Gemcitabine Hydrochloride and Cisplatin or High-Dose Methotrexate, Vinblastine, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Urothelial Cancer

PRIMARY OBJECTIVES

To estimate the difference in the rate of unacceptable toxicity for dose-dense methotrexate,
vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin (GC) in the
adjuvant treatment of urothelial cancer.

SECONDARY OBJECTIVES

To compare rates of disease recurrence at 3 years between dose-dense MVAC and GC.

To determine whether molecular markers excision repair cross-complementing-1 (ERCC-1)
ribonucleoside-diphosphate reductase M-1 (RRM-1), breast cancer 1 (BRCA1) topoisomerase
2-alpha (Top2A) and protein 53 (p53) can predict those patients more likely to benefit from
chemotherapy.

To investigate the potential utility of cytidine deaminase (CDA), ERCC-1, xeroderma
pigmentosum group D (XPD), glutathione S-transferase P-1 (GSTP-1) and glutathione
S-transferase M-1 (GSTM-1) as molecular markers which predict occurrence of significant
toxicity during adjuvant chemotherapy for urothelial cancer.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cisplatin intravenously (IV) on day 1 and gemcitabine hydrochloride
IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence
of disease progression or unacceptable toxicity.

ARM B: Patients receive methotrexate IV on day 1, vinblastine IV, doxorubicin hydrochloride
IV, cisplatin IV on day 2 and pegfilgrastim subcutaneously (SC) on day 3. Treatment repeats
every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years.

Inclusion Criteria:

- Histologically confirmed high-grade urothelial carcinoma, stage T3bN0, T4N0 or any T
stage with lymph node involvement, completely resected; including upper tract
urothelial carcinoma

- The dominant histology must be transitional cell or urothelial but foci of other
histologies less than 20 percent of the total tumor volume are permitted

- Absence of metastatic disease on radiographic imaging

- Patients must be enrolled and able to start treatment within 90 days of radical
cystectomy or radical nephrectomy

- Creatinine less than institutional upper limit of normal (ULN) or clearance greater
or equal to 50 mL/min (may be calculated by Cockcroft-Gault formula or measured from
24-hour urine collection)

- Serum total bilirubin less or equal to 1.5 x ULN (except for patients with Gilbert's)

- Alkaline phosphatase less or equal to 2.5 x ULN

- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate
transaminase (SGPT) less or equal to 2.5 x ULN

- White blood cells (WBC) greater or equal to 3000

- Absolute neutrophil count (ANC) greater or equal to 1500

- Hemoglobin (Hb) greater or equal to 9

- Platelets greater or equal to 100,000

- Normal left ventricular ejection fraction, by echocardiogram or multi gated
acquisition scan (MUGA)

- Patients must be recovered from surgery

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Willing and able to provide informed consent

- Willingness to use barrier contraception during study period

Exclusion Criteria:

- The presence of significant pleural effusion or ascites

- Prior systemic chemotherapy for urothelial carcinoma including neoadjuvant
chemotherapy (prior intravesical therapy is permitted)

- History of malignancy within preceding 5 years, aside from non-melanoma skin cancer
or previously treated or incidentally detected prostate cancer with undetectable PSA
(after radical cystectomy or prostate cancer therapy)

- Peripheral neuropathy greater than grade 1

- The presence of active heart disease such as congestive heart failure or unstable
angina