Four Cycles Versus Six Cycles of Cisplatin-based Chemotherapy in Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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The objective is to show non-inferiority of overall survival between four cycles and six cycles of first-line cisplatin based chemotherapy to determine the optimal duration of chemotherapy in patients with advanced urothelial carcinoma.

Detailed Description
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Urothelial carcinoma is the fifth most common cancer in men and seventh among women all around the world. Although a complete surgical resection with or without perioperative treatment is the most effective way to offer a potentially curative therapy to patients with these cancers, 25% of the patients initially present with locally or systemically advanced disease. Systemic chemotherapy is the only current modality that provides the potential for a long-term survival in patients with advanced or metastatic urothelial disease. Cisplatin based combination chemotherapies such as GP, GP-S, MVAC, and dose dense MVAC with G-CSF supports are regarded as a backbone treatment for patients with advanced bladder cancer on the basis of the results from previous studies. However, there is no consensus on appropriate number of chemotherapy cycles. In phase III trial comparing MVAC with GP, patients were treated with 6 cycles (every 4 weeks) of chemotherapy. In another phase III trial comparing MVAC with HD-MVAC, there is no pre-determined number of cycles, but the median number of cycles were 4 for MVAC and 6 for HD-MVAC. However, it is hard to complete six or more cycles of cisplatin based chemotherapy due to cumulative toxicities of cisplatin such as neuropathy and development of resistance. The median age of patients with urothelial cancer is 70 years old and significant proportion of the patients already showed impaired performance status (ECOG PS ≥2). There has already been reported in several trials of NSCLC, which showed that 4 cycles of chemotherapy containing cisplatin has no significant differences in survival or QoL with lower incidences of toxicities compared with 6 cycles of chemotherapy. The objective of this trial is to assess whether there is any difference in OS between patients who are treated with four cycles of cisplatin based chemotherapy and patients who are treated with 6 cycles of chemotherapy to determine the optimal duration of chemotherapy in patients with advanced urothelial cancer.

Official Title
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Four Cycles of Cisplatin-Based Chemotherapy in Metastatic Urothelial Carcinoma Compared to Six Cycles: Randomized Phase III Trial - FOCUS Study -

Conditions
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Bladder Cancer, Ureter Cancer, Urethral Cancer, Transitional Cell Carcinoma

Intervention / Treatment
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* Drug: Treatment duration of cisplatin based chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with histologically or cytologically confirmed urothelial cancer Unresectable locally advanced (T3b, N2-3), metastatic (M1), or recurrent disease Age 18 years or older Eastern Cooperative Oncology Group performance status 0-1 Not progressed disease status after 2 or 4 cycles of platinum-based chemotherapy Adequate organ and bone marrow function for chemotherapy No history of radiation therapy, or radiation field within 25% of whole marrow would be allowed. If patients underwent radiation therapy in entire pelvis, they are excluded to this study. Patients should discontinue radiation therapy at least 4 weeks before enrollment, and the patients should be recovered from radiation therapy associated adverse events. Women should use contraceptive medication for 6 months after the end of the study or she would be post-menopause status. Men should consent with the contraception for 6 months after the end of the study or he would be infertile. Patients should sign a written informed consent before study entry. Exclusion Criteria: Histologic types other than urothelial cell carcinoma should be excluded. However, urothelial cell types combined with squamous or glandular features are allowed. Patients who showed progressed disease status after 2 or 4 cycles of platinum-based chemotherapy, cannot be treated with additional chemotherapy due to adverse events, or already undertook with reduced dose of more than 50% Presence or history of CNS metastasis Prior systemic chemotherapy (But prior intravesical chemotherapy or immunotherapy was allowed, and recurrent disease after adjuvant or neoadjuvant cisplatin-based systemic chemotherapy is allowed if the last chemotherapy was administered 1 year or more before the patient enrollment) Peripheral sensory neuropathy grade 2 or worse according to NCI CTCAE History of treatment with drugs of another clinical trial within 30 days before enrollment. Concomitant severe medical, surgical, or psychiatric disease or problems which can affect the results of the clinical trial or have possibilities of unexpected medical problems caused be the drug of clinical trial History of another malignancy (but treated malignancy at least two years before enrollment were allowed, and cured non-melanoma skin cancer, any cured in-situ carcinoma, clinically insignificant localized prostate cancer, or papillary thyroid carcinoma are allowed even diagnosed less than 2 years before enrollment). Pregnant or lactating women, women of childbearing potential not employing adequate contraception

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 6 cycles arm<br>Patients without evidence of disease progression or unacceptable toxicities after completion of two or four treatment cycles of cisplatin based chemotherapy (GP, GP-S, MVAC, HD-MVAC with GCSF) were randomly assigned to receive additional two to four cycles of chemotherapy (totally six cycles) | Drug: Treatment duration of cisplatin based chemotherapy<br>* GP regimen: Gemcitabine (1000 mg/m2 D1, D8), Cisplatin (60 mg/m2 D1), every 3 weeks GP-S regimen: Gemcitabine (1000 mg/m2 D1, D8), Cisplatin (35 mg/m2 D1,D 2 or D8), every 3 weeks MVAC regimen: Methotrexate (30 mg/m2 IV bolus, D1, 15, 22), Vinblastine (3 mg/m2 IV bolus, D2, 15, 22), Doxorubicin (30 mg/m2 IV bolus D2), Cisplatin (70 mg/m2 D2), every 4 weeks HD-MVAC with GCSF regimen: Methotrexate (30 mg/m2 IV bolus, D1), Vinblastine (3 mg/m2 IV bolus, D2), Doxorubicin (30 mg/m2 IV bolus D2), Cisplatin (70 mg/m2 D2), G-CSF (240 ug/m2 SC, D4-10), every 2 weeks<br>|
| Experimental: 4 cycles arm<br>Patients without evidence of disease progression or unacceptable toxicities after completion of two or four treatment cycles of cisplatin based chemotherapy (GP, GP-S, MVAC, HD-MVAC with GCSF) were randomly assigned to receive additional zero to two cycles of chemotherapy (totally four cycles) | Drug: Treatment duration of cisplatin based chemotherapy<br>* GP regimen: Gemcitabine (1000 mg/m2 D1, D8), Cisplatin (60 mg/m2 D1), every 3 weeks GP-S regimen: Gemcitabine (1000 mg/m2 D1, D8), Cisplatin (35 mg/m2 D1,D 2 or D8), every 3 weeks MVAC regimen: Methotrexate (30 mg/m2 IV bolus, D1, 15, 22), Vinblastine (3 mg/m2 IV bolus, D2, 15, 22), Doxorubicin (30 mg/m2 IV bolus D2), Cisplatin (70 mg/m2 D2), every 4 weeks HD-MVAC with GCSF regimen: Methotrexate (30 mg/m2 IV bolus, D1), Vinblastine (3 mg/m2 IV bolus, D2), Doxorubicin (30 mg/m2 IV bolus D2), Cisplatin (70 mg/m2 D2), G-CSF (240 ug/m2 SC, D4-10), every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival is defined as the time from enrollment of study until death from any cause (or date of last follow-up for patients still alive) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | PFS is defined as the time from enrollment of study until either first documentation of RECIST-defined disease progression or death due to any cause, whichever come first. | Every 6-8 weeks, from date of enrollment until the date of first documented progression | 
| Tumor response rate | Tumor response rate is defined as the proportion of patients with a complete response (CR) or partial response (PR) among patients with evaluable lesions for response of RECIST. | Every 6-8 weeks, assess the tumor response from date of enrollment | 
| safety using NCI Common Terminology Criteria for Adverse Events (version 4.03) | Toxicity profiles will be evaluated every cycle with physical examination, vital signs, performance status, CBC, and serum chemistry using NCI Common Terminology Criteria for Adverse Events version 4.03. | Every 2-4 weeks, from date of enrollment until 30th days of last cycles treatment or initation of new regimen | 
| Quality of life composite score of EORTC-QoL-C30 and EORTC CIPN20 | Investigators measured Quality of life using EORTC-QoL-C30 and EORTC CIPN20 at the time of enrollment, 12-18 weeks, and 30 weeks | 0-1 week, 12-18 week, 24-34 week after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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urothelial carcinoma, cisplatin, first-line chemotherapy