Paclitaxel and Radiation Therapy With or Without Trastuzumab in Treating Patients Who Have Undergone Surgery for Bladder Cancer

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects of giving paclitaxel together with radiation therapy with or without trastuzumab and to see how well it works to kill any remaining tumor cells in patients who have undergone surgery for bladder cancer. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Paclitaxel may also make tumor cells more sensitive to radiation therapy. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving paclitaxel together with radiation therapy and trastuzumab may kill more tumor cells. Giving these treatments after surgery may kill any remaining tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the acute toxicity (=< 90 days from protocol treatment start) from chemoradiotherapy including paclitaxel +/- trastuzumab and irradiation in non-cystectomy patients with or without her2/neu overexpression. SECONDARY OBJECTIVES: I. To determine the ability of patients with bladder cancer who are non-cystectomy candidates to complete this treatment program. II. To evaluate the efficacy of this treatment program in achieving a complete response of the primary tumor. III. To measure the 5-year disease-free and overall survival of patients with bladder cancer treated with transurethral resection of the bladder followed by chemoradiotherapy. IV. To estimate the value of tumor and/or serum biomarkers as predictors of initial tumor response and recurrence-free survival. OUTLINE: This is a non-randomized, multicenter study. Patients are assigned to 1 of 2 treatment groups according to HER2/neu status (HER2/neu 2+ or 3+ staining [group 1] vs HER2/neu 0 or 1+ staining [group 2]). GROUP I: Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, 15, 22, 29, 36, and 43 and trastuzumab (Herceptin®) IV over 90 minutes on day 1 and then over 30 minutes on days 8, 15, 22, 29, 36, and 43. Patients also undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, 43-47, and 50. Treatment continues in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive paclitaxel and undergo radiotherapy as in group 1. After completion of study treatment, patients are followed at 4-5 weeks, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter.

Official Title
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A Phase I/II Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation Following Transurethral Surgery for Non-Cystectomy Candidates With Muscle-Invasive Bladder Cancer

Conditions
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Bladder Urothelial Carcinoma, Stage I Bladder Cancer AJCC v6 and v7, Stage II Bladder Cancer AJCC v6 and v7, Stage III Bladder Cancer AJCC v6 and v7

Intervention / Treatment
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* Drug: Paclitaxel
* Radiation: Radiation Therapy
* Biological: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed primary transitional cell carcinoma (TCC) of the bladder Histologic evidence of muscularis propria invasion Meets 1 of the following stage criteria: Stage T2-4a; NX, N0, or N1; and M0 disease Clinical stage T1, grade 3/3 disease AND requires definitive local therapy Tumor involvement of the prostatic urethra allowed provided the following criteria are met: Tumor was visibly completely resected No evidence of stromal invasion of the prostate No evidence of distant metastases by chest x-ray (or chest CT scan) within 8 weeks prior to registration No evidence of distant metastases by abdominal/pelvic CT scan (or MRI scan) within 8 weeks prior to registration Has undergone transurethral bladder resection (as thorough as is judged safely possible) within the past 3-8 weeks, including bimanual examination with tumor mapping Sufficient tumor tissue available for HER2/neu analysis Not a candidate for radical cystectomy Performance status - Zubrod 0-2 Absolute neutrophil count >= 1,800/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 8.0 g/dL (transfusion or other intervention allowed) Bilirubin < 2.0 mg/dL Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 times upper limit of normal No hepatic insufficiency resulting in clinical jaundice and/or coagulation defects Creatinine =< 3.0 mg/dL Left ventricular ejection fraction (LVEF) >= 40% by multigated acquisition scan (MUGA) scan or echocardiogram No unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months No transmural myocardial infarction within the past 6 months Not pregnant or nursing No nursing for 6 months after completion of study treatment (for patients receiving trastuzumab [Herceptin®]) Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after completion of study treatment Able to tolerate systemic chemotherapy and pelvic radiotherapy No other invasive malignancy within the past 3 years except nonmelanoma skin cancer No history of allergic reaction to study drugs No history of inflammatory bowel disease No acute bacterial or fungal infection requiring IV antibiotics No AIDS No other severe active comorbidity No prior systemic chemotherapy with anthracyclines or taxanes No prior systemic chemotherapy for TCC No prior pelvic radiotherapy

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (paclitaxel, trastuzumab, radiation therapy)<br>Patients receive paclitaxel IV over 1 hour on days 1, 8, 15, 22, 29, 36, and 43 and trastuzumab IV over 90 minutes on day 1 and then over 30 minutes on days 8, 15, 22, 29, 36, and 43. Patients also undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, 43-47, and 50. Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Biological: Trastuzumab<br>* Given IV<br>* Other names: Trazimera;|
| Experimental: Group II (paclitaxel, radiation therapy)<br>Patients receive paclitaxel and undergo radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, 43-47, and 50. | Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Treatment-related Toxicity | In each group, the number of patients was tabulated by type and grade (gr) of treatment-related toxicity (CTCAE v3.0). Only the following types of toxicity within 90 days of treatment start were considered: ≥ gr4 neutropenia, ≥ gr4 febrile neutropenia, ≥ gr3 diarrhea, ≥ gr3 nausea/vomiting, ≥ gr3 thrombocytopenia, ≥ gr3 renal, pulmonary, hepatic, or neurologic toxicity, ≥ gr3 rectal or genitourinary bleeding, ≥ gr3 left ventricular failure, or ≥ gr2 other cardiac toxicity. The study was designed to estimate the rate of acute treatment-related toxicity separately in each group of patients. Using the Fleming's one-sample multiple test procedure with Type I and II errors each set at 10%, 40 cases/group were required to reject the null hypothesis that the true toxicity rate is greater than 25% in favor of the alternative hypothesis that the true rate is no more than 10%. Six or more patients with the designated toxicities out of 40 would result in rejecting the null hypothesis. | From start of protocol treatment to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Completion | The number of patients within each group who completed all elements of protocol treatment are reported. | From registration to end of treatment; up to 64 days. | 
| Complete Response to Treatment | The number of patients within each group who achieved a complete response to protocol treatment by 12 weeks are reported. Complete response is defined as no gross tumor at cystoscopy or negative biopsies or both by week 12 after completion of protocol treatment. | At 12 weeks from treatment start | 
| Progression-free Survival | Disease (failure) is defined as any bladder cancer progression determined by all measures of disease including physical exam, imaging, and biopsies. Disease-free survival time is defined as time from treatment start to the date of first progression, death, or last known follow-up (censored). Disease-free survival rates are estimated using the Kaplan-Meier method. Analysis occurred after all patients had been on study for at least 5 years. This is a non-randomized phase I/II trial in which the two patient groups are not compared. | From start of treatment to last follow-up. Maximum follow-up at time of analysis was 9.9 years. | 
| Overall Survival | Overall survival time is defined as time from treatment start to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated using the Kaplan-Meier method. Analysis occurred after all patients had been on study for at least 5 years. This is a non-randomized phase I/II trial in which the two patient groups are not compared. | From the date of treatment started to death, assessed up to at least 5 years |