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) 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 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 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

- 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, 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 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 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. 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

- AST(SGOT)/ALT(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 m2

- 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.

- 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 CART
therapy and 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 enrolllment.

- 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 CTCAE less than or equalto Grade 1 from
toxicity due to all prior therapies except alopecia and other non-clinically
significant 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.