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

Phase 1

Completed

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

Interventions: Drug: Paclitaxel
Radiation: Radiation Therapy
Biological: Trastuzumab

Registration Number: NCT00238420

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 70

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I (paclitaxel, trastuzumab, radiation therapy)	Radiation Therapy	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.
Group I (paclitaxel, trastuzumab, radiation therapy)	Trastuzumab	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.
Group II (paclitaxel, radiation therapy)	Radiation Therapy	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.
Group I (paclitaxel, trastuzumab, radiation therapy)	Paclitaxel	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.
Group II (paclitaxel, radiation therapy)	Paclitaxel	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.

Primary Outcome Measures

Name	Time	Method
Acute Treatment-related Toxicity	From start of protocol treatment to 90 days	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.

Secondary Outcome Measures

Name	Time	Method
Treatment Completion	From registration to end of treatment; up to 64 days."	The number of patients within each group who completed all elements of protocol treatment are reported.
Complete Response to Treatment	At 12 weeks from treatment start	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.
Progression-free Survival	From start of treatment to last follow-up. Maximum follow-up at time of analysis was 9.9 years.	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.
Overall Survival	From the date of treatment started to death, assessed up to at least 5 years	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.

Trial Locations

Locations (183): Mobile Infirmary Medical Center
🇺🇸
Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
🇺🇸
Auburn, California, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸
Burbank, California, United States
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
🇺🇸
Cameron Park, California, United States
Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
Sutter Cancer Centers Radiation Oncology Services-Roseville
🇺🇸
Roseville, California, United States
Sutter Medical Center Sacramento
🇺🇸
Sacramento, California, United States
Mercy General Hospital Radiation Oncology Center
🇺🇸
Sacramento, California, United States
Sutter Cancer Centers Radiation Oncology Services-Vacaville
🇺🇸
Vacaville, California, United States
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Mobile Infirmary Medical Center
🇺🇸Mobile, Alabama, United States