Carcinoma, Transitional CellPhase 2NCT02451423
Neoadjuvant Atezolizumab in Localized Bladder Cancer
A Phase 2 study testing Atezolizumab in people with Carcinoma, Transitional Cell, run by Lawrence Fong at 1 site in United States.
Trial summary
This phase II trial studies the best dose of atezolizumab in treating patients with bladder cancer that has not spread to other places in the body. Immunotherapy with monoclonal antibodies may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Carcinoma, Transitional Cell
- What is being tested?
- Atezolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Mar 2016to 31 Mar 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 years of age or older
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1
- Histologically document transitional cell carcinoma with the presence of any of the following stages: Carcinoma in situ (CIS), high-grade Ta, any grade T1, or any grade cT2-T4, considered appropriate for radical cystectomy. Subjects with mixed histology are required to have a dominant transitional cell carcinoma (TCC) pattern.
- For subjects with non-muscle-invasive bladder cancer (NMIBC), Bacillus Calmette-Guerin (BCG) -refractory or BCG-resistant disease. BCG-refractory disease is defined as the absence of a complete response by 6 months in patients who have received induction and maintenance OR two induction courses of BCG. BCG-resistant disease is defined as persistent or recurrent disease after 2 induction courses of BCG within 1 year OR cancer recurrence within 1 year of initiation of therapy for patients who have received induction plus maintenance BCG therapy. Subjects with NMIBC must be suitable for and willing to undergo a radical cystectomy at the completion of study therapy.
- For subjects with muscle invasive disease: not suitable neoadjuvant cisplatin-based chemotherapy as determined by the following:
- Creatinine clearance less than 60ml/min. Glomerular filtration rate (GFR) should be assessed by calculation from serum/plasma creatinine (Cockcroft-Gault formula)
Show all 20Show fewer
- Common Terminology Criteria for Adverse Events (CTCAE) Grade >/= 2 hearing loss
- CTCAE Grade >/= 2 neuropathy
- Subjects with nonmetastatic muscle-invasive bladder cancer (MIBC) not meeting the above criteria are still eligible provided the patient declines neoadjuvant cisplatin-based chemotherapy, after specific informed consent describing the known benefits of cisplatin-based chemotherapy. The reason for declining must be documented.
- Adequate bone marrow function defined as
- White Blood Cell count (WBC) > 2500 cells/mm3
- Absolute Neutrophil Count (ANC) > 1500 cells/mm3
- Hemoglobin > 9 g/dL. Patients may be transfused or receive erythropoietic treatment to meet this criterion.
- Platelet count > 100,000 cells/mm3
- Adequate renal function: Serum creatinine < 2 mg/dL OR calculated Creatinine Clearance (CrCl) > 30ml/min
- Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert's disease)
- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN)
- Ability to understand and willingness to sign a written informed consent.
- Have available evaluable archival tumor tissue for PD-L1 biomarker assessment. Presence of PD-L1 antigen on tumors is NOT required for study entry.
- The effects of MPDL3280A on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception prior to study entry, during study participation, and for 90 days after study treatment discontinuation. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 90 days after completion of study drug administration.
Who cannot join
- Subjects with primary TCC of the ureter, urethra, or renal pelvis without TCC of the bladder are not allowed.
- Known distant metastatic disease (e.g. pulmonary or hepatic metastases).
- Subjects with malignant lymphadenectomy in the abdomen or pelvis considered appropriate for radical cystectomy and lymphadenectomy with the goal of complete resection of all malignant disease are allowed.
- Intravesical chemo- or biologic therapy within 6 weeks of first treatment.
- Prior systemic chemotherapy or radiation therapy for transitional cell carcinoma of the bladder.
- Subjects who have received prior intravesical chemotherapy are allowed.
Show all 33Show fewer
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 therapeutic antibodies.
- History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vacuities, or glomerulonephritis.
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study.
- Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are eligible for this study.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
- History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Chronic liver disease
- HIV or active hepatitis B virus (HBV); chronic or acute; defined as having a positive hepatitis B surface antigen [Bag] test at screening) or active hepatitis C
- Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody (HBcAb) and absence of HBsAg) are eligible. HBV DNA must be obtained in these patients prior to Cycle 1, Day 1, but detection of HBV DNA in these patients will not exclude study participation.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Active tuberculosis
- Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Prior allogeneic stem cell or solid organ transplant
- Administration 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. Inactivated vaccines (such as hepatitis A or polio vaccines) are permitted during the study.
- Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1, Day 1 and for at least 12 weeks after the last dose.
- Clinically significant active infection or uncontrolled medical condition
- Uncontrolled cystitis, significant bladder pain or spasms, or gross hematuria that in the opinion of the treating investigator, should preclude study entry.
- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina
- Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
- Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure other than cystectomy during the course of the study
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
- Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Study Chair.
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed.
- Pregnant or nursing women are excluded
- Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the MPDL3280A formulation
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Malignancies other than Urological Cancers (UC) within 5 years prior to Cycle 1, Day 1, with the exception of those with a low risk of metastasis or death treated with expected curative outcome (such as, but not limited to, adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated with curative intent and absence of Prostate-specific antigen (PSA) relapse, or ductal carcinoma in situ of the breast treated surgically with curative intent) or incidental prostate cancer (T1a, Gleason score ≤ 6 and PSA < 0.5 ng/mL).
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: Phase II Study of Neoadjuvant Atezolizumab-based Immunotherapy for Patients With Urothelial Carcinoma (NEBULA)
This phase II trial studies the best dose of atezolizumab in treating patients with bladder cancer that has not spread to other places in the body. Immunotherapy with monoclonal antibodies may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Read the detailed description
PRIMARY OBJECTIVES:
- To assess the intratumoral immune response associated with increasing numbers of atezolizumab (MPDL3280A) treatments. (Multi-dose cohorts, Cohort A).
II. To assess the anti-tumor activity of MPDL3280A as determined by the pathologic T0 rate (pT0) at the time of cystectomy. (Expansion cohorts, Cohort A).
SECONDARY OBJECTIVES:
- To evaluate the safety and feasibility of administering up to 3 cycles of atezolizumab pre-operatively to patients with resectable urothelial bladder cancer (Multi-dose cohorts).
II. To assess the anti--tumor activity of neoadjuvant treatment as determined by the pathologic partial response (< pT2N0) assessed at the time of radical cystectomy (Expansion cohorts).
III. To determine the 2-year relapse-free survival (RFS) rate and median RFS from time of radical cystectomy in patients treated with neoadjuvant therapy (Expansion cohorts).
IV. To determine the 2-year overall survival (OS) and median OS from time of radical cystectomy in patients treated with neoadjuvant therapy (Expansion cohorts).
- To assess the intratumoral immune response of neoadjuvant by comparing pre-treatment transurethral resection of bladder tumor (TURBT) with post-treatment cystectomy tumor specimens (Expansion cohorts).
EXPLORATORY (CORRELATIVE) OBJECTIVES:
- To assess for tumor-based biomarkers of response and resistance to this combination therapy using single-cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry.
II. To assess the presence of antigen-specific immune responses to a broad panel of candidate tumor antigens.
OUTLINE: This is a dose-escalation study of atezolizumab.
COHORT A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 3 doses prior to cystectomy in the absence of disease progression or unacceptable toxicity.
COHORT B: Cohort B was never opened for enrollment.
After all neoadjuvant study therapy is administered, each subject will undergo cystectomy to evaluate pathologic response to treatment and for immunologic characterization in the resected tissue. Serum and urine will be obtained as well to characterize circulating immune responses.
After completion of study treatment, patients are followed for up every 4 weeks for 12 weeks and then every 12 weeks for up to 2 years.
- Conditions
- Carcinoma, Transitional Cell
- Being tested
- Atezolizumab
- Keywords
- Non-metastatic, Bladder
- Medical subject headings
- Carcinoma, Transitional Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtezolizumabDrug
Also called MPDL3280A
1200 mg Given IV
| Study group | Role | What they receive |
|---|---|---|
| Cohort A1: Atezolizumab (Single dose) | Experimental | Atezolizumab will be given as a neoadjuvant treatment Intravenously (IV) on Day 1 of each 21-day Cycle, for up to 1 cycle (1200mg x 1 dose) Receives: Drug: Atezolizumab |
| Cohort A2: Atezolizumab Monotherapy (2 doses) | Experimental | Atezolizumab will be given as a neoadjuvant treatment Intravenously (IV) on Day 1 of each 21-day Cycle, for up to 2 cycles (1200 mg x 2 doses) Receives: Drug: Atezolizumab |
| Cohort A3: Atezolizumab Monotherapy (3 doses) | Experimental | Atezolizumab will be given as a neoadjuvant treatment Intravenously (IV) on Day 1 of each 21-day Cycle, for up to 3 cycles (1200 mg x 3 doses) Receives: Drug: Atezolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean log2 (Fold Change of CD3+ T-Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the Cluster of differentiation 3 positive (CD3+) T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Measured: Up to 1 year
Mean log2 (Fold Change of CD3+ Ki67+ Proliferative T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD3+ Ki67+ proliferative T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Measured: Up to 1 year
Mean log2 (Fold Change of CD4+ FoxP3- Helper T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the cluster of differentiation 4 positive (CD4+) FoxP3- helper T cells count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Measured: Up to 1 year
Mean log2 (Fold Change of CD4+ FoxP3+ Regulatory T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD4+ FoxP3+ regulatory T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Measured: Up to 1 year
Mean log2 (Fold Change of CD8+ Cytotoxic T Cell Count/µm2) Over Time
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the cluster of differentiation 8 positive (CD8+) cytotoxic T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Measured: Up to 1 year
Percentage of Participants With a Treatment-related Delay
The percentage of participants requiring a treatment-related delay in surgery beyond 12 weeks from study start will be summarized using descriptive statistics.
Measured: Up to 2 years
Number of Participants With Maximum Grade Treatment-related Toxicities Prior to Surgery
Treatment-related adverse events occurring prior to surgery will be summarized by maximum toxicity grade for all participants treated with a particular regimen. The grade of toxicity will be calculated using NCI CTCAE version 4.0.
Measured: Up to 2 years
Secondary outcomes (4)
Near Complete Pathologic Response Rate
Point estimates and 95% confidence intervals of the near complete pathologic response rate, defined as the presence of only pTa or pTis in patients with T2 or greater disease at baseline.
Measured: Up to 2 years
Relapse-free Survival (RFS) Rate Intention-To-Treat (ITT) Population
The percentage of participants with a two- year RFS defined from study start until recurrence of disease or death from any cause, will be obtained using the Kaplan Meier method for the ITT population.
Measured: Up to 2 years
Overall Survival Rate
Overall survival rate will be reported as the percentage of participants from study start until death from any cause obtained by Kaplan Meier method for the ITT population.
Measured: Up to 2 years
Association of Tumor and T-cell PD-L1/PD-1 Immunohistochemical Expression With Disease Response
Fisher's exact test will be used to test the association of baseline tumor and T-cell programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immunohistochemical expression with disease response.
Measured: Up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2015 (estimated)
- Study start29 Mar 2016
- Primary completion31 Mar 2023
- Study completion31 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Carcinoma, Transitional CellStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Lawrence Fong
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc., Bladder Cancer Advocacy Network, Conquer Cancer Foundation, National Cancer Institute (NCI), The V Foundation
- Responsible party
- Sponsor-investigator, Lawrence Fong, University of California, San Francisco
- Investigators
- Lawrence Fong, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02451423
- Sponsor's protocol ID
- 14524
- Other IDs
- NCI-2017-01387, R01CA194511
- Status last verified
- May 2024
- First submitted
- 4 Mar 2015
- Last updated
- 31 May 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Oh DY, Kwek SS, Raju SS, Li T, McCarthy E, Chow E, Aran D, Ilano A, Pai CS, Rancan C, Allaire K, Burra A, Sun Y, Spitzer MH, Mangul S, Porten S, Meng MV, Friedlander TW, Ye CJ, Fong L. Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer. Cell. 2020 Jun 25;181(7):1612-1625.e13. doi: 10.1016/j.cell.2020.05.017. Epub 2020 Jun 3.
PubMed 32497499Friebel E, Kapolou K, Unger S, Nunez NG, Utz S, Rushing EJ, Regli L, Weller M, Greter M, Tugues S, Neidert MC, Becher B. Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes. Cell. 2020 Jun 25;181(7):1626-1642.e20. doi: 10.1016/j.cell.2020.04.055. Epub 2020 May 28.
PubMed 32470397
Study at a glance
From the registry record, last updated by the sponsor on 31 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Study of Neoadjuvant Atezolizumab-based Immunotherapy for Patients With Urothelial Carcinoma (NEBULA)
- ClinicalTrials.gov ID
- NCT02451423
- Acronym / sponsor ID
- 14524
- Conditions
- Carcinoma, Transitional Cell
- Keywords
- Non-metastatic, Bladder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- Lawrence FongUniversity, hospital or other
- Collaborators
- Genentech, Inc., Bladder Cancer Advocacy Network, Conquer Cancer Foundation, National Cancer Institute (NCI), The V Foundation
- Study start
- 29 Mar 2016 (actual)
- Primary completion
- 31 Mar 2023 (actual)
- Study completion
- 31 Mar 2023 (actual)
- First posted
- 22 May 2015 (estimated)
- Results
- Posted 31 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II trial studies the best dose of atezolizumab in treating patients with bladder cancer that has not spread to other places in the body. Immunotherapy with monoclonal antibodies 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:
- To assess the intratumoral immune response associated with increasing numbers of atezolizumab (MPDL3280A) treatments. (Multi-dose cohorts, Cohort A).
II. To assess the anti-tumor activity of MPDL3280A as determined by the pathologic T0 rate (pT0) at the time of cystectomy. (Expansion cohorts, Cohort A).
SECONDARY OBJECTIVES:
- To evaluate the safety and feasibility of administering up to 3 cycles of atezolizumab pre-operatively to patients with resectable urothelial bladder cancer (Multi-dose cohorts).
II. To assess the anti--tumor activity of neoadjuvant treatment as determined by the pathologic partial response (< pT2N0) assessed at the time of radical cystectomy (Expansion cohorts).
III. To determine the 2-year relapse-free survival (RFS) rate and median RFS from time of radical cystectomy in patients treated with neoadjuvant therapy (Expansion cohorts).
IV. To determine the 2-year overall survival (OS) and median OS from time of radical cystectomy in patients treated with neoadjuvant therapy (Expansion cohorts).
- To assess the intratumoral immune response of neoadjuvant by comparing pre-treatment transurethral resection of bladder tumor (TURBT) with post-treatment cystectomy tumor specimens (Expansion cohorts).
EXPLORATORY (CORRELATIVE) OBJECTIVES:
- To assess for tumor-based biomarkers of response and resistance to this combination therapy using single-cell RNA sequencing (scRNA-seq) and high-dimensional flow cytometry.
II. To assess the presence of antigen-specific immune responses to a broad panel of candidate tumor antigens.
OUTLINE: This is a dose-escalation study of atezolizumab.
COHORT A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 3 doses prior to cystectomy in the absence of disease progression or unacceptable toxicity.
COHORT B: Cohort B was never opened for enrollment.
After all neoadjuvant study therapy is administered, each subject will undergo cystectomy to evaluate pathologic response to treatment and for immunologic characterization in the resected tissue. Serum and urine will be obtained as well to characterize circulating immune responses.
After completion of study treatment, patients are followed for up every 4 weeks for 12 weeks and then every 12 weeks for up to 2 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort A1: Atezolizumab (Single dose) | Experimental | Drug: AtezolizumabAtezolizumab will be given as a neoadjuvant treatment Intravenously (IV) on Day 1 of each 21-day Cycle, for up to 1 cycle (1200mg x 1 dose) |
| Cohort A2: Atezolizumab Monotherapy (2 doses) | Experimental | Drug: AtezolizumabAtezolizumab will be given as a neoadjuvant treatment Intravenously (IV) on Day 1 of each 21-day Cycle, for up to 2 cycles (1200 mg x 2 doses) |
| Cohort A3: Atezolizumab Monotherapy (3 doses) | Experimental | Drug: AtezolizumabAtezolizumab will be given as a neoadjuvant treatment Intravenously (IV) on Day 1 of each 21-day Cycle, for up to 3 cycles (1200 mg x 3 doses) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 18 years of age or older
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1
- Histologically document transitional cell carcinoma with the presence of any of the following stages: Carcinoma in situ (CIS), high-grade Ta, any grade T1, or any grade cT2-T4, considered appropriate for radical cystectomy. Subjects with mixed histology are required to have a dominant transitional cell carcinoma (TCC) pattern.
- For subjects with non-muscle-invasive bladder cancer (NMIBC), Bacillus Calmette-Guerin (BCG) -refractory or BCG-resistant disease. BCG-refractory disease is defined as the absence of a complete response by 6 months in patients who have received induction and maintenance OR two induction courses of BCG. BCG-resistant disease is defined as persistent or recurrent disease after 2 induction courses of BCG within 1 year OR cancer recurrence within 1 year of initiation of therapy for patients who have received induction plus maintenance BCG therapy. Subjects with NMIBC must be suitable for and willing to undergo a radical cystectomy at the completion of study therapy.
- For subjects with muscle invasive disease: not suitable neoadjuvant cisplatin-based chemotherapy as determined by the following:
Key exclusion criteria (33 listed)
- Subjects with primary TCC of the ureter, urethra, or renal pelvis without TCC of the bladder are not allowed.
- Known distant metastatic disease (e.g. pulmonary or hepatic metastases).
- Subjects with malignant lymphadenectomy in the abdomen or pelvis considered appropriate for radical cystectomy and lymphadenectomy with the goal of complete resection of all malignant disease are allowed.
- Intravesical chemo- or biologic therapy within 6 weeks of first treatment.
- Prior systemic chemotherapy or radiation therapy for transitional cell carcinoma of the bladder.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AtezolizumabAlso: MPDL3280A1200 mg Given IV | Drug | Cohort A1: Atezolizumab (Single dose), Cohort A2: Atezolizumab Monotherapy (2 doses), Cohort A3: Atezolizumab Monotherapy (3 doses) |
Primary outcome
Mean log2 (Fold Change of CD3+ T-Cell Count/µm2) Over Time
Time frame: Up to 1 year
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the Cluster of differentiation 3 positive (CD3+) T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Mean log2 (Fold Change of CD3+ Ki67+ Proliferative T Cell Count/µm2) Over Time
Time frame: Up to 1 year
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD3+ Ki67+ proliferative T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Mean log2 (Fold Change of CD4+ FoxP3- Helper T Cell Count/µm2) Over Time
Time frame: Up to 1 year
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the cluster of differentiation 4 positive (CD4+) FoxP3- helper T cells count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Mean log2 (Fold Change of CD4+ FoxP3+ Regulatory T Cell Count/µm2) Over Time
Time frame: Up to 1 year
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD4+ FoxP3+ regulatory T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Mean log2 (Fold Change of CD8+ Cytotoxic T Cell Count/µm2) Over Time
Time frame: Up to 1 year
The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the cluster of differentiation 8 positive (CD8+) cytotoxic T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. For each cohort, the mean of the log2 of ratio of post-treatment vs. pre-treatment counts with 95% confidence intervals will be reported.
Percentage of Participants With a Treatment-related Delay
Time frame: Up to 2 years
The percentage of participants requiring a treatment-related delay in surgery beyond 12 weeks from study start will be summarized using descriptive statistics.
Number of Participants With Maximum Grade Treatment-related Toxicities Prior to Surgery
Time frame: Up to 2 years
Treatment-related adverse events occurring prior to surgery will be summarized by maximum toxicity grade for all participants treated with a particular regimen. The grade of toxicity will be calculated using NCI CTCAE version 4.0.
4 secondary outcomes
Near Complete Pathologic Response Rate
Time frame: Up to 2 years
Relapse-free Survival (RFS) Rate Intention-To-Treat (ITT) Population
Time frame: Up to 2 years
Overall Survival Rate
Time frame: Up to 2 years
Association of Tumor and T-cell PD-L1/PD-1 Immunohistochemical Expression With Disease Response
Time frame: Up to 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 May 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32497499Oh DY, Kwek SS, Raju SS, Li T, McCarthy E, Chow E, Aran D, Ilano A, Pai CS, Rancan C, Allaire K, Burra A, Sun Y, Spitzer MH, Mangul S, Porten S, Meng MV, Friedlander TW, Ye CJ, Fong L. Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer. Cell. 2020 Jun 25;181(7):1612-1625.e13. doi: 10.1016/j.cell.2020.05.017. Epub 2020 Jun 3.
- Derived from this study: PubMed 32470397Friebel E, Kapolou K, Unger S, Nunez NG, Utz S, Rushing EJ, Regli L, Weller M, Greter M, Tugues S, Neidert MC, Becher B. Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes. Cell. 2020 Jun 25;181(7):1626-1642.e20. doi: 10.1016/j.cell.2020.04.055. Epub 2020 May 28.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lawrence Fong, MD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Atezolizumab in people with Carcinoma, Transitional Cell, run by Lawrence Fong at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean log2 (Fold Change of CD3+ T-Cell Count/µm2) Over Time (time frame: Up to 1 year). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02451423, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 May 2024.