Neoadjuvant Chemotherapy With Methotrexate, Vinblastine, Adriamycin and Cisplatin (M-VAC) Plus Avastin in Patients With Urothelial Cancer
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Intervention: Avastin; Cisplatin; Doxorubicin; Methotrexate; Vinblastine Sulfate
Intervention description: 10 mg/kg by vein over 90 minutes; 70 mg/m^2 by vein over 4 hours; 30 mg/m^2 by vein over 15 minutes; 30 mg/m^2 by vein over 30 minutes; 3 mg/m^2 by vein over 30 minutes
Intervention MeSH terms: Bevacizumab; Cisplatin; Doxorubicin; Methotrexate; Vinblastine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Bladder Cancer; Urothelial Cancer; Avastin; Bevacizumab; Cisplatin; Doxorubicin; Methotrexate; Vinblastine; M-VAC

Summary:

      The goal of this clinical research study is to learn how well bladder cancer responds to a
      combination treatment with Avastin and M-VAC (methotrexate, doxorubicin, vinblastine, and
      cisplatin) before surgery to remove the tumor.

      Primary Objective:

      To estimate the response of patients with locally advanced urothelial cancer treated with
      neoadjuvant chemotherapy with a combination of Dose Dense Methotrexate, Vinblastine,
      Adriamycin, and Cisplatin (DD-M-VAC) plus Avastin followed by radical surgery with curative
      intent. In this context, response will be defined as the absence of residual muscle invasive
      cancer in the resected specimen (<= pT1, N0.)

      Secondary Objective:

      To estimate the 4-year disease-free survival of patients with locally advanced urothelial
      cancer treated with neoadjuvant chemotherapy with DD-M-VAC plus Avastin followed by radical
      surgery with curative intent.

      Document perioperative morbidity and mortality in this cohort, with reference to
      well-established historical standards.

      Determine the effects of VEGF inhibition on angiogenesis and angiogenesis-related gene
      expression utilizing fluorescent tissue staining techniques that we have developed in the
      laboratory (such as two-color TUNEL, phospho-receptor, and microvessel density).

      Interrogate downstream receptor signaling pathways to provide insight into the development of
      chemotherapy resistance, and hence hypothesis for its prevention.
    

Eligibility criteria:

        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 </= 1; or 2 if of recent onset and due 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) </= 3 * the ULN

               -  Conjugated bilirubin </= 1.5 mg/dl (or total bilirubin </= 2.5 mg/dl)

               -  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 </= 140/90 mmHg.

          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.