Genomic Based Assignment of Therapy in Advanced Urothelial Carcinoma

Background:

• Patients presenting de novo with metastatic bladder cancer, or developing visceral metastatic disease after local treatment, are incurable with currently available therapeutic modalities.
• Only a small number of chemotherapeutic agents have been tested and very few have some single agent activity in the treatment of metastatic urothelial carcinoma. However most (>100) Food and Drug Administration (FDA) approved anticancer agents have yet to be tested in this disease.
• Novel approaches to the development of genomic predictors of chemosensitivity that do not require clinical trials for their identification are urgently needed in order to identify agents that are clinically effective when either repurposed or discovered de novo specifically for urothelial carcinoma. Such repurposing of an FDA approved anticancer agent in order to advance therapy from one cancer to another would require only minimal clinical development, saving billions of dollars and reducing the time required to reach routine clinical practice.
• Our established extramural-intramural National Cancer Institute (NCI) collaboration pulls together significant expertise in biomarker development and clinical trial design in bladder cancer. The innovation of this group lies not only in the novel scientific approaches i.e. CoeXpression ExtrapolatioN (COXEN) under investigation, but also in the successful creation of a cohesive multi-institutional research collaboration dedicated to improved clinical outcomes in bladder cancer patients.
• COXEN uses molecular profiles as a Rosetta Stone for translating drug sensitivities of one set of cancers into predictions for another completely independent set of cell lines or human tumors. The COXEN methodology has been scrutinized and deemed methodologically sound by peer review. The ability of COXEN to predict drug effectiveness in patients a priori, from purely in vitro assays, is unique as no other tool currently either in practice or in development provides similar results.

Objectives:

• To determine the feasibility of using the Co-eXpression ExtrapolatioN (COXEN) model in making a real-time treatment decision (within 3 weeks) in patients with advanced urothelial carcinoma.

Eligibility:

• Patients must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
• Patients must have progressive metastatic disease defined as new or progressive lesions on cross-sectional imaging.
• Patients must have at least:

• One measurable site of disease (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria)
• Or, appearance of one new bone lesion
• Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.
• Archival tumor tissue must be available for enrollment.
• Tumor amenable to biopsy will be mandatory for this study.
• 18 years of age or older
• Eastern Cooperative Oncology Group (ECOG) performance status <2 (Karnofsky >60%)

Design:

• This will be a pilot single-arm, open-label study using the COXEN score to select the best next therapy from a list of 75 FDA approved anti-neoplastic drugs, in patients with metastatic bladder cancer who have progressed despite treatment with cytotoxic chemotherapy. Combinations of the listed agents may also be utilized provided that phase 1 data are available.
• The COXEN algorithm requires a multi-step process (pathology, tissue processing, messenger ribonucleic acid (mRNA) profiling, bioinformatics, etc.) and is potentially labor intensive and time intensive.
• Given the disease state of patients eligible for this protocol, using this algorithm to select a treatment would only be a worthwhile process to undertake if it can be demonstrated that a very high fraction of patients are likely to obtain the benefit from the procedure.

• INCLUSION CRITERIA:
• Patients must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
• Patients must have progressive metastatic disease defined as new or progressive lesions on cross-sectional imaging.
• Patients must have at least:

• One measurable site of disease (according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as more than or equal to 20 mm with conventional techniques or as less than or equal to 10 mm with spiral computed tomography (CT) scan.
• Or, appearance of one new bone lesion
• Patients must have been previously treated with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.
• Archival tumor tissue must be available for enrollment.
• Tumor amenable to biopsy will be mandatory for this study.
• Age more than or equal to 18 years. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky more than or equal to 60%,).
• Patients must have normal organ and marrow function as defined below:

• hemoglobin more than or equal to 9 g/dL
• leukocytes more than or equal to 3,000/mcL
• absolute neutrophil count more than or equal to 1,200/mcL
• platelets more than or equal to 75,000/mcL
• total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST)/Serum glutamic oxaloacetic transaminase (SGOT)/Alanine aminotransferase (ALT)/Serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5 X institutional upper limit of normal
• creatinine 1.5 x the normal institutional limits

OR

--creatinine clearance more than or equal to 40 mL/min/1.73 m^2

• Because many of the therapeutic agents used in this trial are known to be teratogenic, 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 and for the duration of study participation. 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.
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy may be eligible if there are no pharmacokinetic interactions with the agents used on the study, stable on Chimeric antigen receptor T-cell (CART) therapy and cluster of differentiation 4 (CD4) is >200 and viral load is undetectable.
• Ability of subject to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• The patient has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks or biologic agents (e.g., cytokines or antibodies) within 4 weeks prior to study enrollment.
• Patients who are receiving any investigational agents.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastases that are stable after more than or equal to 1 year after primary surgery or radiation will not be excluded.
• The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) less than or equal to Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs(.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who are Hepatitis B or C positive.
• Pregnant women are excluded from this study because the agents used in the study have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated with these agents. These potential risks may also apply to other agents used in this study.