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

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ClinicalTrials.gov Identifier: NCT02844816
Recruitment Status : Active, not recruiting
First Posted : July 26, 2016
Last Update Posted : August 15, 2019
Sponsor:
Collaborator:
Canadian Cancer Trials Group
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE July 22, 2016
First Posted Date  ICMJE July 26, 2016
Last Update Posted Date August 15, 2019
Actual Study Start Date  ICMJE February 7, 2017
Estimated Primary Completion Date April 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 22, 2018)
  • Complete response (CR) rate in the subset of patients with carcinoma in situ (CIS) based on biopsy [ Time Frame: At 25 weeks ]
    Will be estimated to within +/- 12% (95% confidence interval).
  • Event-free survival (EFS) [ Time Frame: From date of registration to first documentation of event, assessed up to 18 months ]
    The 18-month EFS estimate will be obtained using the method of Kaplan and Meier, and the Greenwood formula will be used to estimate the variance. A 90% confidence interval will be estimated for the 18-month EFS estimate. The 99% confidence interval around the 18 month EFS Kaplan-Meier estimate will be constructed.
Original Primary Outcome Measures  ICMJE
 (submitted: July 22, 2016)
Event-free survival (EFS) [ Time Frame: From date of registration to first documentation of event, assessed up to 18 months ]
The 18-month EFS estimate will be obtained using the method of Kaplan and Meier, and the Greenwood formula will be used to estimate the variance. A 95% confidence interval will be estimated for the 18-month EFS estimate. The 99% confidence interval around the 18 month EFS Kaplan-Meier estimate will be constructed.
Change History Complete list of historical versions of study NCT02844816 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
  • Event-free survival (EFS) in the Ta/T1 subset [ Time Frame: 18 months ]
    Will estimate for the subset of patients with papillary cancer (Ta/T1).
  • Progression-free survival (PFS) [ Time Frame: From time of registration to time of first documentation progression or death due to any cause, assessed up to 5 years ]
    Progression will be defined as biopsy proven muscle invasive disease stage >= T2, nodal or distant metastasis and estimated using Kaplan-Meier.
  • Cystectomy-free survival [ Time Frame: Up to 5 years ]
    Estimated using Kaplan-Meier.
  • Bladder cancer specific survival [ Time Frame: From date of registration to date of death due to bladder cancer, assessed up to 5 years ]
    Estimated using Kaplan-Meier.
  • Overall survival [ Time Frame: From date of registration to date of death due to any cause, assessed up to 5 years ]
    Estimated using Kaplan-Meier.
  • Incidence of adverse events [ Time Frame: Up to 18 months ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Qualitative and quantitative toxicity assessment will be provided using CTCAE reporting. Will be estimated to within +/- 9% (95% confidence interval).
Original Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2016)
  • Bladder cancer specific survival [ Time Frame: From date of registration to date of death due to bladder cancer, assessed up to 5 years ]
    Estimated using Kaplan-Meier.
  • Complete response (CR) rate in patients with CIS with CR defined as negative biopsy and negative urine cytology [ Time Frame: At 22 weeks ]
    Will be estimated to within +/- 9% (95% confidence interval).
  • Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 18 months ]
    Qualitative and quantitative toxicity assessment will be provided using CTCAE reporting. Will be estimated to within +/- 9% (95% confidence interval).
  • Overall survival [ Time Frame: From date of registration to date of death due to any cause, assessed up to 5 years ]
    Estimated using Kaplan-Meier.
  • PFS with progression defined as biopsy proven muscle invasive disease stage >= T2, nodal or distant metastasis [ Time Frame: From time of registration to time of first documentation progression or death due to any cause, assessed up to 5 years ]
    Estimated using Kaplan-Meier
Current Other Pre-specified Outcome Measures
 (submitted: October 22, 2018)
  • Recurrence in all patients [ Time Frame: Up to 5 years ]
    Will estimate the level of agreement between local and central pathology review.
  • CR for the CIS subset [ Time Frame: Up to 5 years ]
    Will estimate the level of agreement between local and central pathology review.
  • PD-L1 and CD8 expression [ Time Frame: Up to 5 years ]
    Logistic regression will be used to regress the dichotomous CR status of each CIS patient on the indicator of programmed cell death - ligand (PD-L)1 expression. Fisher's exact test may be used if the proportion of complete responders or proportion of patients expressing PD-L1 is small. Similarly, using all patients, logistic regression will also be used to regress dichotomous 18-month EFS status of each patient on the indicator PD-L1 expression. The analysis will be repeated with CD8 expression as well as other markers. The type I error rate will be controlled at the two-sided alpha=0.05.
  • Immune signature expression [ Time Frame: Up to 5 years ]
    Logistic regression will be used to regress CR status for each CIS patient on an indicator for whether each patient expresses the signature. Similarly, to determine whether pre-defined signatures are predictive of 18-month EFS in all patients, logistic regression will be used to regress 18-month EFS status for each patient on an indicator for whether each patient expresses the signature. This analysis will be repeated for each signature considered. Investigators will again consider using Fisher's exact test if the CR or 18-month EFS rates or the proportion of patients expressing the signature are low. Type I error rate will be controlled at the 2-sided alpha=0.05 level.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Atezolizumab in Treating Patients With Recurrent BCG-Unresponsive Non-muscle Invasive Bladder Cancer
Official Title  ICMJE Phase II Trial of Atezolizumab in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer
Brief 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.
Detailed Description

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:

IIIa. Expression of PD-L1 and CD8 by immunohistochemistry (IHC). IIIb. Expression of immune signatures by ribonucleic acid (RNA)-sequencing (RNA-seq).

IIIc. 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 cycles (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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq
Study Arms  ICMJE Experimental: Treatment (atezolizumab)
Patients receive atezolizumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 17 cycles (51 weeks) in the absence of disease progression or unacceptable toxicity.
Intervention: Drug: Atezolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 10, 2019)
202
Original Estimated Enrollment  ICMJE
 (submitted: July 22, 2016)
143
Estimated Study Completion Date  ICMJE April 1, 2021
Estimated Primary Completion Date April 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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/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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02844816
Other Study ID Numbers  ICMJE NCI-2016-01104
NCI-2016-01104 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1605 ( Other Identifier: SWOG )
S1605 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Canadian Cancer Trials Group
Investigators  ICMJE
Principal Investigator: Peter C Black Southwest Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP