Nivolumab for the Treatment of Patients With Metastatic Urothelial Cancer With ARID1A Mutation and Stratify Response Based on CXCL13 Expression

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies the effect of nivolumab in urothelial cancer that has spread to other places in the body (metastatic), specifically in patients with aberrations in ARID1A gene (ARID1A mutation) and correlate with expression level of CXCL13, an immune cytokine. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab may help control the disease in patients with urothelial cancer or solid tumors. This trial aims at enriching patient selection based on genomic and immunological attributes of the tumor.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To estimate objective response rate (ORR) and overall survival (OS) in patients with ARID1A mutations receiving nivolumab therapy. II. To estimate objective response rate (ORR) and overall survival (OS) in patients with ARID1A mutations plus CXCL13-high expression and ARID1A mutations plus CXCL13-low expression, receiving nivolumab therapy. SECONDARY OBJECTIVES: I. To estimate progression free survival (PFS) in subjects with harboring ARID1A mutation treated with nivolumab monotherapy. II. To estimate progression free survival (PFS) in subjects with ARID1A mutations plus CXCL13-high expression and ARID1A mutations plus CXCL13-low expression, treated with nivolumab monotherapy. III. To assess peripheral and tumor infiltrating immune cell sub-populations in patients with ARID1A mutations, ARID1A plus CXCL13-high and ARID1A plus CXCL13-low expression, to determine predictors of response and resistance. IV. To determine expression pattern of CXCL13 in ARID1A mutant tumors. OUTLINE: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeats 28 days (4 weeks) for up to 2 years in the absence of disease or unacceptable toxicity. After the completion of study treatment, patients are followed up for 100 days, then every 3-6 months thereafter.

Official Title
-----------------
A Phase II Clinical Trial to Investigate ARID1A Mutation and CXCL13 Expression in the Pre-Treatment Tumor Samples as a Combinatorial Predictive Biomarker for Immune Checkpoint Therapy in Metastatic Urothelial Cancer

Conditions
-----------------
Locally Advanced Bladder Urothelial Carcinoma, Locally Advanced Renal Pelvis Urothelial Carcinoma, Locally Advanced Ureter Urothelial Carcinoma, Locally Advanced Urethral Urothelial Carcinoma, Locally Advanced Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Metastatic Urothelial Carcinoma, Recurrent Bladder Urothelial Carcinoma, Recurrent Renal Pelvis Urothelial Carcinoma, Recurrent Ureter Urothelial Carcinoma, Recurrent Urethral Urothelial Carcinoma, Recurrent Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage III Renal Pelvis Cancer AJCC v8, Stage III Ureter Cancer AJCC v8, Stage III Urethral Cancer AJCC v8, Stage IIIA Bladder Cancer AJCC v8, Stage IIIB Bladder Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8, Stage IV Renal Pelvis Cancer AJCC v8, Stage IV Ureter Cancer AJCC v8, Stage IV Urethral Cancer AJCC v8, Stage IVA Bladder Cancer AJCC v8, Stage IVB Bladder Cancer AJCC v8, Unresectable Bladder Urothelial Carcinoma, Unresectable Renal Pelvis Urothelial Carcinoma, Unresectable Ureter Urothelial Carcinoma, Unresectable Urethral Urothelial Carcinoma, Unresectable Urothelial Carcinoma

Intervention / Treatment
-----------------
* Other: Diagnostic Laboratory Biomarker Analysis
* Biological: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient will have a tumor harboring genomic mutation of ARID1A. ARID1A mutation testing will be performed as standard of care Histological or cytological evidence of metastatic or surgically unresectable urothelial cell carcinoma of the urothelial involving the bladder, urethra, ureter, or renal pelvis. Minor histologic variants (< 50% overall) are acceptable Subjects must have progression or recurrence after treatment With at least 1 platinum-containing chemotherapy regimen for metastatic or surgically unresectable locally advanced urothelial cancer, or Within 12 months of peri-operative (neo-adjuvant or adjuvant) treatment with platinum agent in the setting of cystectomy for localized muscle-invasive urothelial cancer Are ineligible or refused frontline chemotherapy All subjects must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria Evaluable tumor tissue (archived or new biopsy) must be provided for biomarker analysis as formalin-fixed paraffin-embedded (FFPE) tumor block or minimum of 10 slides. Archived tissue may be from prior biopsy of unresectable or metastatic disease or from prior surgical resection Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug administration. Patients must have measurable disease outside the radiation field to be eligible. Patients with progression in a previously radiated field will also be eligible White blood cell count (WBC) >= 2000/uL (obtained within 7 days prior to first dose) Neutrophils >= 1500/uL (obtained within 7 days prior to first dose) Platelets >= 100 x1 x10^3/uL (obtained within 7 days prior to first dose) Hemoglobin >= 9.0 g/dL (obtained within 7 days prior to first dose) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) (or =< 5 X ULN for participants with liver metastases) (obtained within 7 days prior to first dose) Total Bilirubin =< 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL (obtained within 7 days prior to first dose) Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 30 mL/min (using the Cockcroft-Gault formula) (obtained within 7 days prior to first dose) Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been treated). If re-enrolled, the subject must be re-consented and inclusion/exclusion criteria reassessed Patients are required to participate in PA13-0291 for correlative studies. Patients will need to consent for biopsy and peripheral blood collection as documented in the study calendar Exclusion Criteria: Prior treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. Where MRI is contraindicated CT scan is acceptable. Cases must be discussed with the medical monitor. Brain lesions are not considered measurable disease. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration Any serious or uncontrolled medical disorder, that in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer without evidence of prostate specific antigen (PSA) progression or carcinoma in situ such as the following: gastric, prostate, cervix, colon, melanoma, or breast for example Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism, due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease All toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia and fatigue must have resolved to grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 5) or baseline before administration of study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll. Neuropathy must have resolved to grade 2 (NCI CTCAE version 5) Treatment with any chemotherapy, radiation therapy, biologics for cancer, or investigational therapy within 28 days of first administration of study treatment. Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug administration Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or chronic infection Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nivolumab)<br>Patients receive nivolumab IV over 30 minutes on day 1. Cycles repeats every 28 days (4 weeks) for up to 2 years in the absence of disease or unacceptable toxicity. | Other: Diagnostic Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Defined as the rate of confirmed complete responses + partial responses as determined by Response Evaluation Criteria in Solid Tumors 1.1 criteria and as assessed by the investigator. In addition, will also calculate the posterior probability that ORR is bigger in CXCL13 high group than in the CXCL low group. | Up to 2 years | 
| Overall survival (OS) | The Kaplan-Meier method will be used to estimate the median OS and 1-year survival rate; the 95% confidence interval (CI) of the 1-year survival rate will also be reported. | From date of first study treatment to death due to any cause, assessed up to 2 years |