Dose Dense MVAC for Muscle Invasive Bladder Cancer

Primary Objective To assess the rate of complete response (pT0) at cystectomy or
ureterectomy following preoperative dose dense MVAC (DD-MVAC) in patients with muscle
invasive urothelial carcinoma of the bladder or high grade upper tract urothelial carcinoma.

Secondary Objectives To assess the toxicity profile of DD-MVAC when given in the neoadjuvant
setting: To define the number of patients who complete all three cycles of treatment without
dose reduction, and to compare incidence of toxicity to the historical standard described by
Grossman et al. To assess the 5 year overall and relapse free survival in patients who
receive neoadjuvant DD-MVAC. To compare complete response rates between the following
subgroups of study patients: Among bladder patients: Clinical N0 versus N1 (Appendix B)
Among bladder patients: T2 stage without high risk features versus T2 with high risk
features plus those with > T2 stage.

Three 14 day cycles of:

Methotrexate 30 mg/m2 IV push or infusion over 2-3 minutes. Day 1

Vinblastine 3 mg/m2 Slow IV push or infusion over Day 1

Doxorubicin 30 mg/m2 Slow IV push or infusion over 15 minutes Day 1

Cisplatin 70 mg/m2 IV infusion over 4 hours Note: May divide dose over two sequential days
(35 mg/m2/d x 2 days) if creatinine clearance 50-59 mL/min Day 1* (or divided over Day 1 and
Day 2)

Pegfilgrastim 6 mg SQ 24-48 hours after completion of chemotherapy.

Followed in 4-8 weeks by radical cystectomy/ureterectomy.

Inclusion Criteria:

- histologically confirmed urothelial carcinoma of bladder, ureter, or renal pelvis.
T2-T4 and muscle invasion must be established by TURBT. Upper tract must be high
grade. N0-N1 are eligible.

- candidate for radical cystectomy, nephroureterectomy, or segmental ureterectomy with
goal of cure.

->/= 18 years old

- ECOG performance status 0-1.

- Adequate marrow and organ function.

- May enter on therapeutic anticoagulation if it can be safely held during
perioperative period.

- No women of childbearing potential, pregnant or breastfeeding.

- LVEF >/= 50 %

- Patients with history of other non-urothelial malignancies may enroll if: 1)no
evidence of distant disease w/in last year. 2)No anticancer treatment for >/= 1 year
other than adjuvant treatment or treatment for secondary prevention. 3) Less than 360
mg/m2 lifetime dose of adriamycin.

- ability to understand and willingness to sign written informed consent and HIPAA.

Exclusion Criteria:

- Intravesicular therapy w/in 4 weeks of study entry or those who have not recovered
from adverse effects of such agents administered more than 4 weeks earlier.

- Patients may not be receiving any investigational agents within 4 weeks of study
entry.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Methotrexate, Vinblastine, Adriamycin or Cisplatin or other agents
used in the study.

- 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.

- Pregnant women are excluded from this study due to the potential for teratogenic or
abortifacient effects of cytotoxic chemotherapy.

- Known HIV-positive patients on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with cytotoxic
chemotherapy. In addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy.

-. Patients who have undergone prior pelvic radiation are excluded due to risk of
life threatening myelosuppression.

- Patients who have received any previous systemic chemotherapy or radiation therapy
for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1
year of study entry are ineligible.