Trial of Paclitaxel Plus Gemcitabine and Cisplatin in Bladder Cancer

Study Overview
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Brief Summary
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This trial is for people with bladder cancer that has spread. The purpose of this research study is to see if the chemotherapy combination of gemcitabine and cisplatin plus paclitaxel is safe and effective treatment for bladder cancer. Paclitaxel, gemcitabine and cisplatin have all been approved by the United States Food and Drug Administration (FDA). Gemcitabine and cisplatin is a standard treatment for bladder cancer. There have been studies that show that paclitaxel and cisplatin have antitumor activity in bladder cancer. European researchers studied paclitaxel, gemcitabine and cisplatin (same drug combination in this trial) and found that the combination provided good disease control and was well tolerated. Investigators are studying the same drug combination, but at different dosages and schedule.

Detailed Description
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The rationale of the present study is to develop a combination based on the pharmacokinetics and mechanisms of action of the agents paclitaxel plus gemcitabine and cisplatin, which are all known active agents in urothelial tumors. Gemcitabine may be synergistic with DNA-damaging drugs such as paclitaxel and cisplatin because it can antagonize DNA repair. Investigators will investigate the combination in this Phase II study.

Official Title
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Phase II Trial of Paclitaxel Plus Gemcitabine and Cisplatin in Urothelial Cancer

Conditions
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Urinary Bladder Neoplasms

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Paclitaxel
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have histologic demonstration of metastatic or locally unresectable transitional cell carcinoma of the urothelium. Minor components (<50% overall) of variants such as glandular or squamous differentiation, or evolution to more aggressive phenotypes, such as sarcomatoid, or small cell changes are acceptable. However, when these atypical histologies are dominant, other treatment approaches may be more appropriate, and such patients are not eligible. All patients must have measurable or evaluable disease. In general, liver and lung lesions should be at least 1 cm, and patients with node-only disease should have lesions of ≥ 1.5 cm in the largest dimension. Patients with disease confined to bone may be eligible if a measurable lytic defect is present. Patients with a 3-dimensional mass or pelvic sidewall fixation on bladder examination under anesthesia are considered to have measurable disease. All patients must have adequate physiologic reserves as evidenced by: Life expectancy of at least 12 weeks. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. No clinical history of heart disease and a normal EKG or an ejection fraction measured by echocardiogram or MUGA scan of at least 45%. Transaminase less than twice the upper limit of normal. Bilirubin <1.5 mg%. Serum creatinine ≤2.0 mg/dL. Patients presenting with obstructive uropathy may be eligible if they show excellent response to nephrostomy drainage. Absolute neutrophil count ≥1500; platelet count ≥100,000. Patients must not have had any previous systemic chemotherapy for bladder cancer, including neoadjuvant or adjuvant treatment given remotely. Gemcitabine/cisplatin is the standard of care for metastatic urothelial cancer. Patients who have received treatment would be either resistant or refractory to additional doses. In addition, they would have residual adverse effects from treatment and would be particularly susceptible to further neuropathic adverse events. Any prior intravesicular therapy is allowed. Women of childbearing potential must have a negative pregnancy test prior to starting therapy. Men and women of childbearing potential must be willing to consent using effective contraceptive while on treatment and for a reasonable period thereafter. Patients must not have an active, or likely to become active, second malignancy. Patients must be at least 6 weeks out from pelvic irradiation, and must not have had more than 10% of the bone marrow irradiated. Exclusion Criteria: Patients with uncontrolled CNS metastasis are not eligible. Patients with a history of peripheral neuropathy greater than grade 1 are not eligible. Pregnant women are excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

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: Combination chemotherapy<br>Combination chemotherapy consisting of gemcitabine and cisplatin plus paclitaxel on a 21-day cycle. | Drug: Gemcitabine<br>* 1000 mg/m2 will be administered as an IV infusion over 10 mg/minute on Days 1 and 8 of each cycle (each cycle is 21 days).<br>* Other names: Gemzar;Drug: Paclitaxel<br>* 175 mg/m2 will be administered as an IVPB over 3 hours on Day 2 of each cycle (each cycle is 21 days).<br>* Other names: Taxol;Drug: Cisplatin<br>* 70 mg/m2 will be administered as an IVPB over 2 hours on Day 2 of each cycle (each cycle is 21 days).<br>* Other names: Platinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Measured by the Objective Response Rate (ORR). | Objective Response Rate (ORR) is defined as the proportion of patients achieving either a complete response or a partial response based on imaging at any time during the study. Complete response or partial response is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Drug Regimen as Measured by Number of Adverse Events | Toxicity assessment will be observational. Numbers and types of events will be quantified and graded according to CTCAE. | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 6 months | 
| Efficacy as Measured by Number Who Progressed | Progression is defined using RECIST 1.1 criteria:  At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial Cancer, Bladder Cancer, Metastatic