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

Sponsor

University of Southern California (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01639521

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Arms

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: cisplatin Drug: gemcitabine hydrochloride Drug: methotrexate Drug: vinblastine Drug: doxorubicin hydrochloride Biological: pegfilgrastim Other: laboratory biomarker analysis	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Randomized Phase II Trial Of Adjuvant Chemotherapy For Urothelial Carcinoma Comparing GC To Dose-Dense MVAC

Study Start Date :

May 1, 2013

Actual Primary Completion Date :

May 1, 2013

Actual Study Completion Date :

May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A (gemcitabine hydrochloride, 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.	Drug: cisplatin Given IV Other Names: CACP CDDP CPDD DDP Drug: gemcitabine hydrochloride Given IV Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar Other: laboratory biomarker analysis Correlative studies
Experimental: Arm B (MVAC) 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.	Drug: cisplatin Given IV Other Names: CACP CDDP CPDD DDP Drug: methotrexate Given IV Other Names: amethopterin Folex methylaminopterin Mexate MTX Drug: vinblastine Given IV Other Names: Velban Velsar VLB Drug: doxorubicin hydrochloride Given IV Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Biological: pegfilgrastim Given SC Other Names: Filgrastim SD-01 GCSF-SD01 Neulasta SD-01 sustained duration G-CSF Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Arm A (gemcitabine hydrochloride, 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.

Drug: cisplatin

Given IV

Other Names:

CACP

CDDP

CPDD

DDP

Drug: gemcitabine hydrochloride

Given IV

Other Names:

dFdC

difluorodeoxycytidine hydrochloride

gemcitabine

Gemzar

Other: laboratory biomarker analysis

Correlative studies

Experimental: Arm B (MVAC)

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.

Drug: cisplatin

Given IV

Other Names:

CACP

CDDP

CPDD

DDP

Drug: methotrexate

Given IV

Other Names:

amethopterin

Folex

methylaminopterin

Mexate

MTX

Drug: vinblastine

Given IV

Other Names:

Velban

Velsar

VLB

Drug: doxorubicin hydrochloride

Given IV

Other Names:

ADM

ADR

Adria

Adriamycin PFS

Adriamycin RDF

Biological: pegfilgrastim

Given SC

Other Names:

Filgrastim SD-01

GCSF-SD01

Neulasta

SD-01 sustained duration G-CSF

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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