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.
