Trial of Combination ABI-007, Carboplatin, and Gemcitabine for First Line Treatment of Advanced Urothelial Cancer

On the basis of the known single agent activity of paclitaxel in urothelial cancer, the
activity of combination therapy with paclitaxel, carboplatin, and gemcitabine in advanced
urothelial cancer coupled with the results from studies in breast cancer demonstrating
improved clinical efficacy of ABI-007 over paclitaxel with a more favorable toxicity
profile, we propose this phase II trial evaluating the efficacy and safety of the
combination of ABI-007, carboplatin, and gemcitabine in patients with advanced urothelial
cancer.

Carboplatin and gemcitabine dosing and schedule is based on our previous trial of
paclitaxel, carboplatin, and gemcitabine which showed acceptable toxicity.

Due to the extent of hematologic toxicities expected with this combination and reported with
weekly schedules of ABI-007 based combinations as well as our experience on UMCC protocol
2007.061 which originally utilized a weekly ABI-007 with gemcitabine and carboplatin, we do
not feel continuous weekly dosing will be feasible. Therefore this trial is designed with
ABI-007 on a D1 only schedule every 21 days. The starting dose of ABI-007 will be 220 mg/m2,
because of the risk of significant bone marrow suppression, with the option of a dose
escalation in patients who tolerate therapy well after the first cycle to 260 mg/m2 every 21
days.

Inclusion Criteria:

- Male and female patients at least 18 years of age.

- Histologic or cytologic diagnosis of urothelial carcinoma (transitional cell
carcinoma either pure or mixed histology) that is metastatic or locally recurrent or
locally advanced and not eligible for higher priority trials.

- must have measurable disease.

- Patients must have recovered from any radiation therapy and must not have had more
than 25% of the bone marrow irradiated.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix 1.)

- Life expectancy of at least 12 weeks.

- Adequate organ and marrow function as defined below obtained within 14 days from
registration:

- absolute neutrophil count >1,500/µL

- platelets >100,000/µL

- total bilirubin =1.5 mg/dL

- creatinine <2.0 mg/dL

- AST and ALT <2.5 X upper limits of normal

- Timing guideline for pre-study labs and measurements:

- All pre-study labs required for determination of eligibility are to be completed
within 14 days prior to registration.

- X-rays and/or scans to assess all disease sites are to be completed within 1
month prior to registration (or the next business day if falls on a weekend or
holiday).

- All patients must be informed of the investigational nature of this study and must
sign an informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

- Previous systemic chemotherapy for the current stage of disease.

- Prior treatment with ABI-007 or other taxane (prior treatment with taxane in
neoadjuvant or adjuvant setting more than one year prior to registration is allowed).

- Pre-existing neuropathy that is > grade 2 (i.e. interfering with patient function).

- History of or known spinal cord compression, or carcinomatous meningitis, or evidence
of symptomatic brain or leptomeningeal disease on screening CT or MRI scan.

- Known HIV positive patients may not participate. This is to avoid additional
complications that immune suppression and HIV infection may cause due to the intense
nature of the chemotherapy in this trial.

- Concurrent treatment on another therapeutic clinical trial. Supportive care trials or
non-treatment trials, e.g. QOL, are allowed.

- Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female subjects with reproductive potential must have a negative
pregnancy test (serum) prior to enrollment. Male subjects must be surgically sterile
or must agree to use effective contraception during the period of therapy. The
definition of effective contraception will be based on the judgment of the principal
investigator or a designated associate.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the subject inappropriate for entry
into this study.