Overview

This is a single arm, Phase II trial involving the use of atezolizumab plus platinum and etoposide for patients with locally advanced urothelial cancer. The primary goal of this trial is to assess the pathologic complete response rate at cystectomy in patients after being treated with a combination therapy of atezolizumab, platinum, and etoposide.

Eligibility

Inclusion Criteria:

• 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
  • localized ≥ cT1-T4aN1

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