Neoadjuvant Atezolizumab in Localized Bladder Cancer

NCT02451423 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: 14524NCI-2017-01387R01CA194511
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Carcinoma, Transitional Cell

Keywords

Non-metastatic; Bladder

Outcome Measures

Primary Outcomes (7)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  Up to 2 years

Secondary Outcomes (4)

• Near Complete Pathologic Response Rate

  Up to 2 years

• Relapse-free Survival (RFS) Rate Intention-To-Treat (ITT) Population

  Up to 2 years

• Overall Survival Rate

  Up to 2 years

• Association of Tumor and T-cell PD-L1/PD-1 Immunohistochemical Expression With Disease Response

  Up to 2 years

Study Arms (3)

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)

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)

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)

Drug: Atezolizumab

Interventions

Atezolizumab DRUG

1200 mg Given IV

Also known as: MPDL3280A

Cohort A1: Atezolizumab (Single dose); Cohort A2: Atezolizumab Monotherapy (2 doses); Cohort A3: Atezolizumab Monotherapy (3 doses)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 Creatinine Clearance (CrCl) \> 30ml/min

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Lawrence Fong: lead
• Genentech, Inc.: collaborator
• Bladder Cancer Advocacy Network: collaborator
• Conquer Cancer Foundation: collaborator
• National Cancer Institute (NCI): collaborator
• The V Foundation: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Publications (2)

• 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.

  PMID: 32497499 DERIVED

• Friebel 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.

  PMID: 32470397 DERIVED

MeSH Terms

Conditions

Carcinoma, Transitional Cell

Interventions

atezolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Results Point of Contact

• Title: Dr. Lawrence Fong, MD
• Organization: University of California, San Francsico

lawrence.fong@ucsf.edu

(415) 514-3160

Study Officials

• Lawrence Fong, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor in Residence

Study Record Dates

• First Submitted: March 4, 2015
• First Posted: May 22, 2015
• Study Start: March 29, 2016
• Primary Completion: March 31, 2023
• Study Completion: March 31, 2023
• Last Updated: May 31, 2024
• Results First Posted: May 31, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)