Gemcitabine Hydrochloride and Cisplatin or High-Dose Methotrexate, Vinblastine, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Urothelial Cancer

Phase 2

Withdrawn

• Conditions: Anterior Urethral Cancer; Localized Transitional Cell Cancer of the Renal Pelvis and Ureter; Posterior Urethral Cancer; Recurrent Bladder Cancer; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Ureter Cancer; Urethral Cancer Associated With Invasive Bladder Cancer
• Interventions: Drug: cisplatin; Drug: gemcitabine hydrochloride; Drug: methotrexate; Other: laboratory biomarker analysis; Drug: vinblastine; Drug: doxorubicin hydrochloride; Biological: pegfilgrastim

• Registration Number: NCT01639521
• Lead Sponsor: University of Southern California

Brief Summary

This study is about two chemotherapy study drug combinations (regimens) that are used for urothelial (bladder or upper urinary tract) cancer. Both study drug regimens, gemcitabine (gemcitabine hydrochloride) plus cisplatin, and high-dose-intensity MVAC (methotrexate, vinblastine, doxorubicin plus cisplatin), are standard chemotherapy regimens. Both regimens are used to treat people with urothelial cancer that has spread to other organs. Both study drug regimens have been proven to be effective in lowering the risk of the cancer coming back, but it is not known which regimen is the best. This study hopes to learn whether there is a difference in the effectiveness and side effects of these two study drug regimens when they are given to people who have had their urothelial cancer completely removed.

Detailed Description

PRIMARY OBJECTIVES

To estimate the difference in the rate of unacceptable toxicity for dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin (GC) in the adjuvant treatment of urothelial cancer.

SECONDARY OBJECTIVES

To compare rates of disease recurrence at 3 years between dose-dense MVAC and GC.

To determine whether molecular markers excision repair cross-complementing-1 (ERCC-1) ribonucleoside-diphosphate reductase M-1 (RRM-1), breast cancer 1 (BRCA1) topoisomerase 2-alpha (Top2A) and protein 53 (p53) can predict those patients more likely to benefit from chemotherapy.

To investigate the potential utility of cytidine deaminase (CDA), ERCC-1, xeroderma pigmentosum group D (XPD), glutathione S-transferase P-1 (GSTP-1) and glutathione S-transferase M-1 (GSTM-1) as molecular markers which predict occurrence of significant toxicity during adjuvant chemotherapy for urothelial cancer.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive cisplatin intravenously (IV) on day 1 and gemcitabine hydrochloride IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive methotrexate IV on day 1, vinblastine IV, doxorubicin hydrochloride IV, cisplatin IV on day 2 and pegfilgrastim subcutaneously (SC) on day 3. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years.

Study Timeline

• Study First Submitted: 2012-07-10
• Study First Submitted QC: 2012-07-11
• Study First Posted: 2012-07-12
• Study Start: 2013-05
• Primary Completion: 2013-05
• Study Completion: 2013-05
• Status Verified: 2014-01
• Last Update Submitted: 2014-01-27
• Last Update Posted: 2014-01-29

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Histologically confirmed high-grade urothelial carcinoma, stage T3bN0, T4N0 or any T stage with lymph node involvement, completely resected; including upper tract urothelial carcinoma
• The dominant histology must be transitional cell or urothelial but foci of other histologies less than 20 percent of the total tumor volume are permitted
• Absence of metastatic disease on radiographic imaging
• Patients must be enrolled and able to start treatment within 90 days of radical cystectomy or radical nephrectomy
• Creatinine less than institutional upper limit of normal (ULN) or clearance greater or equal to 50 mL/min (may be calculated by Cockcroft-Gault formula or measured from 24-hour urine collection)
• Serum total bilirubin less or equal to 1.5 x ULN (except for patients with Gilbert's)
• Alkaline phosphatase less or equal to 2.5 x ULN
• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) less or equal to 2.5 x ULN
• White blood cells (WBC) greater or equal to 3000
• Absolute neutrophil count (ANC) greater or equal to 1500
• Hemoglobin (Hb) greater or equal to 9
• Platelets greater or equal to 100,000
• Normal left ventricular ejection fraction, by echocardiogram or multi gated acquisition scan (MUGA)
• Patients must be recovered from surgery
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Willing and able to provide informed consent
• Willingness to use barrier contraception during study period

Exclusion Criteria

• The presence of significant pleural effusion or ascites
• Prior systemic chemotherapy for urothelial carcinoma including neoadjuvant chemotherapy (prior intravesical therapy is permitted)
• History of malignancy within preceding 5 years, aside from non-melanoma skin cancer or previously treated or incidentally detected prostate cancer with undetectable PSA (after radical cystectomy or prostate cancer therapy)
• Peripheral neuropathy greater than grade 1
• The presence of active heart disease such as congestive heart failure or unstable angina

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (gemcitabine hydrochloride, cisplatin)	laboratory biomarker analysis	Patients receive cisplatin IV on day 1 and gemcitabine hydrochloride IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm A (gemcitabine hydrochloride, cisplatin)	gemcitabine hydrochloride	Patients receive cisplatin IV on day 1 and gemcitabine hydrochloride IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm B (MVAC)	pegfilgrastim	Patients receive methotrexate IV on day 1 and vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV on day 2. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm B (MVAC)	laboratory biomarker analysis	Patients receive methotrexate IV on day 1 and vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV on day 2. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm A (gemcitabine hydrochloride, cisplatin)	cisplatin	Patients receive cisplatin IV on day 1 and gemcitabine hydrochloride IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm B (MVAC)	cisplatin	Patients receive methotrexate IV on day 1 and vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV on day 2. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm B (MVAC)	methotrexate	Patients receive methotrexate IV on day 1 and vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV on day 2. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm B (MVAC)	vinblastine	Patients receive methotrexate IV on day 1 and vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV on day 2. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm B (MVAC)	doxorubicin hydrochloride	Patients receive methotrexate IV on day 1 and vinblastine IV, doxorubicin hydrochloride IV, and cisplatin IV on day 2. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Rate of unacceptable toxicity graded according to Common Terminology Criteria (CTC) v4.0	Assessed up to 3 years	80% confidence intervals (CI) will be constructed; for unacceptable toxicity, the confidence interval will be one-sided.

Secondary Outcome Measures

Name	Time	Method
Disease-free survival	From radical cystectomy to the time cancer recurrence is detected by clinical findings or during surveillance imaging, at 3 years