Atezolizumab in Treating Patients With Recurrent BCG-Unresponsive Non-muscle Invasive Bladder Cancer
Condition: Recurrent Bladder Urothelial Carcinoma; Stage 0a Bladder Urothelial Carcinoma AJCC v6 and v7; Stage 0is Bladder Urothelial Carcinoma AJCC v6 and v7; Stage I Bladder Urothelial Carcinoma AJCC v6 and v7
MeSH terms: Carcinoma; Carcinoma, Transitional Cell; Non-Muscle Invasive Bladder Neoplasms
Intervention: Atezolizumab
Intervention description: Given IV
Intervention MeSH terms: Atezolizumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 172.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well atezolizumab works in treating patients with non-muscle
      invasive bladder cancer that has come back (recurrent) and has not responded to treatment
      (refractory) with Bacillus Calmette-Guerin (BCG). Immunotherapy with monoclonal antibodies,
      such as atezolizumab, may help the body's immune system attack the cancer, and may interfere
      with the ability of tumor cells to grow and spread.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically proven, recurrent, non-muscle invasive urothelial
             carcinoma of the bladder within 60 days prior to registration; the carcinoma must be
             stage T1 high-grade, stage CIS, or stage Ta high-grade

          -  Patients with mixed urothelial carcinoma and a glandular and/or squamous component
             will be eligible for the trial, but the presence of other histologic variants, pure
             adenocarcinoma, or pure squamous cell carcinoma, or pure squamous carcinoma in situ
             will make a patient ineligible

          -  Patients must have had all visible tumor resected completely within 60 days prior to
             registration; CIS disease is not expected to be completely excised; all patients must
             have tumor tissue from the histologic diagnosis of recurrence available for central
             pathology review submission; failure to submit these materials will make the patient
             ineligible for this study

          -  Patients must have had cystoscopy confirming no visible papillary tumor within 21 days
             prior to registration; (CIS disease is not expected to have been completely excised);
             if the transurethral resection of bladder tumor (TURBT) or bladder biopsy falls within
             21 days of registration it will fulfill this criterion

          -  Patients must have had urine cytology within 21 days prior to registration; cytology
             for patients with CIS component is not expected to be negative for malignant cells; if
             the cytology for male patients with only Ta/T1 disease in the absence of CIS is
             positive for malignant cells, patient must have had a biopsy of the prostatic urethra
             within the previous six months

          -  All patients with T1 urothelial carcinoma at study entry must undergo re-TURBT within
             60 days prior to registration, and must have evidence of uninvolved muscularis propria
             in the pathologic specimen from either the first or the second TURBT; tissue from the
             re-resection must be submitted for central review in addition to the tissue from the
             first TURBT; the TURBT that identified the recurrent T1 disease may have taken place
             more than 60 days prior to registration but not more than 120 days; patients with high
             grade Ta or CIS do not require a re-TURBT, but if this is performed at the discretion
             of the treating physician, the second TURBT must be within 60 days of registration;
             there is no requirement for muscularis propria in the specimen of Ta/CIS patients, but
             the tissue from the first and second TURBTs must be submitted for central review; if a
             patient with Ta/T1 disease undergoes repeat TURBT, the patient will be stratified as
             having CIS if there is CIS on either TURBT

          -  Patients must not have had urothelial carcinoma in the prostatic urethra within the
             previous 24 months or muscle invasive urothelial carcinoma of the bladder at any time;
             patients with prior urothelial carcinoma in the upper urinary tract within the
             previous 24 months will only be eligible if they had =< T1 carcinoma and were treated
             with nephroureterectomy; patients must have a computed tomography (CT) or magnetic
             resonance imaging (MRI) (including CT-intravenous pyelogram [IVP], CT-urogram or
             MR-urogram) of the abdomen and pelvis to rule out upper tract malignancy and
             intra-abdominal metastases within 90 days prior to registration; if a patient cannot
             tolerate intravenous contrast, a retrograde pyelogram should be performed within 90
             days prior to registration

          -  Patients must be deemed unfit for radical cystectomy by the treating physician, or the
             patient must refuse radical cystectomy, which is considered standard of care for these
             patients; the reason for patients not to undergo cystectomy will be clearly documented

          -  Patients must be BCG-unresponsive; a patient is BCG-unresponsive if they meet one or
             more of the following criteria:

               -  Patient has persistent or recurrent high-grade Ta/CIS urothelial carcinoma after
                  completing therapy with at least induction BCG (>= 5 doses) and first round
                  maintenance (>= 2 doses) or second induction BCG (>= 2 doses); both rounds of BCG
                  must have been administered within a 12 month period; these patients must have
                  either had high-grade Ta tumors and did not achieve a disease-free state for more
                  than 6 months following last dose of BCG, or they had CIS and did not achieve a
                  CR; S1605 registration must occur within 9 months of the last dose of BCG

                    -  If a patient does not meet these criteria only because the last dose of BCG
                       was more than 9 months ago, the patient may become eligible if he/she shows
                       histologically proven high-grade recurrence after an additional round of
                       induction or maintenance BCG (>= 3 doses) within 9 months prior to
                       registration

               -  Patient has persistent or recurrent high grade T1 urothelial carcinoma after
                  completing therapy with at least induction BCG (>= 5 doses); patients with
                  recurrent high grade T1 urothelial carcinoma after additional rounds of BCG will
                  also be eligible, but one round of maintenance therapy or a second induction is
                  not a pre-requisite for these patients. Trial registration must occur within 9
                  months of the last dose of BCG

                    -  If a patient does not meet these criteria only because the last dose of BCG
                       was more than 9 months ago, the patient may become eligible if he/she shows
                       histologically proven high grade recurrence after an additional round of
                       induction or maintenance BCG (>= 3 doses) within 9 months prior to
                       registration

               -  Patient achieves disease-free state at 6 month time point (i.e., complete
                  response; presence of only low-grade tumor at this timepoint is still considered
                  complete response) after induction and maintenance (or second round of induction)
                  BCG but later experiences a high-grade Ta/T1 recurrence (with or without
                  concomitant CIS) within 6 months after the last dose of BCG or recurrent CIS (in
                  absence of concomitant Ta/T1 tumor) within 12 months after the last BCG dose; the
                  time of eligibility is measured from the last dose of BCG to the time of disease
                  recurrence; the patient must be registered on the trial within 60 days of this
                  recurrence, or within 60 days of a re-TURBT if indicated

          -  All adverse events associated with any prior surgery and intravesical therapy must
             have resolved to grade =< 2 prior to registration

          -  Absolute neutrophil count (ANC) >= 1,500 microliter (mcL) (within 42 days prior to
             registration)

          -  Platelets >= 100,000/mcL (within 42 days prior to registration)

          -  Hemoglobin >= 9 g/dL (within 42 days prior to registration)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except Gilbert's
             syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 42 days prior to
             registration)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2 x IULN (within
             42 days prior to registration)

          -  Serum creatinine =< 1.5 ULN OR measured or calculated creatinine clearance >= 30
             mL/min (within 42 days prior to registration)

          -  Patients must have Zubrod performance status =< 2

          -  Patients must have a baseline electrocardiograph (ECG) performed within 42 days prior
             to registration

          -  Patients positive for human immunodeficiency virus (HIV) are eligible only if they
             have all of the following:

               -  A stable regimen of highly active anti-retroviral therapy (HAART)

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  PCR-based tests

          -  No other prior malignancy is allowed except, for the following: adequately treated
             basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
             stage I or II cancer from which the patient is currently in complete remission, or any
             other cancer from which the patient has been disease free for five years

          -  Patients must be offered the opportunity to participate in specimen banking for future
             studies, to include translational medicine studies

          -  Patients must be informed of the investigational nature of this study and must sign
             and give written informed consent in accordance with institutional and federal
             guidelines

          -  As a part of the oncology patient enrollment network (OPEN) registration process the
             treating institution's identity is provided in order to ensure that the current
             (within 365 days) date of institutional review board approval for this study has been
             entered in the system

        Exclusion Criteria:

          -  Patients must not have had prior systemic chemotherapy for bladder cancer or systemic
             immunotherapy, including, but not limited to interferon alfa-2b, high dose interleukin
             2 (IL-2), pegylated interferon (PEG-IFN), PD-1, anti-PD-L1, intra-tumoral; patients
             must not have had vaccine therapies within 6 weeks prior to registration; patients
             must not have received or be planning to receive any of the prohibited therapies
             during protocol treatment; prior intravesical administration of chemotherapy,
             interferon, Vicinium (VB4-485), BC-819 or Instiladrin (rAd-interferon-alpha/Syn3) is
             allowed if all other criteria are met and the last administration was >= 30 days
             before registration

          -  Patients must not be planning to receive concomitant other biologic therapy, radiation
             therapy, intravesical chemotherapy, surgery, or other anti-cancer therapy while on
             this protocol

          -  Patients must not have received any prior radiation to the bladder for bladder cancer

          -  Patients must not have received treatment with systemic immunosuppressive medications
             (including, but not limited to, prednisone, cyclophosphamide, azathioprine,
             methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 4
             weeks prior to registration; exceptions: (1) patients may have received acute, low
             dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone
             for nausea); (2) the use of inhaled corticosteroids and mineralocorticoids (e.g.,
             fludrocortisone) for patients with orthostatic hypotension or adrenocortical
             insufficiency is allowed

          -  Patients must not have received a live, attenuated vaccine within 4 weeks before
             registration or anticipation that such a live, attenuated vaccine will be required
             during the study and up to 5 months after the last dose of atezolizumab

               -  Influenza vaccination should be given during influenza season only (approximately
                  October to March); patients must not receive live, attenuated influenza vaccine
                  within 4 weeks prior to cycle 1, day 1 or at any time during the study

          -  Patients must not require treatment with a RANKL inhibitor (e.g. denosumab) who cannot
             discontinue it before treatment with atezolizumab

          -  Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis (including
             drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
             organizing pneumonia, etc.), or evidence of active pneumonitis

          -  Patients must not have an active infection requiring oral or IV antibiotics within 14
             days prior to registration; patients receiving prophylactic antibiotics (e.g., for
             prevention of a urinary tract infection or chronic obstructive pulmonary disease) are
             eligible

          -  Patients must not have severe infections within 28 days prior to registration,
             including but not limited to hospitalization for complications of infection,
             bacteremia, or severe pneumonia

          -  Patients must not have active autoimmune disease that has required systemic treatment
             in past two years (i.e., with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment; autoimmune diseases include, but
             are not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
             bowel disease, vascular thrombosis associated with antiphospholipid syndrome,
             Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome,
             multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis

          -  Patients must not have undergone prior allogeneic bone marrow transplantation or prior
             solid organ transplantation

          -  Patient must not have active tuberculosis

          -  Patients must not have active hepatitis B (chronic or acute) or active hepatitis C
             infection

               -  Patients with past or resolved hepatitis B infection (defined as having a
                  negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
                  [antibody to hepatitis B core antigen] antibody test) are eligible

               -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
                  polymerase chain reaction (PCR) is negative for HCV RNA

          -  Patients must not be pregnant or nursing due to the potential teratogenic side effects
             of the protocol treatment; administration of atezolizumab may have an adverse effect
             on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of
             child-bearing potential and men must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry, for the duration of
             study participation, and for 5 months (150 days) after the last dose of study agent; a
             woman is considered to be of "reproductive potential" if she has had menses at any
             time in the preceding 12 consecutive months; should a woman become pregnant or suspect
             she is pregnant while she or her partner is participating in this study, she should
             inform her treating physician immediately

          -  Due to the potential drug reaction with atezolizumab, patients must not be known to be
             allergic to Chinese hamster egg or ovaries