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Histologically confirmed invasive carcinoma of the bladder with pure, or any component of, small cell or high grade neuroendocrine features with or without urothelial cancer |
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localized ≥ cT1-T4aN1 |
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A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or |
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at least 15 slides containing unstained, freshly cut, serial sections should be submitted |
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along with an associated pathology report prior to study enrollment. If less than 15 slides |
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are available, the patient may still be eligible for the study, after Principal |
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Investigator confirmation has been obtained |
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If archival tumor tissue is unavailable or is determined to be unsuitable for required |
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testing, tumor tissue must be obtained from a biopsy performed at screening |
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Medically fit to undergo chemotherapy, immunotherapy and cystectomy |
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years old at time of consent |
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ECOG performance status of 0 or 1 |
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Adequate hematologic and end organ function, defined by the following laboratory |
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results obtained within 14 days prior to randomization |
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ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support |
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Lymphocyte count ≥ 500/μL |
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Platelet count ≥ 100,000/μL without transfusion |
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Hemoglobin ≥ 9.0 g/dL -patients may be transfused to meet this criterion |
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INR or aPTT ≤ 1.5 × upper limit of normal (ULN) This applies only to patients who are |
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not receiving therapeutic anticoagulation; patients receiving therapeutic |
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anticoagulation should be on a stable dose |
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AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN |
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Serum bilirubin ≤ 1.5 × ULN Patients with known Gilbert disease who have serum |
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bilirubin level ≤3 × ULN may be enrolled |
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Serum albumin >= 25 g/L (2.5 g/dL) |
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Negative HIV test at screening (with the following exception: patients with a positive |
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HIV test at screening are eligible provided they are stable on anti-retroviral |
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therapy, have a CD4 count >= 200/µL, and have an undetectable viral load) |
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Negative hepatitis B surface antigen (HBsAg) test at screening |
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Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total |
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HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening The |
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HBV DNA test will be performed only for patients who have a negative HBsAg test and a |
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positive total HBcAb test |
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Creatinine clearance >30. Patients receiving cisplatin must have creatinine clearance |
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>50 |
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For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain |
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from heterosexual intercourse) or use contraceptive methods, and agreement to refrain |
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from donating eggs, as defined below |
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Women must remain abstinent or use contraceptive methods with a failure rate of <1% |
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per year during the treatment period and for 5 months after the final dose of |
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atezolizumab and for 30 days after the final dose of cisplatin/ carboplatin and |
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etoposide. Women must refrain from donating eggs during this same period |
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A woman is considered to be of childbearing potential if she is postmenarchal, has not |
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reached a postmenopausal state (>= 12 continuous months of amenorrhea with no |
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identified cause other than menopause), and has not undergone surgical sterilization |
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(removal of ovaries and/or uterus). The definition of childbearing potential may be |
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adapted for alignment with local guidelines or requirements |
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Examples of contraceptive methods with a failure rate of < 1% per year include |
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bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit |
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ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices |
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The reliability of sexual abstinence should be evaluated in relation to the duration of the |
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clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence |
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(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not |
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adequate methods of contraception |
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For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use |
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contraceptive measures, and agreement to refrain from donating sperm, as defined |
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below |
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With a female partner of childbearing potential who is not pregnant, or a pregnant |
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female partner men who are not surgically sterile must remain abstinent or use a |
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condom plus an additional contraceptive method that together result in a failure rate |
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of < 1% per year during the treatment period and for 8 months after the final dose of |
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atezolizumab and 120 days after the final dose of etoposide. Men must refrain from |
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donating sperm during this same period |
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The reliability of sexual abstinence should be evaluated in relation to the duration |
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of the clinical trial and the preferred and usual lifestyle of the patient. Periodic |
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abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and |
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withdrawal are not adequate methods of contraception |
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Patients who give a written informed consent obtained according to local guidelines |
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Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for |
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chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids |
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for orthostatic hypotension or adrenal insufficiency are eligible for the study |
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No prior systemic treatment for small-cell bladder cancer (SCBC)
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Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive
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urothelial carcinoma. (NOTE: Patients with history of non-invasive (Ta, Tis) upper
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tract urothelial carcinoma that has been definitively treated with at least one post-
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treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no
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evidence of residual disease are eligible). Individual cases will be discussed at
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investigator discretion
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Patients with another active second malignancy other than non-melanoma skin cancers
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and biochemical relapsed prostate cancer. Patients that have completed all necessary
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therapy and are considered to be at less than 30% risk of relapse are not considered
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to have an active second malignancy and are eligible for enrollment
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Patients who have received prior systemic chemotherapy for urothelial bladder cancer
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Prior BCG and intravesical chemotherapy are allowed
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Any metastatic disease including leptomeningeal disease or brain metastasis on
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baseline brain imaging
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Uncontrolled tumor-related pain - Patients requiring pain medication must be on a
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stable regimen at study entry
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Patients requiring pain medication must be on a stable regimen at study entry
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Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL
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or corrected serum calcium > ULN
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Active or history of autoimmune disease or immune deficiency, including, but not
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limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
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erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
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antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome
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or multiple sclerosis, with the following exceptions
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Patients with a history of autoimmune-related hypothyroidism who are on thyroid-
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replacement hormone are eligible for the study
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Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are
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eligible for the study
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Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
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dermatologic manifestations only (e.g., patients with psoriatic arthritis are
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excluded) are eligible for the study provided all of following conditions are met
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Rash must cover < 10% of body surface area
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Disease is well controlled at baseline and requires only low-potency topical
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corticosteroids
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No occurrence of acute exacerbations of the underlying condition requiring psoralen
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plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
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calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12
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months
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Individual cases can be discussed at investigator discretion. Refer to Appendix H for
|
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more details
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History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
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obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
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active pneumonitis on screening chest computed tomography (CT) scan. History of
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radiation pneumonitis in the radiation field (fibrosis) is permitted
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Active tuberculosis
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Significant cardiovascular disease (such as New York Heart Association Class II or
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greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3
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months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
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Patients who have undergone major surgery (e.g. intra-thoracic, intra- abdominal or
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intra-pelvic), open biopsy or significant traumatic injury ≤ 4 weeks prior to starting
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study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous
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biopsies or placement of vascular access device ≤1 week prior to starting study drug
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or who have not recovered from side effects of such procedure or injury
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History of malignancy other than small cell bladder cancer within 5 years prior to
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screening, with the exception of malignancies with a negligible risk of metastasis or
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death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of
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the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal carcinoma
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in situ, or Stage I uterine cancer
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|
Severe infection within 4 weeks prior to initiation of study treatment, including, but
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|
not limited to, hospitalization for complications of infection, bacteremia, or severe
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|
pneumonia
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Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
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|
|
of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
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|
|
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
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|
eligible for the study
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Prior allogeneic stem cell or solid organ transplantation
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Any other disease, metabolic dysfunction, physical examination finding, or clinical
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|
|
laboratory finding that contraindicates the use of an investigational drug, may affect
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|
the interpretation of the results, or may render the patient at high risk from
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|
treatment complications
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Treatment with a live, attenuated vaccine (e.g., FluMist®) within 4 weeks prior to
|
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|
|
initiation of study treatment, or anticipation of need for such a vaccine during
|
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|
|
|
|
atezolizumab treatment or within 5 months after the final dose of Atezolizumab
|
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|
Current treatment with anti-viral therapy for HBV
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|
Treatment with investigational therapy within 28 days prior to initiation of study
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|
treatment
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Prior treatment with CD137 agonists or other immune checkpoint blockade therapies
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|
|
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
|
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|
|
Treatment with systemic immunostimulatory agents (including, but not limited to
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|
|
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
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|
(whichever is longer) prior to initiation of study treatment
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|
Treatment with systemic immunosuppressive medication (including, but not limited to
|
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|
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
|
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|
|
|
|
TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation
|
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|
|
of need for systemic immunosuppressive medication during study treatment
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|
Patients who received acute, low-dose systemic immunosuppressant medication or a
|
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|
|
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
|
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|
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|
|
corticosteroids for a contrast allergy) are eligible for the study after Principal
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Investigator confirmation has been obtained
|
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|
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
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|
or fusion proteins
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|
Known hypersensitivity to Chinese hamster ovary cell products or to any component of
|
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|
|
the atezolizumab formulation
|
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|
Known allergy or hypersensitivity to any component of Cisplatin, carboplatin or
|
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|
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|
|
etoposide
|
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|
Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
|
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|
|
or within 5 months of atezolizumab after the final dose of study treatment. Women of
|
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|
|
|
|
childbearing potential must have a negative serum pregnancy test result within 14 days
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|
|
prior to initiation of study treatment
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Patients who have had radiotherapy to the bladder, or radiotherapy ≤ 4 weeks prior to
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starting study drug, or who have not recovered from radiotherapy toxicities
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|