Ensayos clínicos

Inclusion Criteria:

Signed Written Informed Consent

• Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study.

Target Population

• All subjects must be status post radical surgical resection (R0) for IUC, performed within 120 days prior to randomization. Subjects with carcinoma in situ in surgical margins are not eligible for study entry.
• All subjects must have pathologic evidence of urothelial carcinoma (originating in bladder, ureter, or renal pelvis) at high risk of recurrence based on pathologic staging of radical surgery tissue as described in one of the two below scenarios (i or ii):
  • Subjects who have not received neo-adjuvant cisplatin chemotherapy: pT3-pT4a or pN+ and are not eligible for or refusing adjuvant cisplatin chemotherapy.
    • Subjects ineligible for adjuvant cisplatin due to any of the following criteria:50
      • Creatinine Clearance (using the Cockcroft-Gault formula): < 60 mL/min;
      • Common Terminology Criteria for Adverse Events (CTCAE) version 4, grade 2 or above audiometric hearing loss;
      • CTCAE version 4, grade 2 peripheral neuropathy;
      • Eastern Cooperative Oncology Group Performance Scale (ECOG PS) 2;
      • NYHA Class III or IV Heart Failure.
    • Subjects that are eligible for cisplatin may be candidates if they refuse available adjuvant chemotherapy, despite being informed by the investigator about the treatment options. The subject’s refusal must be thoroughly documented.
  • Subjects who received neo-adjuvant cisplatin chemotherapy: ypT2-pT4a or ypN+.
    • Dominant component of histology needs to be urothelial carcinoma or transitional cell carcinoma. Foci of varied histologies (e.g., minor variants) are accepted.
    • All subjects must have disease-free status defined as no clinical or radiographic evidence of recurrence of disease documented by a complete physical examination and imaging studies within 4 weeks prior to randomization. Subjects with equivocal nodes less than 15 mm in short axis not considered by the investigator to represent malignant disease may be eligible if discussed and approved by BMS Medical Monitor. All suspect lesions identified during screening radiographic procedures should be discussed with the Medical Monitor prior to randomization.
      • Imaging studies must include CT of chest and CT or MRI of abdomen, pelvis, and all known sites of resected disease including cystoscopy in subjects with upper GU primaries who still have  bladder intact. Brain imaging (MRI except where contraindicated in which CT scan is acceptable) must be completed within 28 days prior to randomization for subjects with clinical suspicion or history of brain/leptomeningeal metastases.
      • Subjects who are found to have high-risk NMIBC at the time of screening are not eligible for study entry. Patients with low-risk papillary lesions may enter the study if rendered free of disease at cystoscopy. Subjects with intermediate-risk NMIBC may enter the study if intravesical chemotherapy or BCG is not required. Screening cystoscopy may occur within 60 days of  randomization and is encouraged to be done prior to other imaging. Any suspect lesions seen on cystoscopy should be biopsied to rule-out the possibility of high-risk lesions.
  • Low-risk NMIBC is defined as low-grade lesions or papillary urothelial neoplasms of low malignant potential (PUNLMP; WHO/ISUP 2004 grading system), or TaG1 lesions (WHO 1973 grading system) that are less than 3 cm in diameter.
  • High-risk NMIBC is defined as any T1 lesion, any lesion containing carcinoma in situ (CIS) either alone or concomitantly with papillary disease (e.g., CIS with Ta/T1 lesions), and any Ta high-grade (TaHG; WHO/ISUP 2004 grading system) or TaG3 (WHO 1973 grading system) lesion.
  • Intermediate-risk NMIBC is defined as lesions not meeting the criteria of high-risk or lowrisk.
    • Tumor tissue from the most recently resected site of disease (preferable) or from the transurethral resection that yielded the initial muscle invasive diagnosis must be provided for biomarker analyses. In order to be randomized, a subject must have a PD-L1 expression level classification ( 1%, < 1%, indeterminate) as determined by the central lab. If insufficient tumor tissue content is provided for analysis (e.g., unevaluable), acquisition of additional archived tumor tissue from the most recent resection (preferable) or from the transurethral resection that yielded the initial muscle invasive diagnosis is required.
    • Life expectancy 6 months.
    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Per inclusion 2 b) i) (1), ECOG PS 2 is listed as part of cisplatin ineligibility criteria.
    • Subjects who have not received cisplatin based neoadjuvant chemotherapy and are considered ineligible for cisplatin adjuvant chemotherapy, may enter the study with ECOG PS 2.
    • Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration. Trans-urethral resection of bladder tumor (TURBT) must be completed 14 days before randomization.
    • Adequate hematologic, renal, and liver function (using CTCAE v4). (All baseline laboratory requirements will be assessed and should be obtained within 14 days prior to randomization):
      • WBC 2000/μL;
      • Neutrophils 1500/μL;
      • Platelets 100 x 103/μL;
      • Hemoglobin 9.0 g/dL;
      • Serum creatinine 1.5 x ULN or creatinine clearance (CrCl) 30 mL/min (using the Cockcroft-Gault formula):
        • Female CrCl = (140 - age in years) x weight in kg x 0.85
                                     72 x serum creatinine in mg/dL
        • Male CrCl = (140 - age in years) x weight in kg x 1.00
                                     72 x serum creatinine in mg/dL;
      • AST 3 x ULN;
      • ALT 3 x ULN;
      • Total Bilirubin 1.5 x ULN (except in subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL).
    • Re-enrollment: This study permits the re-enrollment of a subject who has discontinued the study as a pre-treatment failure prior to randomization. If re-enrolled, the subject must be re-consented. A new subject identification number will be assigned by IVRS at the time of re-enrollment.

Age and Reproductive Status

• Men and women, ages 18 years of age.
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug.
• Women must not be breastfeeding.
• WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug(s) plus 5 months post-treatment completion.
• Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 7 months posttreatment completion.
• Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in these sections.
• Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
• Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly.
• At a minimum, subjects must agree to the use of one method of highly effective contraception.

Exclusion Criteria:

Target Disease Exceptions

• Partial cystectomy in the setting of bladder cancer primary tumor or partial nephrectomy in the setting of renal pelvis primary tumor.
• Adjuvant systemic or radiation therapy for urothelial or prostatic carcinoma following radical surgical resection of urothelial carcinoma.

Medical History and Concurrent Diseases.

• Any 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 subject to receive protocol therapy, or interfere with the interpretation of study results.
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer with evidence of undetectable Prostate Specific  Antigen (PSA) or carcinoma in situ of the prostate, cervix or breast. Patients with known history of recent metastatic urothelial carcinoma will be excluded.
• Subjects with active, known or suspected autoimmune disease.
• Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Subjects with history of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to reoccur with standard countermeasures (e.g., hormone replacement after adrenal crisis).
• All toxicities attributed to prior anti-cancer therapy other than nephropathy, neuropathy, hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll.
• Treatment with any chemotherapy radiation therapy, biologics for cancer, intravesical therapy, or investigational therapy within 28 days of first administration of study treatment.
• Subjects who have received a live/attenuated vaccine within 30 days of randomization (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella [MMR]).
• Treatment with botanical preparations (e.g,. herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment.

Physical and Laboratory Test Findings

• Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus (ribonucleic acid or HCV antibody) indicating acute or chronic infection prior to randomization.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

Allergies and Adverse Drug Reaction

• History of allergy to study drug components.
• History of severe hypersensitivity reaction to any monoclonal antibody.

Sex and Reproductive Status

• WOCBP who are pregnant or breastfeeding.
• Women with a positive pregnancy test at enrollment or prior to administration of study medication.

Other Exclusion Criteria

• Prisoners or subjects who are involuntarily incarcerated.
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
• Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.
• Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.
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