agree to abstain from sexual intercourse with a female partner or agree
to use a double barrier method of contraception (i.e. condom with spermicide, in
addition to having their female partner use some contraceptive measures such as oral
contraceptive drugs, intrauterine device (IUD) hormonal contraception, or cervical
caps), for the duration of the study and for 6 months after participation in the study
11. Willingness and ability of patients to comply with the protocol for the duration of
the study including undergoing treatment as well as availability for scheduled visits
and examinations including follow up.
Exclusion Criteria:
1. Prior treatment with any immune checkpoint inhibitor therapy (e.g., CTLA4, PD-1, or
PD-L1 targeting agent).*
2. Presence of active second malignancy and/or prior malignancy in the last 2 years is
allowed except for the following:
1. adequately treated basal cell or squamous cell skin cancer,
2. adequately treated Stage I or II cancer from which the patient is currently in
complete remission per investigators' clinical judgment.
3. Patient receiving radiation therapy within 4 weeks before inclusion.
4. Active or prior documented autoimmune disease within the past 2 years. Note:
Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment
(within the past 2 years) are not excluded.
5. Active or prior documented inflammatory bowel disease (e.g.., Crohn's disease and
ulcerative colitis).
6. History of allogeneic organ transplant.
7. Subjects having a diagnosis of immunodeficiency or are receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 28 days prior to the
first dose of trial treatment.
8. Current or prior use of immunosuppressive medication within 7 days prior to enrolment,
except the following:
a. Intranasal, inhaled, topical steroids, or local steroid injections i. Systemic
corticosteroids at physiologic doses =10 mg/day of prednisone or equivalent; ii.
Steroids as premedication for hypersensitivity reactions
9. The subject has uncontrolled, significant intercurrent or recent illness (within 6
months prior to inclusion) including, but not limited to, the following conditions:
a. Cardiovascular disorders: i. Class 3 or 4 congestive heart failure as defined by
the New York Heart Association, unstable angina pectoris, and serious cardiac
arrhythmias. ii. Uncontrolled hypertension defined as sustained blood press > 150 mm
hg systolic or > 100 mm hg diastolic despite optimal antihypertensive treatment. iii.
Stroke (including Transient Ischemic Attack (TIA)), myocardial infarction, other
ischemic event, or thromboembolic event within 6 months before inclusion. Subjects
with a more recent diagnosis of Deep Vein Thrombosis (DVT) are allowed if stable,
asymptomatic, and treated with Low Molecular Weight Heparin (LMWH) for at least 6
weeks before study treatment.
b. Gastrointestinal disorders (e.g., malabsorption syndrome or gastric outlet
obstruction) including those associated with a high risk of perforation or fistula
formulation: i. Tumours invading the GI tract, active peptic ulcer disease,
inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis,
symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of
the pancreatic or biliary duct, or gastric outlet obstruction. ii. Abdominal fistula,
GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before
inclusion. Note: complete healing of an intra-abdominal abscess must be confirmed
prior to start of the treatment.
c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 ml) of
red blood or history of other significant bleeding within 3 months before treatment.
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
e. Lesions invading major pulmonary blood vessels.
f. Other clinically significant disorders such as: i. Active infection requiring
systemic treatment, infection with human immunodeficiency virus or acquired
immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection.
ii. Serious non-healing wound/ulcer/bone fracture. iii. Malabsorption syndrome. iv.
Moderate to severe hepatic impairment (child-pugh B or C). v. Requirement for
hemodialysis or peritoneal dialysis. vi. Uncontrolled diabetes mellitus.
10. Major surgery (e.g., GI surgery and removal or biopsy of brain metastasis) within 8
weeks before inclusion. Complete wound healing from major surgery must have occurred 4
weeks before study treatment and from minor surgery at least 10 days before study
treatment. Subjects with clinically relevant ongoing complications from prior surgery
are not eligible.
11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness.
12. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or
chronic infection.
13. Women who are pregnant or are breastfeeding.
14. Male patients must be surgically sterile or must agree to use effective contraception
during the period of therapy.
15. Any of the following within 6 months prior to study entry: myocardial infarction,
uncontrolled angina, uncontrolled hypertension, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident or transient
ischemic attack.
16. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
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