Gemcitabine, Paclitaxel, Doxorubicin in Metastatic or Unresectable Bladder Cancer With Decreased Kidney Function

Study Overview
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Brief Summary
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This phase II trial is studying how well giving gemcitabine, paclitaxel, and doxorubicin together with pegfilgrastim works in treating patients with metastatic or unresectable bladder cancer or urinary tract cancer and kidney dysfunction. Drugs used in chemotherapy, such as gemcitabine, paclitaxel, and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Colony stimulating factors, such as pegfilgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving combination chemotherapy together with pegfilgrastim may kill more tumor cells. Chemotherapy drugs may have different effects in patients who have changes in their kidney function.

Detailed Description
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PRIMARY OBJECTIVES: I. Assess the efficacy of gemcitabine hydrochloride, paclitaxel, doxorubicin hydrochloride, and pegfilgrastim, in terms of response rate, in patients with metastatic or unresectable transitional cell carcinoma of the bladder or urinary tract and renal insufficiency. SECONDARY OBJECTIVES: I. Assess the safety and tolerability of this regimen in these patients. II. Determine the median time to progression in patients treated with this regimen. III. Determine the median survival duration in patients treated with this regimen. IV. Assess the safety and efficacy of pegfilgrastim in these patients. OUTLINE: This is a multicenter study. Patients receive doxorubicin hydrochloride intravenous (IV) over 20 minutes, paclitaxel IV over 60 minutes, gemcitabine hydrochloride IV over 90 minutes, and pegfilgrastim subcutaneously on day 1. Treatment repeats every 14 days for up to 9 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 3 years.

Official Title
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A Phase II Study of Gemcitabine, Paclitaxel, and Doxorubicin, With Pegfilgrastim for the Treatment of Patients With Metastatic Transitional Cell Carcinoma and Renal Insufficiency

Conditions
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Distal Urethral Cancer, Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter, Proximal Urethral Cancer, Recurrent Bladder Cancer, Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter, Recurrent Urethral Cancer, Regional Transitional Cell Cancer of the Renal Pelvis and Ureter, Stage III Bladder Cancer, Stage IV Bladder Cancer, Transitional Cell Carcinoma of the Bladder, Urethral Cancer Associated With Invasive Bladder Cancer

Intervention / Treatment
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* Drug: Gemcitabine hydrochloride
* Drug: Paclitaxel
* Drug: Doxorubicin hydrochloride
* Drug: Pegfilgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed transitional cell carcinoma (TCC) of the bladder, urethra, or upper urinary tract Mixed TCC and variant histologies (i.e., small cell, squamous cell, adenocarcinoma, or sarcoma) allowed if present in < 50% of the biopsy specimen Patients must sign an informed consent indicating that they are aware of the investigational nature of this study, in keeping with the policies of the institution. Measurable disease: may include radiographic detection of metastases in lymph nodes (>= 1.5 cm) or liver or lung (>= 1.0 cm) OR pelvic mass palpable on examination under anesthesia Creatinine clearance < 60 mL/min; no renal insufficiency that requires hemodialysis; no renal insufficiency that is reversible in patients with tumor confined to the primary site (i.e., that is potentially resectable with neoadjuvant chemotherapy) Zubrod performance status 0-2 Platelet count > 100,000/mm^3 Absolute granulocyte count > 1,500/mm^3 Bilirubin =< 2.0 mg/dL Aminotransferases (AST and ALT) =< 2 times upper limit of normal Left ventricular ejection fraction (LVEF) > 40% OR normal electrocardiogram (EKG or ECG) and no history of cardiac disease All patients must be evaluated in the Department of Genitourinary Medical Oncology at M. D. Anderson Cancer Center or participating CCOP center prior to signing informed consent. No prior systemic chemotherapy including, adjuvant or neoadjuvant therapy Prior intravesicular chemotherapy allowed Exclusion Criteria: No brain metastases Not pregnant or nursing No severe or uncontrolled infection No New York Heart Association class III-IV congestive heart failure, unstable angina, or history of myocardial infarction within the past 6 months No peripheral neuropathy >= grade 2 No persistently uncontrolled diabetes mellitus No chronic liver disease No HIV positivity No other malignancy except nonmelanoma skin cancer unless disease-free for the past 3 years No overt psychosis, mental disability, or other condition that would preclude giving informed consent No known sickle cell disease No uncontrolled severe hypertension Renal insufficiency that requires hemodialysis or renal insufficiency that is reversible in patients with tumor confined to the primary site (i.e., that is potentially resectable with neoadjuvant chemotherapy).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine, Paclitaxel and Doxorubicin<br>Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 min; Doxorubicin 40 mg/m^2 IV over 20 min; treatment may repeat every 2 weeks for up to nine courses. Injection of Pegfilgrastim on day 1. | Drug: Gemcitabine hydrochloride<br>* Gemcitabine 900 mg/m^2 IV over 90 minutes repeat every 14 days.<br>* Other names: Gemzar;Drug: Paclitaxel<br>* 135 mg/m^2 IV over 1 hour<br>* Other names: Taxol;Drug: Doxorubicin hydrochloride<br>* Doxorubicin 40 mg/m^2 IV over 20 minutes<br>* Other names: Adriamycin RDF;Drug: Pegfilgrastim<br>* Subcutaneously injection on day 1.<br>* Other names: SD-01 sustained duration G-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The percentage of participants with either Complete Response (CR) or Partial Response (PR) in their disease burden based upon the rules of the Response Evaluation Criteria in Solid Tumors (RECIST). A participant with of all of the lesions disappearing is a CR. A participant with at least a 30 percent decrease in the measured lesions is a PR. | Up to 12 weeks, or following completion 6 cycles of chemotherapy, respectively; the best response achieved within 6 cycles of starting chemotherapy used to calculate response rate. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) of Participants With a Continuous Complete Response, Partial Response and Stable Disease | The overall survival was determined by grouping participants based upon their response based on RECIST. The groups are Complete Response(CR): All the cancerous lesion disappear, Partial Response (PR): All the measured lesions decrease by at least 30 percent, and Stable Disease(SD): No significant change in the disease burden. OS of complete response or partial response participants were compared to the reference group of stable disease participants in a Hazard Ratio(HR). If HR is greater than 1, the experimental group has a better outcome than the reference group. If HR is less than 1, the reference group has the better outcome. | Registration Date of each participant for up to three years or death whichever came first | 
| Safety and Efficacy of Same-day Pegfilgrastim | Determined the number of participants who had either a fever due to abnormally low level of neutrophils, a type of white blood cell, on the day of study drug treatment, or the participants who had the study drug treatment delayed due to an abnormally low level of neutrophils. | Up to 3 years |