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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT00506155
First received: July 23, 2007
Last updated: January 21, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Bladder Cancer
Drug: Avastin
Drug: Cisplatin
Drug: Doxorubicin
Drug: Methotrexate
Drug: Vinblastine Sulfate
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Clinical Trial of Neoadjuvant Chemotherapy With M-VAC Plus Avastin in Patients With Locally Advanced Urothelial Cancer

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Number of Patients with Response [ Time Frame: Following 18 months of therapy ] [ Designated as safety issue: No ]
    Response defined as the absence of residual muscle invasive cancer in the resected specimen.


Estimated Enrollment: 60
Study Start Date: June 2007
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Neoadjuvant Chemotherapy with M-VAC + Avastin
Avastin 10 mg/kg by vein over 90 minutes. Cisplatin 70 mg/m^2 by vein over 4 hours. Doxorubicin 30 mg/m^2 by vein over 15 minutes. Methotrexate 30 mg/m^2 by vein over 30 minutes. Vinblastine Sulfate 3 mg/m^2 by vein over 30 minutes.
Drug: Avastin
10 mg/kg by vein over 90 minutes
Other Names:
  • Bevacizumab
  • Anti-VEGF monoclonal antibody
  • rhuMAb-VEGF
Drug: Cisplatin
70 mg/m^2 by vein over 4 hours
Other Names:
  • Platinol-AQ
  • Platinol
  • CDDP
Drug: Doxorubicin
30 mg/m^2 by vein over 15 minutes
Other Names:
  • Adriamycin
  • Rubex
Drug: Methotrexate
30 mg/m^2 by vein over 30 minutes
Drug: Vinblastine Sulfate
3 mg/m^2 by vein over 30 minutes

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00506155

Locations
United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Genentech
Investigators
Principal Investigator: Arlene Siefker-Radtke, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00506155     History of Changes
Other Study ID Numbers: 2006-0620
Study First Received: July 23, 2007
Last Updated: January 21, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Bladder Cancer
Urothelial Cancer
Avastin
Bevacizumab
Cisplatin
Doxorubicin
Methotrexate
Vinblastine
M-VAC

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Antibodies, Monoclonal
Methotrexate
Bevacizumab
Cisplatin
Doxorubicin
Vinblastine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Radiation-Sensitizing Agents
Antibiotics, Antineoplastic
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents

ClinicalTrials.gov processed this record on April 17, 2014