Los requisitos de elegibilidad de los participantes incluyen la edad, el sexo, el tipo y el estadio de la enfermedad, y los problemas de salud o tratamientos previos. Las pautas difieren de un estudio a otro e identifican quiénes pueden o no pueden participar. No hay garantía de que cada persona elegible que desee participar en un ensayo se inscribirá. Comunícate con el equipo del estudio para analizar la elegibilidad del estudio y la posible participación.
Inclusion Criteria:
- Histologically or cytologically-confirmed diagnosis of advanced or metastatic
urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell
and mixed transitional/non-transitional cell histologies except for small-cell
histology), including N3 only disease prior to start of first-line platinum-based
chemotherapy.
- Prior first-line treatment must have consisted of 4-6 cycles of 1st-line therapy
(platinum-based chemotherapy; gemcitabine-cisplatin, gemcitabine-carboplatin,
methotrexate, vinblastine, doxorubicin and cisplatin [MVAC] or dose-dense [dd]MVAC).
- No more than 1 line of prior chemotherapy for metastatic or locally advanced disease
(neoadjuvant or adjuvant chemotherapy will be allowed if given 12 or more months prior
to registration).
- Tumor objective response of CR, PR, or SD upon completion of first line platinum-based
chemotherapy by treating physician's assessment.
- The last dose of first-line chemotherapy must have been received no less than 3 weeks,
and no more than 10 weeks, prior to randomization in the present study.
- No prior immunotherapy with IL-2, IFN-alpha, or an anti-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.
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Not pregnant and not nursing, because this study involves an agent that has known
genotoxic, mutagenic and teratogenic effects.
- Women of childbearing potential must have a negative pregnancy test ≤ 14 days prior
to registration.
- Women of childbearing potential include women who have experienced menarche and
who have not undergone successful surgical sterilization (hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post
menopause is defined as amenorrhea ≥ 12 consecutive months.
Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing
potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,
ovarian suppression or any other reversible reason.
- No use of immunosuppressive medication within 7 days prior to randomization except:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
intra-articular injection);
- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or
equivalent;
- Steroids as premedication for hypersensitivity reactions (e.g., computed
tomography [CT] scan premedication).
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.
- Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease
not requiring immunosuppressive treatment are eligible.
- Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
- Platelet count ≥ 100,000/mm^3.
- Hemoglobin ≥ 8 g/dL.
- Calculated (Calc.) creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault
equation: (140 - age) × weight (kg)/(serum creatinine [mg/dL] × 72).
- Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN).
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (or ≤ 5
x ULN for patients with liver metastases or Gilbert's disease).
- Urine protein creatinine (UPC) ratio ≤ 1 or 24-hour protein < 1 g.
Exclusion Criteria:
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent.
- No known symptomatic central nervous system (CNS) metastases. 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 randomization, have discontinued corticosteroid treatment for at least 2 weeks, and are neurologically stable. Baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility.
- No major surgery within 4 weeks prior to randomization. Subjects must have complete
wound healing from surgery before randomization. Subjects with clinically relevant
ongoing complications from prior surgery are not eligible.
- No palliative radiotherapy within 48 hours prior to patient randomization.
- No hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood, clinically significant
hematuria, hematemesis, coagulopathy, or other history of significant bleeding (e.g.,
pulmonary hemorrhage) within 3 months before randomization.
- No known cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
- No administration of a live, attenuated vaccine within 30 days prior to randomization.
The use of inactivated (killed) vaccines for the prevention of infectious disease is
permitted. The use of COVID-19 vaccines is permitted.
- No uncontrolled, significant intercurrent or recent illness including, but not limited
to, the following conditions:
- Cardiovascular disorders including:
- Congestive heart failure (CHF): New York Heart Association (NYHA) class III
(moderate) or class IV (severe) at the time of screening;
- Concurrent uncontrolled hypertension defined as sustained blood pressure
(BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal
antihypertensive treatment;
- The patient has a known history of corrected QT interval calculated by the
Fridericia formula (QTcF) > 500 ms and confirmed by electrocardiogram (ECG)
within 28 days before randomization.
Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3
minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard;
- Any history of congenital long QT syndrome;
- Stroke, transient ischemic attack (TIA), myocardial infarction, or other
symptomatic ischemic event or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism (DVT/PE) within 6 months before
randomization. Subjects with a diagnosis of incidental, subsegmental PE or
DVT within 6 months are allowed if asymptomatic and stable at screening and
treated with low molecular weight heparin (LMWH) or the direct factor Xa
inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before
randomization. Non-symptomatic white matter disease in the brain is
acceptable;
- No significant gastrointestinal disorders, particularly those associated with a
high risk of perforation or fistula formation including unresolved active peptic
ulcer disease, cholecystitis, diverticulitis, symptomatic cholangitis or
appendicitis, or malabsorption syndrome within 28 days of randomization.
- No other clinically significant disorders such as:
- Any active infection requiring systemic treatment within 14 days before
randomization. Subjects receiving oral (including prophylactic) antibiotics
with no symptoms of infection at randomization are eligible;
- Serious non-healing wound/ulcer/bone fracture within 28 days before
randomization;
- History of organ or allogeneic stem cell transplant;
- No persisting toxicity related to prior therapy grade > 2 constituting a safety
risk based on the investigator's judgment;
- No diagnosis of any other malignancy within 3 years prior to randomization,
except for locally curable cancers that have been adequately treated such as
basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of
the cervix, Gleason < 7 prostate cancer on surveillance without any plans for
treatment intervention (e.g., surgery, radiation, or castration), or prostate
cancer that has been adequately treated with prostatectomy or radiotherapy and
currently with no evidence of disease or symptoms and no indication for treatment;
- No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct
thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or
platelet inhibitors (e.g., clopidogrel).
- Allowed anticoagulants are the following:
- Prophylactic use of low-dose aspirin for cardio-protection (per local
applicable guidelines) and low-dose low molecular weight heparins
(LMWH).Therapeutic doses of LMWH or anticoagulation with direct factor
Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without
known brain metastases who are on a stable dose of the anticoagulant
for at least 1 week before first dose of study treatment without clinically
significant hemorrhagic complications from the anticoagulation regimen or the tumor.
- Physicians should consider whether any of the following may render the patient
inappropriate for this protocol:
- Psychiatric illness which would prevent the patient from giving informed consent;
- Uncontrolled medical conditions which, in the opinion of the treating physician,
would make this protocol unreasonably hazardous for the patient;
- Patients who cannot swallow oral formulations of the agent(s).
In addition:
- Women and men of reproductive potential should agree to use an appropriate method of
birth control throughout their participation in this study due to the teratogenic
potential of the therapy utilized in this trial. Include as applicable: Appropriate
methods of birth control include abstinence, oral contraceptives, implantable hormonal
contraceptives or double barrier method (diaphragm plus condom);
- Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's
syndrome and psoriasis controlled with topical medication and or steroids equivalent
to < 10 mg prednisone daily, not on immunosuppressive medications and patients with
positive serology are eligible. Patients with vitiligo, endocrine deficiencies including
hypo or hyper thyroid disease managed with replacement, diabetes type 1 are
eligible.
- Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (e.g., male or female condom) during the study and continue
for 4 months after the last dose of study drugs, even if oral contraceptives are also
used.
Note: Other protocol defined Inclusion/Exclusion Criteria may apply.
Eligibility last updated 8/22/22. Questions regarding updates should be directed to the study team contact.