4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer

NCT ID: NCT00005047

Last Updated: 2017-06-08

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 521 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1997-08-31
• Study Completion Date: 2014-12-31

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective than observation alone in treating bladder cancer.

PURPOSE: This randomized phase III trial is studying combination chemotherapy to see how well it works compared to observation alone in treating patients with bladder cancer.

Detailed Description

OBJECTIVES:

• Compare the recurrence-free and overall survival in patients with transitional cell carcinoma of the bladder with p53 gene alterations treated with methotrexate, vinblastine, doxorubicin, and cisplatin vs observation alone.
• Compare the recurrence-free and overall survival in patients with or without p53 gene alterations treated with observation alone.
• Examine the expression of p53 and other genes, particularly RB, p21, and p16, involved in cell cycle regulation that may be involved in the response to chemotherapy in these patients.
• Correlate p53 mutational gene status with p53 protein expression by immunohistochemistry, outcome (recurrence-free and overall survival), response to chemotherapy, and expression of key molecules in the p53-mediated apoptotic pathway in patients treated with this regimen vs observation alone.

OUTLINE: This is a randomized, multicenter study. Patients are assigned to 1 of 2 treatment groups based on the status of the p53 gene in the bladder tumor.

• Group A (p53 gene alteration, defined by greater than 10% nuclear reactivity): Patients are stratified according to age (under 65 vs 65 and over), stage (P1 vs P2a vs P2b), grade (1 or 2 vs 3 or 4), and p21 status. Patients are randomized to 1 of 2 treatment arms within 10 weeks after radical cystectomy and bilateral pelvic lymphadenectomy and within 2 weeks after registration.

• Arm I: Within 2 weeks after randomization, patients receive methotrexate IV on days 1, 15, and 22; vinblastine IV on days 2, 15, and 22; and doxorubicin IV and cisplatin IV on day 2. Treatment repeats every 4 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo observation for recurrence but do not receive adjuvant chemotherapy after surgery.

Patients who are eligible for randomization but decline to be randomized undergo observation for recurrence.

• Group B (p53 gene normal, defined by less than 10% nuclear reactivity): Patients undergo observation for recurrence but do not receive adjuvant chemotherapy after surgery.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study within 4.75 years.

Conditions

Bladder Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I: M-VAC x 3

Patients with altered (+) p53, reconsented to randomization, randomized to three cycles of MVAC

Group Type: EXPERIMENTAL

cisplatin

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

vinblastine

Intervention Type: DRUG

Arm II: Observation

Patients with altered (+) p53, reconsented to randomization, randomized to observation

Group Type: NO_INTERVENTION

No interventions assigned to this group

Arm III: Observation

Patients with unaltered (-) p53

Group Type: NO_INTERVENTION

No interventions assigned to this group

Arm IV: Observation

Patients with altered (+) p53, patients did not consent to randomization

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

cisplatin

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

methotrexate

Intervention Type: DRUG

vinblastine

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• p53 gene alteration present
• Randomization occurs within 10 weeks after surgery
• Those who are randomized to receive (MVAC) methotrexate, vinblastine, doxorubicin, and cisplatin begin MVAC within 12 weeks after cystectomy
• No metastatic disease by physical exam and chest x-ray or CT scan of the chest
• No prohibitive medical risk for chemotherapy

PATIENT CHARACTERISTICS:

Age

• Any age

Performance status

• ECOG 0-1 OR
• Karnofsky 70-100%

Life expectancy

• Not specified

Hematopoietic

• WBC at least 4,000/mm^3
• Platelet count at least 150,000/mm^3

Hepatic

• SGOT or SGPT no greater than 2 times normal
• Alkaline phosphatase no greater than 2 times normal
• Bilirubin normal

Renal

• Creatinine no greater than 1.8 mg/dL OR
• Creatinine clearance at least 50 mL/min
• Blood urea nitrogen normal

Cardiovascular

• No serious arrhythmias
• No congestive heart disease with New York Heart Association class III or IV status
• Randomization group:

• Ejection fraction must be at least 50% by MUGA scan if there is a clinical concern regarding the patient's cardiac status

Other

• No other malignancy (including synchronous papillary or invasive upper urinary tract malignancy) within the past 5 years except incidental prostate cancer (found at cystectomy), basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix
• No concurrent advanced medical illness or psychologic disease
• No prohibitive medical risk for chemotherapy
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics
• No prior systemic chemotherapy for bladder cancer
• At least 5 years since other prior systemic chemotherapy
• Prior intravesical therapy allowed
• Randomization group:

• Prior intravesical therapy allowed if administered prior to cystectomy

Endocrine therapy

• Not specified

Radiotherapy

• No prior pelvic irradiation

Surgery

• See Disease Characteristics

• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: collaborator

University of Southern California

OTHER

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Richard J. Cote, MD, FRCPath

Role: STUDY_CHAIR

University of Southern California

Laurence H. Klotz, MD

Role: STUDY_CHAIR

Toronto Sunnybrook Regional Cancer Centre

Seth P Lerner, MD

Role: STUDY_CHAIR

Baylor College of Medicine

Locations

Banner Thunderbird Medical Center

Glendale, Arizona, United States

Banner Good Samaritan Medical Center

Phoenix, Arizona, United States

CCOP - Western Regional, Arizona

Phoenix, Arizona, United States

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, United States

North Colorado Medical Center

Greeley, Colorado, United States

McKee Medical Center

Loveland, Colorado, United States

Saint Anthony's Hospital at Saint Anthony's Health Center

Alton, Illinois, United States

Cardinal Bernardin Cancer Center at Loyola University Medical Center

Maywood, Illinois, United States

Good Samaritan Regional Health Center

Mount Vernon, Illinois, United States

St. Francis Hospital and Health Centers - Beech Grove Campus

Beech Grove, Indiana, United States

Cancer Center of Kansas, P.A. - Chanute

Chanute, Kansas, United States

Cancer Center of Kansas, P.A. - Dodge City

Dodge City, Kansas, United States

Cancer Center of Kansas, P.A. - El Dorado

El Dorado, Kansas, United States

Veterans Affairs Medical Center - Kansas City

Kansas City, Kansas, United States

Cancer Center of Kansas, P.A. - Kingman

Kingman, Kansas, United States

Southwest Medical Center

Liberal, Kansas, United States

Cancer Center of Kansas, P.A. - Newton

Newton, Kansas, United States

Cancer Center of Kansas, P.A. - Parsons

Parsons, Kansas, United States

Cancer Center of Kansas, P.A. - Pratt

Pratt, Kansas, United States

Cancer Center of Kansas, P.A. - Salina

Salina, Kansas, United States

Salina Regional Health Center

Salina, Kansas, United States

Cancer Center of Kansas, P.A. - Wellington

Wellington, Kansas, United States

Associates in Womens Health, P.A. - North Review

Wichita, Kansas, United States

Cancer Center of Kansas, P.A. - Medical Arts Tower

Wichita, Kansas, United States

Cancer Center of Kansas, P.A. - Wichita

Wichita, Kansas, United States

CCOP - Wichita

Wichita, Kansas, United States

Via Christi Cancer Center at Via Christi Regional Medical Center

Wichita, Kansas, United States

Cancer Center of Kansas, P.A. - Winfield

Winfield, Kansas, United States

Veterans Affairs Medical Center - Shreveport

Shreveport, Louisiana, United States

Feist-Weiller Cancer Center at Louisiana State University Health Sciences

Shreveport, Louisiana, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

William Beaumont Hospital - Royal Oak Campus

Royal Oak, Michigan, United States

Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital

Cape Girardeau, Missouri, United States

St. Francis Medical Center

Cape Girardeau, Missouri, United States

CCOP - St. Louis-Cape Girardeau

St Louis, Missouri, United States

David C. Pratt Cancer Center at St. John's Mercy

St Louis, Missouri, United States

Big Sky Oncology

Great Falls, Montana, United States

Sletten Regional Cancer Institute

Great Falls, Montana, United States

Herbert Irving Comprehensive Cancer Center at Columbia University

New York, New York, United States

James P. Wilmot Cancer Center at University of Rochester Medical Center

Rochester, New York, United States

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, United States

Grandview Hospital

Dayton, Ohio, United States

Good Samaritan Hospital

Dayton, Ohio, United States

David L. Rike Cancer Center at Miami Valley Hospital

Dayton, Ohio, United States

Samaritan North Cancer Care Center

Dayton, Ohio, United States

Veterans Affairs Medical Center - Dayton

Dayton, Ohio, United States

CCOP - Dayton

Dayton, Ohio, United States

Community Oncology Group at Cleveland Clinic Cancer Center

Independence, Ohio, United States

Charles F. Kettering Memorial Hospital

Kettering, Ohio, United States

Middletown Regional Hospital

Middletown, Ohio, United States

UVMC Cancer Care Center at Upper Valley Medical Center

Troy, Ohio, United States

Cleveland Clinic - Wooster

Wooster, Ohio, United States

Ruth G. McMillan Cancer Center at Greene Memorial Hospital

Xenia, Ohio, United States

Brooke Army Medical Center

Fort Sam Houston, Texas, United States

Wilford Hall Medical Center

Lackland Air Force Base, Texas, United States

Veterans Affairs Medical Center - San Antonio (Murphy)

San Antonio, Texas, United States

Cancer Therapy and Research Center

San Antonio, Texas, United States

University Hospital - San Antonio

San Antonio, Texas, United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Sentara Cancer Institute at Sentara Norfolk General Hospital

Norfolk, Virginia, United States

St. Joseph Hospital Community Cancer Center

Bellingham, Washington, United States

Olympic Hematology and Oncology

Bremerton, Washington, United States

Skagit Valley Hospital Cancer Care Center

Mount Vernon, Washington, United States

CCOP - Virginia Mason Research Center

Seattle, Washington, United States

Group Health Central Hospital

Seattle, Washington, United States

Harborview Medical Center

Seattle, Washington, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Swedish Cancer Institute at Swedish Medical Center - First Hill Campus

Seattle, Washington, United States

University Cancer Center at University of Washington Medical Center

Seattle, Washington, United States

North Puget Oncology at United General Hospital

Sedro-Woolley, Washington, United States

Cancer Care Northwest - Spokane South

Spokane, Washington, United States

Wenatchee Valley Clinic

Wenatchee, Washington, United States

Community Comprehensive Cancer Center at Camden-Clark Memorial Hospital

Parkersburg, West Virginia, United States

Toronto Sunnybrook Regional Cancer Centre at Sunnybrook and Women's College Health Sciences Centre

Toronto, Ontario, Canada

Countries

United States; Canada

References

von Rundstedt FC, Mata DA, Groshen S, Stein JP, Skinner DG, Stadler WM, Cote RJ, Kryvenko ON, Godoy G, Lerner SP. Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial. BJU Int. 2015 Jul;116(1):44-9. doi: 10.1111/bju.12997. Epub 2015 Mar 25.

Reference Type: DERIVED

PMID: 25413313 (View on PubMed)

Other Identifiers

LAC-USC-4B951

Identifier Type: OTHER

Identifier Source: secondary_id

SWOG-4B951

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-G00-1715

Identifier Type: OTHER

Identifier Source: secondary_id

NYU-9852

Identifier Type: OTHER

Identifier Source: secondary_id

CAN-NCIC-BL10

Identifier Type: OTHER

Identifier Source: secondary_id

CCCWFU-88198

Identifier Type: -

Identifier Source: secondary_id

U10CA032102

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CDR0000067639

Identifier Type: -

Identifier Source: org_study_id