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4B951, Combination Chemotherapy in Treating Patients With Bladder Cancer

This study has been terminated.
(Accrual was halted on the basis of the Data and Safety Monitoring Board review of a futility analysis.)
Sponsor:
Collaborators:
National Cancer Institute (NCI)
NCIC Clinical Trials Group
University of Southern California
Information provided by (Responsible Party):
Southwest Oncology Group
ClinicalTrials.gov Identifier:
NCT00005047
First received: April 6, 2000
Last updated: May 10, 2017
Last verified: May 2017
  Purpose

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.


Condition Intervention Phase
Bladder Cancer Drug: cisplatin Drug: doxorubicin hydrochloride Drug: methotrexate Drug: vinblastine Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: MVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) in Organ-Confined Bladder Cancer Based on p53 Status

Resource links provided by NLM:


Further study details as provided by Southwest Oncology Group:

Primary Outcome Measures:
  • Probability of Recurring [ Time Frame: 5 years ]

    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.



Secondary Outcome Measures:
  • Probability of Overall Survival [ Time Frame: 5 years ]
    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.

  • Probability of Recurrence [ Time Frame: 5 years ]

    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.


  • Probability of Overall Survival [ Time Frame: 5 years ]
    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.


Enrollment: 521
Actual Study Start Date: August 1997
Study Completion Date: December 2014
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I: M-VAC x 3
Patients with altered (+) p53, reconsented to randomization, randomized to three cycles of MVAC
Drug: cisplatin Drug: doxorubicin hydrochloride Drug: methotrexate Drug: vinblastine
No Intervention: Arm II: Observation
Patients with altered (+) p53, reconsented to randomization, randomized to observation
No Intervention: Arm III: Observation
Patients with unaltered (-) p53
No Intervention: Arm IV: Observation
Patients with altered (+) p53, patients did not consent to randomization

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.

  Eligibility

Ages Eligible for Study:   up to 120 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00005047

  Show 74 Study Locations
Sponsors and Collaborators
Southwest Oncology Group
National Cancer Institute (NCI)
NCIC Clinical Trials Group
University of Southern California
Investigators
Study Chair: Richard J. Cote, MD, FRCPath University of Southern California
Study Chair: Laurence H. Klotz, MD Toronto Sunnybrook Regional Cancer Centre
Study Chair: Seth P Lerner, MD Baylor College of Medicine
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Southwest Oncology Group
ClinicalTrials.gov Identifier: NCT00005047     History of Changes
Other Study ID Numbers: CDR0000067639
LAC-USC-4B951 ( Other Identifier: USC )
SWOG-4B951 ( Other Identifier: SWOG )
NCI-G00-1715 ( Other Identifier: NCI )
NYU-9852 ( Other Identifier: NYU )
CAN-NCIC-BL10 ( Other Identifier: NCIC-CTG )
CCCWFU-88198
U10CA032102 ( U.S. NIH Grant/Contract )
Study First Received: April 6, 2000
Results First Received: March 23, 2017
Last Updated: May 10, 2017

Keywords provided by Southwest Oncology Group:
stage I bladder cancer
stage II bladder cancer
transitional cell carcinoma of the bladder

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Liposomal doxorubicin
Cisplatin
Methotrexate
Doxorubicin
Vinblastine
Antineoplastic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on July 21, 2017