Neoadjuvant Dose Dense MVAC in MIBC and Locally Advanced Urothelial Carcinoma

Study Overview
=================
Brief Summary
-----------------
The objective is to investigate the efficacy and safety of four cycles of ddMVAC with G-CSF support in patients with MIBC and locally advanced UC

Detailed Description
-----------------
Currently, most treatment guidelines including NCCN recommend a neoadjuvant chemotherapy (NAC) as a standard of care in muscle invasive bladder cancer (MIBC). Although standard NAC regimen is controversial due to rare of head to head study between each regimens, cisplatin based multidrug combination regimens such as MVAC, GP, and dose dense MVAC (ddMVAC) with G-CSF supports are regarded as a backbone treatment on the basis of the results from previous studies. Application of NAC is still relatively slow adoption in real practice. These slow adoption result from intuitive concerns such as significant toxicity of multidrug combination chemotherapy represented by MVAC and delayed application of radical surgical treatment in non-responder The ddMVAC with G-CSF support regimen showed an improved efficacy compared with GP regimen, and tolerable compared with standard MVAC using application of routine G-CSF support and high intensity of cisplatin. In case of clinically lymph node evolvement (cN+) is not for strict NAC, but patient with cN+ UC have been treated induction chemotherapy of similar NAC regimens and surgical treatment. So, this study included MIBC plus cN+ UC as locally advanced UC. In Korea, there is a low adoption of NAC, additionally rare of ddMVAC with G-CFS in locally advanced UC. It is supposed concerns related with toxicity of ddMVAC. Although the concern is likely not true considering the previous result of the Western, there has not been studied ddMVAC as NAC in Asian including Korean. The objective of this trial is to assess the efficacy and safety of four cycles of ddMVAC with G-CSF support in patients with locally advanced UC.

Official Title
-----------------
Efficacy and Safety of Neoadjuvant Chemotherapy With Dose Dense MVAC Followed by Radical Surgery in Patients With MIBC and Locally Advanced Urothelial Carcinoma of Bladder: Phase II, Single-arm Study

Conditions
-----------------
Muscle Invasive Bladder Cancer, Urothelial Carcinoma, Neoadjuvant Chemotherapy

Intervention / Treatment
-----------------
* Drug: dose dense MVAC with pegylated GCSF


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically or cytologically confirmed urothelial cancer of bladder. Locally advanced status for planning surgical treatment (Bladder, confirm muscle invasiveness using TURBT, or cT3-4a and N1-3 using imaging studies) Age 18 years or older Eastern Cooperative Oncology Group performance status 0-1 Adequate organ and bone marrow function for cisplatin based chemotherapy A. Adequate bone marrow function: Absolute Neutrophil Count (ANC) ≥ 1,500/µL, platelets ≥ 100,000/µL, hemoglobin ≥ 9 g/dL) B. Adequate renal function: creatinine < 1.5 x upper normal limit (UNL) or creatinine clearance(Ccr) using Cockroft and Gault formula ≥ 50 ml/min C. Adequate hepatic function: bilirubin < 1.5 x UNL, AST/ALT levels <5.0 x UNL, alkaline phosphatase < 5 x UNL (except in case of bone metastasis without any liver disease) 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. Excess of 4 weeks after initial imaging studies. But, allow the patients to enrollment of study if they is reassessed and reconfirm the localized status using subsequent imaging studies. In this case, clinical stage is decided as following imaging studies. Prior systemic chemotherapy (But prior intravesical chemotherapy was allowed) 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 A. Unstable angina, myocardial infarction, uncontrolled arrhythmias, symptomatic angina pectoris, cardiac failure within the previous 6 months B. Active infection which would compromise the patients C. Liver cirrohosis or chronic active hepatitis D. Poor pulmonary function (DLCO ≤ 50% of normal or resting O2 saturation ≤ 90%) E. Clinically significant hemoptysis or gastrointestinal bleeding within previous 6 months F. Major psychiatric disorders or other inadequate psychiatric problems according to the physicians decision 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
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective, Single institution, Open-label, Phase 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ddMVAC<br>4 cycles of neoadjuvant chemotherapy using dose dense MVAC with G-CSF | Drug: dose dense MVAC with pegylated GCSF<br>* Methotrexate, 30 mg/m2 IV bolus, Day 1 Vinblastine, 3 mg/m2 IV bolus, Day2 Doxorubicin, 30 mg/m2 IV bolus, Day2 Cisplatin, 70 mg/m2 IV over 1hr, Day2 Pegylated G-CSF, 6mg SC, Day 3 every 2 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathologic response | No residual tumor (ypT0N0) and partial response (ypTis-1N0) in surgical specimen | From date of enrollment until curative intended surgical treatment, assess up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of pathologic complete response (pCR rate) | No residual tumor (ypT0N0) in surgical specimen | From date of enrollment until curative intended surgical treatment, assess up to 2 years | 
| Overall survival (OS) | Time from enrollment until death from any cause | From date of enrollment until death, assess up to 3 years | 
| Event free survival (EFS) | Time from enrollment until the earliest occurrence of disease progression in inoperablity, locoregional recurrence, distant metastasis, or death from any cause | From date of enrollment until death, assess up to 3 years | 
| Adverse events related with ddMVAC | Adverse events related with ddMVAC using CTCAE 4.0 | From date of enrollment until 8 weeks after last chemotherapy of ddMVAC | 
| Surgical treatment related complication | Surgical treatment related complication | From surgical treatment until 60 the days after surgical treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
dose dense MVAC, neoadjuvant chemotherapy, Urothelial carcinoma