Neoadjuvant Chemotherapy With Methotrexate, Vinblastine, Adriamycin and Cisplatin (M-VAC) Plus Avastin in Patients With Urothelial Cancer

Avastin is designed to prevent or slow down the growth of cancer cells by blocking the
growth of blood vessels. Methotrexate, vinblastine, and doxorubicin are designed to disrupt
the growth of cancer cells, which causes cancer cells to start to die. Cisplatin has an atom
at its center that contains platinum. The platinum is designed to poison the cancer cells,
which may cause them to eventually die.

If you are found to be eligible to take part in this study, you will be treated with the
combination of Avastin, methotrexate, vinblastine, doxorubicin, and cisplatin. The study
drugs and saline will be given through a needle in your vein. Avastin will be given over 90
minutes. Methotrexate will be given over 30 minutes. Vinblastine will be given over 30
minutes. Doxorubicin will be given over 15 minutes. Cisplatin will be given over 4 hours.
You will also receive saline for hydration after you have completed the infusion of
cisplatin. This will take up to 20 hours. If you have a catheter in place, the chemotherapy
drugs as well as the saline will be given through the catheter. You will receive the study
drugs 1 time every 2 weeks. Every 2 weeks is called a study "cycle".

On Day 1 of each cycle, you will have a physical exam, including measurement of your vital
signs, height, and weight. You will be asked about any side effects you have experienced
since your last visit. Blood (about 2 teaspoons) and urine will be collected for routine
tests.

After 3 cycles of therapy, you will have a bone scan if your screening test showed signs of
bone disease. You will also have a repeat cystoscopy. These tests will be done to check the
status of the disease.

You will receive a total of 4 cycles of chemotherapy. At least 6 weeks after the last dose
of Avastin, you will have a cystectomy (removal of your tumor). Your doctor will explain
this procedure to you in detail. You will sign a separate consent form for this procedure.

After surgery, if you do not have disease in your lymph nodes or other sites, you will be
taken off-study.

After surgery, if you still have disease in your lymph nodes or other sites, you will be
eligible to continue treatment with Avastin. Therapy can be restarted no sooner than 28 days
after your surgery. You will receive Avastin every 2 or 3 weeks through a needle in your
vein. Every 2 or 3 weeks will be considered a study cycle.

Before each cycle of treatment, blood (about 1 teaspoon) will be drawn for routine tests.
Urine will be collected every cycle for routine testing. Every 3 months you will have a CT
scan or MRI to check the status of the disease.

You may continue to receive the study drug for up to 18 months of therapy. You will be taken
off study in the disease gets worse or intolerable side effects occur.

Once you are off-study, you will have long term follow-up visits every 3-6 months for the
first 30 months and then every year after that. These visits will continue for up to 4
years, or longer if your doctor thinks it is necessary. At these visits, you will have a CT
or MRI scan of your abdomen and pelvis and a chest x-ray. Blood (about 1 teaspoons) will be
drawn for routine testing.

This is an investigational study. Avastin is not FDA approved or commercially available for
this indication. Its use in this study is considered to be investigational. Methotrexate,
doxorubicin, vinblastine, and cisplatin are all FDA approved and commercially available. Up
to 60 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients must have histologic proof of urothelial cancer. Patients with all
histologic subtypes are eligible as long as transitional cell carcinoma predominant,
with 2 exceptions:

- More than a few clusters of small cell carcinoma are treated with different
chemotherapy and are ineligible for this study

- Patients with micropapillary tumor will be allowed irrespective of the extent of
transitional cell carcinoma. A transitional cell component is not required in
the setting of pure or extensive micropapillary tumors. Note that minor
histologic components are acceptable.

2. Patients with primary tumors arising in the bladder or urethra are eligible if they
demonstrate any of the following features:

- A 3-dimensional mass on examination under anesthesia (EUA); ie: cT3b disease

- Direct invasion of prostatic stroma or the vaginal wall: ie:cT4a disease

- Lymphovascular invasion on the specimen with >/= cT1 disease

- Hydronephrosis present on CT scan or on renal ultrasound

- Tumor involving bladder diverticulum.

3. Patients with more than a few areas of micropapillary histology are eligible, even if
they do not meet the anatomic criteria for locally advanced disease enumerated above.
Patients with micropapillary histology will be analyzed as a separate cohort.

4. Patients with primary tumors arising in the ureter or renal pelvis are eligible they
have either grade 3 tumor, or a radiographic abnormality large enough to recognize as
an abnormal mass by CT or MRI imaging. These patients may also be analyzed
separately, since we do not have benchmark data for upper tract disease.

5. Patients must have an evaluation in the department of urology, and be deemed an
acceptable surgical candidate.

6. Patients must have adequate physiologic reserves as by:

- Zubrod performance status (PS) of entirely to the cancer and not due to comorbidity (especially if the compromised
performance status is related to uncontrolled pain which is expected to be
rapidly reversible when therapy starts)

- Normal WBC, ANC >/= 1,800, and platelet count >/= 150,000. Supranormal values
judged to be of benign or inconsequential etiology are acceptable

- Transaminase (AST or ALT)
- Conjugated bilirubin
- Normal Serum Creatinine or Creatinine clearance (either measured or by
Cockcroft-Gault formula) of >/= 50 ml/min.Cockcroft-Gault: CLcr = [(140-age) *
wt(kg)]/[72 * Cr(mg/dL)] (For females, multiply by 0.85)

7. Patients (Pts) must NOT have clinical evidence of disease beyond the involved organ
by either CT or MRI of the abdomen and pelvis, and chest X-ray. Pts with lymph node
involvement are not eligible. In absence of a bone scan, pts should be free of bone
pain and have an alk. phos. < 150% of the ULN, or a normal bone fraction of alk.
phos. If these features are present, pts should have a bone scan and this should be
interpreted as showing no evidence of metastatic disease to be eligible. In case of
bladder tumors, cancer invading local organs (pT4a) but not pelvis sidewall (pT4b)
are allowed.

8. Patients must have a determination of LV function with an EF >/= 50% to participate.

9. Women of child-bearing potential (i.e., who has had menses at any time in the
preceding 24 consecutive months) must have a negative pregnancy test. Elevations of
BHCG which are related to tumor (and not the rapid escalation associated with
pregnancy, i.e. doubling time of 3-5 days) are acceptable.

10. Patients of child-bearing or child-fathering potential must agree to use an
acceptable form of birth control while on the study, i.e. condoms.

11. Patients with second malignancies are eligible provided that the expected outcome
from the second cancer is such that this will not interfere in the delivery of this
therapy, or the assessment of response in the cystectomy specimen. The expected
survival from the prior malignancy should reliably be > 4 years to be eligible for
this study.

12. Patients must be >/= 18 years of age.

Exclusion Criteria:

1. Patients must not have current, recent (within 3 weeks), or planned participation
with other experimental medication clinical trials.

2. Prior systemic cytoreductive chemotherapy for bladder cancer. Please note, that prior
intra-vesical therapy is allowed.

3. Blood pressure of > 140/90 mmHg. Patients whose blood pressure is controlled with
oral medication are eligible, as long as the blood pressure is
4. Any prior history of hypertensive crisis or hypertensive encephalopathy.

5. New York Heart Association (NYHA) Grade II or greater congestive heart failure.

6. History of myocardial infarction or unstable angina within 6 months prior to study
enrollment.

7. History of stroke or transient ischemic attack within 6 months prior to study
enrollment.

8. Clinically significant peripheral vascular disease (e.g., aortic aneurysm, aortic
dissection).

9. Symptomatic peripheral vascular disease.

10. Evidence of bleeding diathesis or coagulopathy.

11. Known history of central nervous system or brain metastases.

12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to Day 1, anticipation of need for major surgical procedure during the course
of the study. For the purpose of this study, Cystoscopy and ureteroscopy is not
included as a major surgical procedure.

13. Lactating women.

14. Proteinuria at screening as demonstrated by either:

- Urine protein:creatinine (UPC) ratio >/= 1.0 at screening OR

- Urine dipstick for proteinuria > 2+ (or > 100 protein on urinalysis) Patients
discovered to have >2+ proteinuria on dipstick urinalysis or >100 on urinalysis
at baseline should undergo a 24 hour urine collection and must demonstrate <= 1g
of protein in 24 hours to be eligible.

15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to therapy. Patients with Crohn's disease will be
excluded.

16. Serious, non-healing wound, ulcer, or bone fracture.

17. Lung carcinoma of squamous cell histology or any histology in close proximity to a
major vessel, cavitation, or history of hemoptysis (bright red blood of 1/2 teaspoon
or more; non-small cell lung cancer trials only).

18. Inability to comply with study and/or follow-up procedures, or sign informed consent.

19. Patients who are not candidates for surgery, or are unwilling to undergo surgery.

20. Patients with fluid collections (such as ascites, or pleural effusions) are not
eligible for therapy as such collections may serve as a reservoir for methotrexate.

21. Know hypersensitivity to any component of Avastin.