Atezolizumab in Treating Patients With Recurrent BCG-Unresponsive Non-muscle Invasive Bladder Cancer

PRIMARY OBJECTIVES:

I. To estimate complete response at 25 weeks after registration for those with a carcinoma in
situ (CIS) component and to evaluate event-free survival at 18 months in patients with
BCG-unresponsive high-risk non-muscle invasive bladder cancer (Ta/T1/CIS) treated with
atezolizumab.

SECONDARY OBJECTIVES:

I. To estimate event-free survival at 18 months for the subset of patients with papillary
cancer (Ta/T1).

II. To estimate progression-free survival, cystectomy-free survival, bladder cancer-specific
survival, overall survival in all patients.

ADDITIONAL OBJECTIVES:

I. To estimate the level of agreement between local and central pathology review in terms of
recurrence (for all patients) and complete response (for the CIS subset).

II. To identify markers that predict response to atezolizumab in the CIS population and that
are associated with event-free survival (EFS) in patients with Ta/T1/CIS BCG-unresponsive
non-muscle invasive bladder cancer. The following markers will be tested: expression of PD-L1
and CD8 by immunohistochemistry (IHC); expression of immune signatures by ribonucleic acid
(RNA)-sequencing (RNA-seq); peripheral immune response by mass cytometry (CyTOF) and
TruCulture.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1. Treatment repeats
every 21 days for up to 17 courses (51 weeks) in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years and
then every 24 weeks for 3 years.

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 prostate 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/T1recurrence (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

- 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

- 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

- 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 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 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

- 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