PHASE III RANDOMIZED TRIAL OF CONCURRENT CHEMORADIOTHERAPY WITH OR WITHOUT ATEZOLIZUMAB IN LOCALIZED MUSCLE INVASIVE BLADDER CANCER

ENROLLING
Protocol # :
19-569
Conditions
Bladder Urothelial Carcinoma
Muscle Invasive Bladder Carcinoma
Stage II Bladder Cancer AJCC v8
Stage IIIA Bladder Cancer AJCC v8
Phase
III
Disease Sites
Urinary Bladder
Principal Investigator
Efstathiou, Jason, A
Site Investigator
Mouw, Kent
Site Research Nurses
Jundzil, Theresa
Mann, Eileen, Marie
Spicer, Beverly, A.
Sweet, Amanda

Trial Description

This phase III trial studies how well chemotherapy and radiation therapy work with or without
atezolizumab in treating patients with localized muscle invasive bladder cancer. Radiation
therapy uses high energy rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such
as gemcitabine, cisplatin, fluorouracil and mitomycin-C, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Giving chemotherapy with radiation therapy may kill more tumor
cells. 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. Giving atezolizumab with radiation therapy and chemotherapy may work better in
treating patients with localized muscle invasive bladder cancer compared to radiation therapy
and chemotherapy without atezolizumab.

Eligibility Requirements

Inclusion Criteria:

- STEP 1 REGISTRATION: If this will be the first patient from a registering site to
receive a given RT modality (3DCRT vs. IMRT), the site must first submit pre-RT
planning documents within 3 days of Step 1 registration and receive approval from
Imaging and Radiation Oncology Core (IROC) before randomizing the patient to Step 2.
If this will not be the first patient to receive a specific RT modality, the patient
should be immediately randomized to Step 2 on the same day.

- STEP 2 RANDOMIZATION: If patient required review of pre-RT planning, randomization
must occur within 14 days of initial registration.

- Patients must have histologically proven, T2-T4a N0M0 urothelial carcinoma of the
bladder within 120 days prior to randomization and no intervening treatment between
the histologic proof and randomization. Patients with mixed urothelial carcinoma will
be eligible for the trial, but the presence of small cell carcinoma will make a
patient ineligible. Patients with lymph nodes >= 1.0 cm in shortest cross-sectional
diameter on imaging (computed tomography [CT]/magnetic resonance imaging [MRI] of
abdomen and pelvis) must have a biopsy of the enlarged lymph node showing no tumor
involvement within 70 days prior to randomization. These patients may be suitable for
neoadjuvant chemotherapy and radical cystectomy and are eligible for this trial if
they seek out a bladder sparing treatment strategy, however patients who have received
prior systemic chemotherapy for bladder cancer are not eligible for the trial.

- Patients must undergo a transurethral resection of bladder tumor (TURBT) within 70
days prior to randomization. In a situation where a patient is referred from outside
to the enrolling institution, patient must have a repeat office cystoscopy by the
urologist who will be following the patient on the clinical trial to assess the
adequacy of the prior TURBT. This cystoscopy can be performed in urologist office
without general anesthesia. Patient may then undergo repeat TURBT if deemed necessary
as standard of care by the treating urologist. Patients may have either completely or
partially resected tumors as long as the treating urologist attempted maximal
resection. Patient must not have T4b disease

- Patients must undergo radiological staging within 70 days prior to randomization.
Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Patients must
not have evidence of T4bN1-3 disease. Eligibility is based on the local radiology
report.

- Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and
kidney function meets criteria specified.

- Patients must not have had urothelial carcinoma or histological variant at any site
outside of the urinary bladder within the previous 24 months except Ta/T1/carcinoma in
situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient
had undergone complete nephroureterectomy.

- Patients must not have diffuse CIS based on cystoscopy and biopsy.

- Patient must be planning to receive one of the protocol specified chemotherapy
regimens.

- All adverse events associated with any prior surgery and intravesical therapy must
have resolved to Common Terminology Criteria for Adverse Events (CTCAE) grade =< 2
prior to randomization.

- Patients must be >= 18 years of age

- Patient must not have received any systemic chemotherapy for their bladder cancer.

- Patient must not have had prior pelvic radiation.

- Patients must not have received prior treatment for muscle invasive bladder cancer
including neoadjuvant chemotherapy for the current tumor.

- Patients must not have received any systemic therapy (including, but not limited to,
interferon alfa-2b, high dose IL-2, pegylated interferon [PEG-IFN], anti-PD-1,
anti-PD-L1), for non-muscle invasive bladder cancer. Prior intravesical bacillus
Calmette-Guerin (BCG), interferon, and intravesical chemotherapy are allowed.

- Patients must not have received any of the following prohibited therapies within 28
days prior to randomization or be planning to receive any of the following prohibited
therapies during protocol treatment:

- Anti-cancer systemic chemotherapy or biological therapy not specified in the
protocol.

- Immunotherapy not specified in this protocol.

- Systemic or intravesical use of any non-study anti-cancer agent (investigational
or non-investigational).

- Investigational agents other than atezolizumab.

- Live vaccines: Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies,
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g. Flu-Mist) are live attenuated vaccines, and are not allowed. Prior
administration of intravesical BCG is allowed.

- Glucocorticoids for any purpose other than to modulate symptoms from an event of
suspected immunologic etiology. The use of physiologic doses of corticosteroids
(defined as 10 mg prednisone) are acceptable, however site investigators should
consult with the study chair for any dose higher than 10 mg prednisone.
Dexamethasone 4 mg IV with chemotherapy to prevent nausea is allowed.

- RANKL infusion: Concurrent denosumab (which binds the cytokine RANKL) for any
known indication is prohibited due to interaction with study medication.

- Patients must not have a major surgical procedure within 28 days prior to
randomization. If patient had any surgical procedure then they should have recovered
to full presurgical performance status and surgical adverse events should have
resolved to grade =< 2. TURBT is not considered a major surgical procedure.

- 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 14
days prior to randomization. Exceptions:

- Patients may have received acute, low dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea).

- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
for patients with orthostatic hypotension or adrenocortical insufficiency is
allowed. Physiological doses equivalent of 10 mg prednisone daily are allowed.
Short term steroids given as antiemetic therapy, e.g. 4 mg dexamethasone or
equivalent once a week, is allowed.

- Patients must not have received a live, attenuated vaccine within 4 weeks prior to
randomization or anticipate that such a live, attenuated vaccine will be required
while on protocol treatment and up to 5 months after the last dose of protocol
treatment.

- Inactivated 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 randomization or while on protocol
treatment and up to 5 months after the last dose of protocol treatment.

- Patients must not have undergone prior allogeneic bone marrow transplantation or prior
solid organ transplantation.

- Patient may or may not be radical cystectomy candidates.

- Absolute neutrophil count (ANC) >=1,500/microliter (mcL) (within 28 days prior to
randomization).

- Platelets >= 100,000/mcL (within 28 days prior to randomization).

- Hemoglobin >= 9 g/dL (within 28 days prior to randomization).

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except patients
with Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 28 days
prior to randomization).

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x IULN
(within 28 days prior to randomization).

- Patients must not have clinically significant liver disease that precludes patient
from treatment regimens prescribed on the study (including, but not limited to, active
viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease).

- Patients must have adequate renal function as evidenced by calculated creatinine
clearance >= 25 mL/min. The creatinine used to calculate the clearance result must
have been obtained within 28 days prior to randomization.

- Patients must have Zubrod performance status =< 2.

- Patients must have a baseline electrocardiography (ECG) performed within 30 days prior
to randomization.

- 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 randomization. Patients receiving prophylactic antibiotics (e.g., for
prevention of a urinary tract infection or chronic obstructive pulmonary disease) are
not eligible. If patient develops urinary tract infection after TURBT they must have
recovered from the infection prior to registration.

- 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, Graves' disease treated
with methimazole or glomerulonephritis.

- Patient must not have a history of active tuberculosis.

- If patient has a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV),
they must meet the following criteria within 28 days prior to randomization.

- 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 ribonucleic acid (RNA).

- Patients who are known to be 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 within 28 days prior to randomization.

- 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 two years. Patients with
localized prostate cancer who are being followed by an active surveillance program are
also eligible.

- Female patients of childbearing potential must have a serum pregnancy test prior to
randomization. Patients must not be pregnant or nursing due to the potential
teratogenic side effects of the protocol treatment. 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 protocol treatment, and
for 5 months (150 days) after the last dose of all study drugs. A woman is considered
to be of "reproductive potential" if she has had a menses at any time in the preceding
12 consecutive months.

- Patients must not be known to be allergic to Chinese hamster egg or ovary cell
products and must not have any known major allergic reactions to any study drug.

- Patients must be offered the opportunity to participate in specimen banking for future
studies.

- Patients who can complete Patient-Reported Outcome instruments in English or Spanish
must agree to complete the EORTC QLQ-C30, the EORTC QLQ-BLM30, the EPIC Bowel
Assessment, and the EQ-5D-5L per protocol schedule of assessment.

- 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.

19-569