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Neoadjuvant Atezolizumab in Localized Bladder Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02451423
Recruitment Status : Recruiting
First Posted : May 22, 2015
Last Update Posted : March 30, 2020
Sponsor:
Collaborators:
Genentech, Inc.
The Bladder Cancer Advocacy Network
Conquer Cancer Foundation
Information provided by (Responsible Party):
Lawrence Fong, University of California, San Francisco

Brief Summary:

This is a single arm, open label Phase II study of MPDL3280A, an anti-PD-L1 antibody administered as neoadjuvant therapy to subjects with either BCG-refractory non-muscle invasive transitional cell carcinoma (TCC) of the bladder, or muscle-invasive TCC appropriate for cystectomy and refusing or ineligible for neoadjuvant chemotherapy. Enrolled patients will be assigned sequentially to dose levels in cohorts of 6 patients per dose level. The starting dose level is 1200mg x 1 dose and will be escalated in subsequent cohorts to 1200mg q 3 weeks x 2 doses, and finally 1200mg q 3 weeks x 3 doses to determine the impact of increasing number of treatments on the modulated immune response with the tumor tissue. Subjects with adverse pathology (pT3/pT4 or N+) will be offered the option of adjuvant MPDL3280A for up to 16 cumulative cycles of treatment.

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 the multi-dose portion of the study has completed accrual two expansion cohorts of up to 15 patients each with Non-muscle-invasive bladder cancer (NMIBC) or Non-metastatic muscle-invasive bladder cancer (MIBC) will be accrued at the highest dose level for further characterization of safety, efficacy, and immunologic analysis. Patients with pT3, pT4, or N+ disease at the time of cystectomy and no metastatic disease will be offered the option of adjuvant MPDL3280A for up to a total of 16 cumulative cycles. All subjects will be followed clinically for up to 2 years to assess for disease recurrence.


Condition or disease Intervention/treatment Phase
Carcinoma, Transitional Cell Drug: MPDL3280A Dose Level 1 Drug: MPDL3280A Dose Level 2 Drug: MPDL3280A Dose Level 3 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of the Anti-PD-L1 Antibody MPDL3280A in Subjects With Non-metastatic Transitional Cell Carcinoma of the Bladder
Actual Study Start Date : June 28, 2016
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: MPDL3280A
MPDL3280A: Intravenously; Day 1 of each 21-day Cycle
Drug: MPDL3280A Dose Level 1
1200 mg x 1 dose

Drug: MPDL3280A Dose Level 2
1200 mg every 3 weeks x 2 doses

Drug: MPDL3280A Dose Level 3
1200 mg evert 3 weeks x 3 doses




Primary Outcome Measures :
  1. Change in CD3+ T cell count/µm2 in the multi-dose cohorts [ Time Frame: Up to 1 year ]
    The immunologic effect MPDL3280A activity within bladder tissue will be measured by a change in the CD3+ T cell count/µm2 between pretreatment biopsy and cystectomy tissue following MPDL3280A infusions. Tissue will be designated into 3 distinct compartments: benign epithelium, tumor centers, and tumor interfaces. Tumor interfaces will be defined as fields where malignant and benign epithelium are present. Cell count for each compartment will be reported in a table as mean for each of the 5 quantitated fields. For each cohort, change of T cell counts from pre-treatment to post-treatment will be calculated for each compartment as log2 of ratio of post-treatment vs. pre-treatment counts. Two-sample Wilcoxon rank sum test will be used to compare difference of change from pretreatment to post-treatment between cohorts to assess if intratumoral immune response associated with increasing numbers of MPDL3280A treatments.

  2. Pathologic T0 rate in expansion cohorts [ Time Frame: Up to 1 year ]
    Pathologic T0 rate at the time of cystectomy, defined as the pathologic absence of disease in the bladder after resection. Point estimates and 95% confidence intervals of pathologic T0 rate at the time of cystectomy will be obtained for expansion-cohort subjects treated with MPDL3280A. Pathologic T0 rate at the time of cystectomy will be compared with the null hypothesis rate separately by using one-sample proportion test


Secondary Outcome Measures :
  1. Tolerability of MPDL3280A [ Time Frame: Up to 2 years ]
    A stopping rule for safety will halt accrual to the study and prompt reevaluation of the dose if unacceptable treatment-related toxicity (defined as any Grade 4 toxicity, any recurrent Grade 3 toxicity (starting from the first dose of MPDL3280A until 30 days after the last administration), or any Grade 3 toxicity persisting more than 2 weeks), or treatment-related delay in cystectomy beyond 12 weeks (including both the treatment period and any delay due to an adverse event), is observed at a frequency of ≥33% in any individual dosing cohort prior to cystectomy. Because of the known excellent safety profile of MPDL320A, this safety review will occur after all 6 subjects have been accrued to each individual dosing cohort in the multidose phase and treated with at least once dose of study.

  2. Percentage of subjects with a treatment-related delay for multi-dose cohort [ Time Frame: Up to 2 years ]
    The percentage of subjects requiring a treatment related delay in surgery beyond 12 weeks from study start will be summarized using descriptive statistics.

  3. Frequency of all grade treatment-related toxicities occuring prior to surgery in multi-dose cohort [ Time Frame: Up to 2 years ]
    Adverse events occurring prior to surgery will be summarized by maximum toxicity grade for each dose level of MPDL3280A in the multi-dose phase. The toxicity grade for laboratory data will be calculated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and the lab data will be summarized according to the subjects' baseline grade and maximum grade for each cycle of therapy.

  4. Frequency of all grade treatment-related toxicities during adjuvant therapy in multi-dose cohorts [ Time Frame: Up to 2 years ]
    Adjuvant MPDL3280A therapy given every 3 weeks for up to 16 cumulative cycles (including neoadjuvant therapy) will be offered as optional therapy for subjects with adverse pathology (pT3/pT4, or N+) at the time of surgery. Frequency of all grade treatment-related toxicities during adjuvant therapy, according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 will be reported

  5. Pathologic T0 rate in expansion cohort for patients with PD-L1 Immunohistochemistry (IHC) 2/3 [ Time Frame: Up to 2 years ]
    Pathologic T0 rate at the time of cystectomy, defined as the pathologic absence of disease in the bladder after resection in patients with PD-L1 IHC 2/3

  6. 2-year relapse-free survival (RFS) rate in expansion cohort Intention-To-Treat (ITT) population [ Time Frame: Up to 2 years ]
    2 year RFS rate defined from study start until recurrence of disease or death from any cause will be obtained for the ITT population at each dose level of MPDL3280A. RFS will be calculated by Kaplan Meier method

  7. Median RFS in the expansion cohort ITT population [ Time Frame: Up to 2 years ]
    Median RFS rate is defined as number of months from study start until recurrence of disease or death from any cause will be obtained for the ITT population at each dose level of MPDL3280A.

  8. 2-year RFS rate in expansion cohort patients with PD-L1 IHC 2/3 [ Time Frame: Up to 2 years ]
    2 year RFS rate defined from study start until recurrence of disease or death from any cause will be obtained for subjects with PD-L1 IHC 2/3 at each dose level of MPDL3280A. RFS will be calculated by Kaplan Meier method

  9. Median RFS in expansion cohort patients with PD-L1 IHC 2/3 [ Time Frame: Up to 2 years ]
    Median RFS rate is defined as number of months from study start until recurrence of disease or death from any cause will be obtained for subjects with PD-L1 IHC 2/3 at each dose level of MPDL3280A.

  10. 2-year RFS rate in expansion cohort for subjects undergoing adjuvant MPDL3280A [ Time Frame: Up to 2 years ]
    2 year RFS rate defined from study start until recurrence of disease or death from any cause will be obtained for subjects subjects undergoing adjuvant MPDL3280A at each dose level. RFS will be calculated by Kaplan Meier method

  11. Median RFS in expansion cohort for subjects undergoing adjuvant MPDL3280A [ Time Frame: Up to 2 years ]
    Median RFS rate is defined as number of months from study start until recurrence of disease or death from any cause will be obtained for subjects undergoing adjuvant MPDL3280A at each dose level.

  12. Pathologic Response in expansion cohort [ Time Frame: Up to 2 years ]
    Point estimates and 95% confidence intervals of the pathologic T0 rate at the time of cystectomy, the near complete pathologic response rate, defined as the presence of only pTa or pTis in patients with T2 of greater disease at baseline will be obtained for subjects with PD-L1 IHC 2/3 at each dose level of MPDL3280A, and compared with the null hypothesis rate separately by using one-sample proportion test..

  13. Association of tumor and T-cell PD-L1/PD-1 immunohistochemical expression with disease response in expansion cohort [ Time Frame: Up to 2 years ]
    For each dose level as well as for each individual expansion cohort, Fisher's exact test will be used to test the association of baseline tumor and T-cell PD-L1/PD-1 immunohistochemical expression with disease response.

  14. Association of prior BCG therapy with tumor PD-L1 expression in expansion cohort [ Time Frame: Up to 2 years ]
    Fisher's exact test will be used to test the relationship of prior BCG therapy with tumor PD-L1 expression in each of the expansion cohorts,

  15. Association of prior BCG therapy with pT0 rate in expansion cohort [ Time Frame: Up to 2 years ]
    Fisher's exact test will be used to test the relationship of prior BCG therapy with pT0 rate in each of the expansion cohorts

  16. Frequency of all grade treatment-related toxicities occuring prior to surgery in expansion cohort [ Time Frame: Up to 2 years ]
    Frequency of all grade treatment-related toxicities occuring prior to surgery, according to NCI CTCAE v4.0

  17. Frequency of all grade treatment-related toxicities during adjuvant therapy in expansion cohort [ Time Frame: Up to 2 years ]
    Frequency of all grade treatment-related toxicities during adjuvant therapy, according to NCI CTCAE v4.0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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)
  • 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 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.

Exclusion Criteria:

  • 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.
  • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti CTLA-4, anti-PD1 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02451423


Contacts
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Contact: Lawrence Fong, MD 877-827-3222 cancertrials@ucsf.edu

Locations
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United States, California
University of California, Davis Not yet recruiting
Davis, California, United States, 95817
Contact: Mamta Parikh, MD    916-734-3771    mbparikh@ucdavis.edu   
Principal Investigator: Mamta Parikh, MD         
University of Southern California Not yet recruiting
Los Angeles, California, United States, 90033
Contact: Tanya Dorff, MD    323-865-3905    Tanya.Dorff@med.usc.edu   
Principal Investigator: Tanya Dorff, MD         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Lawrence Fong, MD    877-827-3222    cancertrials@ucsf.edu   
Sponsors and Collaborators
Lawrence Fong
Genentech, Inc.
The Bladder Cancer Advocacy Network
Conquer Cancer Foundation
Investigators
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Principal Investigator: Lawrence Fong, MD University of California, San Francisco
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Responsible Party: Lawrence Fong, Professor in Residence, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02451423    
Other Study ID Numbers: 14524
NCI-2017-01387 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: May 22, 2015    Key Record Dates
Last Update Posted: March 30, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lawrence Fong, University of California, San Francisco:
Non-metastatic
Bladder
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs