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Bladder CancerPhase 3NCT00005047

4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer

A Phase 3 study testing cisplatin, doxorubicin hydrochloride and methotrexate in people with Bladder Cancer, run by SWOG Cancer Research Network at 74 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 120 years
Conditions the study is for
Bladder Cancer
What is being tested?
cisplatin, doxorubicin hydrochloride and methotrexate
Could I receive a placebo?
No, everyone receives an active treatment
How many people
521 participants
Where
74 sitesin 2 countries
Study dates
Aug 1997to Dec 2014
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 120 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

DISEASE CHARACTERISTICS:

  • Histologically proven organ confined transitional cell carcinoma (TCC) of the bladder
  • Must have undergone radical cystectomy and bilateral pelvic lymphadenectomy with pathologic stage from definitive cystectomy specimen of P1, P2a, or P2b and N0, M0 TCC with or without squamous/glandular differentiation (no adenocarcinoma, squamous cell carcinoma, or small cell carcinoma)
  • Margins must be negative for invasive or in situ TCC
  • In situ TCC in the urethra or ureter(s) allowed provided margins are negative
  • Clinical stage T1, T2a, or T2b based on transurethral resection bladder tumor specimen with P0 or PIS and N0, M0 TCC allowed
  • Incidental pT2a (Gleason score no greater than 7), pT2b (Gleason score no greater than 7), or pT2c (Gleason score no greater than 7) adenocarcinoma of the prostate allowed
  • No invasive tumor into ureter(s) or urethra
  • Must have potentially curable disease
  • Must register within 9 weeks after surgery
  • No metastatic disease by physical exam and chest x-ray or CT scan of the chest
  • Eligible for randomization if:
  • 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

Trial locations and contacts

74 sites in 2 countries.

74 sites in 2 countries

United States73 sites

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

    Alton, Illinois, 62002

  • University of Michigan Comprehensive Cancer Center

    Ann Arbor, Michigan, 48109-0942

  • St. Francis Hospital and Health Centers - Beech Grove Campus

    Beech Grove, Indiana, 46107

  • St. Joseph Hospital Community Cancer Center

    Bellingham, Washington, 98225

  • Olympic Hematology and Oncology

    Bremerton, Washington, 98310

  • Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital

    Cape Girardeau, Missouri, 63701

  • St. Francis Medical Center

    Cape Girardeau, Missouri, 63701

  • Cancer Center of Kansas, P.A. - Chanute

    Chanute, Kansas, 66720

  • Cleveland Clinic Taussig Cancer Center

    Cleveland, Ohio, 44195

  • Grandview Hospital

    Dayton, Ohio, 45405

  • Good Samaritan Hospital

    Dayton, Ohio, 45406

  • David L. Rike Cancer Center at Miami Valley Hospital

    Dayton, Ohio, 45409

  • Samaritan North Cancer Care Center

    Dayton, Ohio, 45415

  • Veterans Affairs Medical Center - Dayton

    Dayton, Ohio, 45428

  • CCOP - Dayton

    Dayton, Ohio, 45429

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

    Dodge City, Kansas, 67801

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

    El Dorado, Kansas, 67042

  • Brooke Army Medical Center

    Fort Sam Houston, Texas, 78234

  • Banner Thunderbird Medical Center

    Glendale, Arizona, 85306

  • Big Sky Oncology

    Great Falls, Montana, 59405

  • Sletten Regional Cancer Institute

    Great Falls, Montana, 59405

  • North Colorado Medical Center

    Greeley, Colorado, 80631

  • Community Oncology Group at Cleveland Clinic Cancer Center

    Independence, Ohio, 44131

  • Veterans Affairs Medical Center - Kansas City

    Kansas City, Kansas, 64128

  • Charles F. Kettering Memorial Hospital

    Kettering, Ohio, 45429

  • Cancer Center of Kansas, P.A. - Kingman

    Kingman, Kansas, 67068

  • Wilford Hall Medical Center

    Lackland Air Force Base, Texas, 78236

  • Southwest Medical Center

    Liberal, Kansas, 67901

  • USC/Norris Comprehensive Cancer Center and Hospital

    Los Angeles, California, 90089-9181

  • McKee Medical Center

    Loveland, Colorado, 80539

  • Cardinal Bernardin Cancer Center at Loyola University Medical Center

    Maywood, Illinois, 60153

  • Middletown Regional Hospital

    Middletown, Ohio, 45044

  • Good Samaritan Regional Health Center

    Mount Vernon, Illinois, 62864

  • Skagit Valley Hospital Cancer Care Center

    Mount Vernon, Washington, 98273

  • Herbert Irving Comprehensive Cancer Center at Columbia University

    New York, New York, 10032

  • Cancer Center of Kansas, P.A. - Newton

    Newton, Kansas, 67114

  • Sentara Cancer Institute at Sentara Norfolk General Hospital

    Norfolk, Virginia, 23507

  • Community Comprehensive Cancer Center at Camden-Clark Memorial Hospital

    Parkersburg, West Virginia, 26102

  • Cancer Center of Kansas, P.A. - Parsons

    Parsons, Kansas, 67357

  • Banner Good Samaritan Medical Center

    Phoenix, Arizona, 85006

  • CCOP - Western Regional, Arizona

    Phoenix, Arizona, 85006

  • Cancer Center of Kansas, P.A. - Pratt

    Pratt, Kansas, 67124

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

    Rochester, New York, 14642

  • William Beaumont Hospital - Royal Oak Campus

    Royal Oak, Michigan, 48073

  • Cancer Center of Kansas, P.A. - Salina

    Salina, Kansas, 67042

  • Salina Regional Health Center

    Salina, Kansas, 67401

  • Veterans Affairs Medical Center - San Antonio (Murphy)

    San Antonio, Texas, 78209

  • Cancer Therapy and Research Center

    San Antonio, Texas, 78229

  • University Hospital - San Antonio

    San Antonio, Texas, 78229

  • University of Texas Health Science Center at San Antonio

    San Antonio, Texas, 78284-7811

  • CCOP - Virginia Mason Research Center

    Seattle, Washington, 98101

  • Group Health Central Hospital

    Seattle, Washington, 98104

  • Harborview Medical Center

    Seattle, Washington, 98104

  • Fred Hutchinson Cancer Research Center

    Seattle, Washington, 98109-1024

  • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus

    Seattle, Washington, 98114

  • University Cancer Center at University of Washington Medical Center

    Seattle, Washington, 98195-6043

  • North Puget Oncology at United General Hospital

    Sedro-Woolley, Washington, 98284

  • Veterans Affairs Medical Center - Shreveport

    Shreveport, Louisiana, 71101

  • Feist-Weiller Cancer Center at Louisiana State University Health Sciences

    Shreveport, Louisiana, 71130-3932

  • Cancer Care Northwest - Spokane South

    Spokane, Washington, 99202

  • CCOP - St. Louis-Cape Girardeau

    St Louis, Missouri, 63141

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

    St Louis, Missouri, 63141

  • UVMC Cancer Care Center at Upper Valley Medical Center

    Troy, Ohio, 45373-1300

  • Cancer Center of Kansas, P.A. - Wellington

    Wellington, Kansas, 67152

  • Wenatchee Valley Clinic

    Wenatchee, Washington, 98801

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

    Wichita, Kansas, 67203

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

    Wichita, Kansas, 67208

  • Cancer Center of Kansas, P.A. - Wichita

    Wichita, Kansas, 67214

  • CCOP - Wichita

    Wichita, Kansas, 67214

  • Via Christi Cancer Center at Via Christi Regional Medical Center

    Wichita, Kansas, 67214

  • Cancer Center of Kansas, P.A. - Winfield

    Winfield, Kansas, 67156

  • Cleveland Clinic - Wooster

    Wooster, Ohio, 44691

  • Ruth G. McMillan Cancer Center at Greene Memorial Hospital

    Xenia, Ohio, 45385

Other trials in United States

Canada1 site

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

    Toronto, Ontario, M4N 3M5

Other trials in Canada

About this study

Official title: MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) in Organ-Confined Bladder Cancer Based on p53 Status

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.

Read the 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
Keywords
stage I bladder cancer, stage II bladder cancer, transitional cell carcinoma of the bladder
Medical subject headings
Urinary Bladder Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT00005047
Study groupRoleWhat they receive
Arm I: M-VAC x 3ExperimentalPatients with altered (+) p53, reconsented to randomization, randomized to three cycles of MVAC
Receives: Drug: cisplatin; Drug: doxorubicin hydrochloride; Drug: methotrexate; Drug: vinblastine
Arm II: ObservationNo interventionPatients with altered (+) p53, reconsented to randomization, randomized to observation
Arm III: ObservationNo interventionPatients with unaltered (-) p53
Arm IV: ObservationNo interventionPatients with altered (+) p53, patients did not consent to randomization

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Probability of Recurring

    p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Time from registration to the first observation of disease recurrence, censoring patients who died of unrelated causes. Probabilities of recurring were based on cumulative incidence curves.

    Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care.

    Measured: 5 years

Secondary outcomes (3)

  1. Probability of Overall Survival

    p53 positive patients randomized to MVAC (arm I) compared to p53 positive patients randomized to observation (arm II). Survival is calculated from registration to death due to any cause. Probabilities of survival were based on the Kaplan-Meier product-limit method.

    Measured: 5 years

  2. Probability of Recurrence

    Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations.

    Probabilities of recurring were based on cumulative incidence curves. Recurrence is defined as first radiological appearance of bladder cancer, per local standard of care.

    Measured: 5 years

  3. Probability of Overall Survival

    Patients with tumors demonstrating alteration in p53 compared to patients with no p53 alterations. Probabilities of survival were based on the Kaplan-Meier product-limit method.

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2003 (estimated)
  2. Study startAug 1997
  3. Primary completionMar 2011
  4. Study completionDec 2014

Why it stopped: Accrual was halted on the basis of the Data and Safety Monitoring Board review of a futility analysis.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
521 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00005047
Sponsor's protocol ID
CDR0000067639
Other IDs
LAC-USC-4B951, SWOG-4B951, NCI-G00-1715, NYU-9852, CAN-NCIC-BL10, CCCWFU-88198, U10CA032102
Status last verified
May 2017
First submitted
6 Apr 2000
Last updated
8 Jun 2017
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 25413313

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing cisplatin, doxorubicin hydrochloride and methotrexate in people with Bladder Cancer, run by SWOG Cancer Research Network at 74 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 74 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Probability of Recurring (time frame: 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00005047, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jun 2017.

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