| Eligibility |
Inclusion Criteria:
1. 18 years old or older
2. Histologic diagnosis of predominantly urothelial carcinoma of the bladder. Focal
differentiation allowed other than small cell histology.
3. Stage T2-T3 N0M0 (AJCC-TNM version 6) based on trans-urethral resection of bladder
tumor (TURBT), CT or MRI imaging, +/- bimanual examination under anaesthesia.
4. FDG-PET within 6 weeks from the start of treatments, showing no evidence of lymph
nodes or metastatic disease.
5. Attempt of complete trans urethral resection of bladder tumour (TURBT) within 56 days
(8 weeks) prior to the start of chemoradiotherapy. If TURBT was performed > 8 weeks
prior but a recent cystoscopy shows no residual disease, then a repeat TURBT is not
necessary.
6. Life expectancy greater than 6 months
7. Eastern Cooperative Oncology Group (ECOG) performance status of 1 or better
8. Another primary cancer is allowed only if treated with curative intent at least 3
years prior to enrolment without evidence of recurrence or if the untreated cancer is
clinically indolent (e.g., lower risk prostate cancer).
9. Patients must be considered able to tolerate systemic chemotherapy combined with
pelvic intensity-modulated radiation therapy (IMRT) by the joint agreement of the
participating radiation oncologist and medical oncologist.
10. Able and willing to give written informed consent.
11. For women of childbearing potential (WOCBP), study participants must use a
contraceptive method that is highly effective (with a failure rate of < 1% per year)
for at least 5 months after the last dose of study intervention. Men receiving any
study drug and who are sexually active with WOCBP will be instructed to adhere to
contraception for a period of 6 months after the last dose of chemotherapy with
cisplatin or nab-paclitaxel.
The investigator or a designated associate is requested to advise the subject how to
achieve an adequate birth control. Adequate contraception is defined in the study as
any medically recommend method (or combination of methods) as per standard of care.
Acceptable methods are oral contraceptives, hormonal implants, hormonal patches, IDU,
Diaphragm with spermicides, cervical cape with spermicide, and condom with spermicide.
12. Adequate bone-marrow, liver, and renal function as assessed by the following
laboratory requirements conducted within 7 days of starting the study treatment:
13. Total bilirubin =1·5 × the upper limit of normal (ULN).
14. Alanine aminotransferase and aspartate aminotransferase =2 × ULN (=5 × ULN for
patients with liver involvement of their cancer).
15. International normalized ratio (INR) and partial thromboplastin time (PTT) =1·5 × ULN.
Subjects who are therapeutically treated with an agent such as warfarin or heparin
will be allowed to participate if no prior evidence of an underlying abnormality in
coagulation parameters exists. Close monitoring with at least weekly evaluations will
be performed until INR and PTT are stable based on a pre-dose measurement as defined
by the local standard of care.
16. Platelet count =100 000/mm3, haemoglobin >9 g/dl, absolute neutrophil count
>1,500/mm3.
17. Alkaline phosphatase limit =2·5 × ULN (=5 × ULN for patients with liver involvement of
their cancer).
18. Creatinine clearance greater than 40 ml/min as evaluated by Cockcroft-Gault formula.
Exclusion Criteria:
1. Prior systemic therapy for other urothelial tumours.
2. Prior RT to the pelvis
3. Treatment with any other investigational agent or participation in another clinical
trial with therapeutic intent within 28 days or five half-lives of the drug, whichever
is longer, prior to enrolment.
4. Malignancies other than urothelial cancer within 3 years prior to Cycle 1, Day 1:
1. Patients with localized lower risk prostate cancer (defined as Stage =T2b,
Gleason score = 7, and PSA at prostate cancer diagnosis = 20 ng/mL [if measured])
treated with radical prostatectomy and without prostate-specific antigen (PSA)
recurrence are eligible.
2. Patients with lower risk prostate cancer (defined as Stage T1/T2a, Gleason score
= 7 and PSA = 10 ng/mL) who are treatment-naive and undergoing active
surveillance are eligible.
3. Patients with malignancies of a negligible risk of metastasis or death (e.g.,
risk of metastasis or death <5% at 5 years) are eligible provided they meet all
the following criteria:
4. Malignancy treated with expected curative intent (such as adequately treated
carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal
carcinoma in situ of the breast treated surgically with curative intent) No
evidence of recurrence or metastasis by follow-up imaging and any
disease-specific tumor markers.
5. Pre-existing medical conditions precluding treatment (e.g., previous history of
immune-related adverse reactions, pneumonitis, colitis, etc.)
6. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
7. History of autoimmune disease, including, but not limited to, myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may
be eligible for this study. Patients with controlled Type I diabetes mellitus on a
stable dose of insulin regimen may be eligible for this study.
8. Active tuberculosis
9. For women of childbearing potential (WOCBP), study participants must use a
contraceptive method that is highly effective (with a failure rate of < 1% per year)
for at least 5 months after the last dose of study intervention. Men receiving any
study drug and who are sexually active with WOCBP will be instructed to adhere to
contraception for a period of 6 months after the last dose of chemotherapy with
cisplatin or nab-paclitaxel.
Acceptable methods are oral contraceptives, hormonal implants, hormonal patches, IDU,
Diaphragm with spermicides, cervical cape with spermicide, and condom with spermicide.
10. Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
anti-PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB
ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).
11. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF]
agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for
systemic immunosuppressive medications during the trial.
12. Active autoimmune disease that has required systemic treatment in past 2 years.
13. Received or will receive a live vaccine within 4 weeks prior to first dose of study
drug except for vaccine against SARS-CoViD2. Influenza vaccination should be given
during influenza season only (approximately October through May in the Northern
Hemisphere and approximately April through September in the Southern Hemisphere).
Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®)
within 28 days prior to randomization, during treatment or within 5 months following
the last dose of nivolumab.
14. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan History of radiation pneumonitis in the
radiation field (fibrosis) is permitted.
15. Active infection requiring IV systemic therapy.
16. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1.
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or to prevent chronic obstructive pulmonary disease exacerbation) are
eligible.
17. Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), myocardial infarction within the previous 3 months, unstable
arrhythmias, or unstable angina. Patients with known coronary artery disease,
congestive heart failure not meeting the above criteria, or left ventricular ejection
fraction < 50% must be on a stable medical regimen that is optimized in the opinion of
the treating physician, in consultation with a cardiologist if appropriate.
18. Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day
1, or anticipation of need for a major surgical procedure during the course of the
study
19. Prior allogeneic stem cell or solid organ transplant
20. Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications.
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
22. Patients with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
23. Not willing or unable to sign a consent form.
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