Summary

for people ages 18 years and up (full criteria)
at San Francisco, California and other locations
study started
estimated completion:

Description

Summary

This phase II trial studies how well atezolizumab works in treating patients with non-muscle invasive bladder cancer that has come back and has not responded to treatment 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.

Official Title

Phase II Trial of Atezolizumab in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer

Details

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

TERTIARY OBJECTIVES:

  1. 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).

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.

Keywords

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 Carcinoma Urinary Bladder Neoplasms Carcinoma, Transitional Cell Carcinoma in Situ Atezolizumab Antibodies, Monoclonal Laboratory Biomarker Analysis

Eligibility

For people ages 18 years and up

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, 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)
  • Patients must have had 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 patients with only Ta/T1 disease 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 must undergo re-transurethral resection of bladder tumor (TURBT) within 60 days prior to registration, and must have uninvolved muscularis propria in the pathologic specimen from either the first or the second TURBT; tissue from the re-resection must be submitted; the TURBT that identified the recurrent T1 disease may have taken place more than 60 days prior to registration
  • Patients must not have had urothelial carcinoma in the prostate or upper urinary tract within the previous 24 months, or muscle invasive urothelial carcinoma of the bladder at any time; patients must have a computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis to rule out upper tract malignancy and intra-abdominal metastases 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 or second induction BCG (>= 2 doses)
  • Patient has high grade T1 urothelial carcinoma after induction BCG (>= 5 doses)only or after induction BCG (>= 5 doses) and first round maintenance or second induction BCG (>= 2 doses)
  • Patient is disease-free at 6 months after starting BCG (i.e., complete response)but then experiences a high-grade recurrence within 6 months after the last BCG dose
  • 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 systemic chemotherapy or 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, or vaccine therapies within 6 weeks prior to cycle 1, day 1; patients must not have received or be planning to receive any of the prohibited therapies during protocol treatment; prior intravesical interferon therapy is allowed
  • Patients must not be planning to receive concomitant other biologic therapy, radiation therapy, intravesical chemotherapy, surgery, or other 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 cycle 1, day 1; 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 of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 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)
  • Alkaline phosphatase =< 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

Locations

  • UCSF Medical Center-Mission Bay accepting new patients
    San Francisco California 94158 United States
  • Stanford Cancer Institute Palo Alto accepting new patients
    Palo Alto California 94304 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
National Cancer Institute (NCI)
ID
NCT02844816
Phase
Phase 2
Study Type
Interventional
Last Updated