S1314, Co-expression Extrapolation (COXEN) Program to Predict Chemotherapy Response in Patients With Bladder Cancer

Study Overview
=================
Brief Summary
-----------------
The primary focus of this study is to see if looking at tumor biomarkers using a program called coexpression extrapolation or COXEN may predict a patient's response to chemotherapy before surgery.

Detailed Description
-----------------
The COXEN program will not select a patient's therapy, but the type of chemotherapy that he/she will receive will be randomly decided. The patient's response to chemotherapy will be used to test the usefulness of the COXEN program, which is the main goal of this trial. Other potential tests to predict a patient's response to chemotherapy will also be evaluated. In this study, the patient may receive the treatment in Arm 1 (gemcitabine and cisplatin) or the treatment in Arm 2 [methotrexate, vinblastine, doxorubicin, cisplatin, and filgrastim (or pegfilgrastim)]. There will be about 230 people taking part in this study (115 in each arm).

Official Title
-----------------
A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer

Conditions
-----------------
Bladder Cancer

Intervention / Treatment
-----------------
* Drug: Gemcitabine
* Drug: Cisplatin
* Drug: Methotrexate
* Drug: Vinblastine
* Drug: Doxorubicin
* Drug: Filgrastim


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven bladder cancer (pure small cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma histologies are excluded). Stage cT2-T4a N0 M0 disease. Documented muscle invasive disease with at least one of the following: disease measuring at least 10 mm on cross-sectional imaging OR the presence of tumor-associated hydronephrosis. Staging scans with abdominal/pelvic CT or MRI scan and CT scan or x-ray of the chest within 56 days prior to registration. If alkaline phosphatase is above the treating institution's upper limit of normal (ULN), presence of suspicious bone pain, or if other clinical suspicion, a whole body bone scan is required within 56 days prior to registration. Performance status = 0 or 1 18 years of age or older Must have tumor tissue from transurethral resection of the bladder tumor (TURBT) available for submission that is sufficient for COXEN testing and must agree to submission of 20 (10 micron) slides plus 2 (5 micron) slides from the start and end of the 20 slides for a total of 22 unstained slides. Must agree to collection of tissue (if residual disease is present), urine, and whole blood. Must agree to participate in the translational medicine studies outlined in the protocol Exclusion Criteria: Prior systemic cytotoxic chemotherapy or systemic anthracycline Peripheral neuropathy >/= Grade 2 Class III/IV heart failure or known left ventricular ejection fraction (LVEF) < 50% Clinically relevant hearing impairment > Grade 2 Renal function, calculated creatinine clearance < 60 mL/min Hepatic function, total bilirubin > 1.5 x institutional upper limit of normal (IULN) (or > 2.5 x IULN with Gilbert's disease); AST & ALT > 2 X IULN Hematologic function, absolute neutrophil count (ANC) < 1,500/mcL, hemoglobin < 9 g/dL, and platelets < 100,000/mcL Hypersensitivity to cisplatin, gemcitabine, doxorubicin, vinblastine, methotrexate, or filgrastim/pegfilgrastim Incidence of or uncontrolled medical illness (e.g. active cardiac symptoms, active systemic infection, etc.) Pregnant or nursing females No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years. However, patients with localized prostate cancer who are being followed by an active surveillance program are eligible.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine & Cisplatin<br>Gemcitabine, 1000 mg/m2, IV, Days 1&8, q 21 days x 4 cycles Cisplatin, 70 mg/m2, IV, Day 1, q 21 days x 4 cycles | Drug: Gemcitabine<br>* Gemcitabine, 1000 mg/m2, IV (in the vein) on Days 1 and 8 of each 21 day cycle. Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Gemzar;Drug: Cisplatin<br>* Cisplatin, 70 mg/m2, IV (in the vein) on Day 1 of each 21 day cycle (or Day 1 or 2 of each 14 day cycle). Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Platinol;|
| Experimental: Dose Dense MVAC<br>Methotrexate, 30 mg/m2, IV, Day 1, q 14 days x 4 cycles Vinblastine, 3 mg/m2, IV, Day 1 or 2, q 14 days x 4 cycles Doxorubicin, 30 mg/m2, IV, Day 1 or 2, q 14 days x 4 cycles Cisplatin, 70 mg/m2, IV, Day 1 or 2, q 14 days x 4 cycles Filgrastim, 5 mcg/kg, SubQ/IV, Days 3-7, q 14 days x 4 cycles | Drug: Cisplatin<br>* Cisplatin, 70 mg/m2, IV (in the vein) on Day 1 of each 21 day cycle (or Day 1 or 2 of each 14 day cycle). Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Platinol;Drug: Methotrexate<br>* Methotrexate, 30 mg/m2, IV (in the vein) on Days 1 of each 14 day cycle. Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Trexall;Drug: Vinblastine<br>* Vinblastine, 3 mg/m2, IV (in the vein) on Days 1 or 2 of each 14 day cycle. Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Velban;Drug: Doxorubicin<br>* Doxorubicin, 30 mg/m2, IV (in the vein) on Days 1 or 2 of each 14 day cycle. Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Adriamycin;Drug: Filgrastim<br>* Filgrastim, 5 mcg/kg, SubQ/IV (in the vein) on Days 3-7 of each 14 day cycle. Number of Cycles: 4 cycles or until progression or unacceptable toxicity develops.<br>* Other names: Neupogen;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Whether the Treatment-specific COXEN Score is Prognostic of pT0 Rate | The proportion of participants achieving pT0 in both favorable and unfavorable treatment specific-COXEN score categories. Unit of measure is the number of participants in each category that achieved pT0 _____________________________________________________________________________________________________________________ The relationship of dose-dense methotrexate, vinblastin, doxorubicin, and cisplatin (DDMVAC)- and gemcitabine+cisplatin (GC)- specific CO-eXpression ExtrapolatioN (COXEN) scores This will be done in two ways: By assessing whether the treatment-specific COXEN score is prognostic of pT0 rate or ≤ pT1 in this patient population and to assess in a preliminary fashion whether the COXEN score is a predictive factor distinguishing between these two chemotherapy regimens. . By evaluating the correlation between the GC- and the DDMVAC-COXEN score. | Up to 5 years post registration | 
| Assessment of Whether the Treatment-specific COXEN Score is Prognostic of ≤ pT1 Rate | The proportion of participants achieving <=pT1 in both favorable and unfavorable treatment specific-COXEN score categories. Unit of measure is the number of participants in each category that achieved <= pT1 ____________________________________________________________________________________________________________________ The relationship of dose-dense methotrexate, vinblastin, doxorubicin, and cisplatin (DDMVAC)- and gemcitabine+cisplatin (GC)- specific CO-eXpression ExtrapolatioN (COXEN) scores This will be done in two ways: By assessing whether the treatment-specific COXEN score is prognostic of pT0 rate or ≤ pT1 in this patient population and to assess in a preliminary fashion whether the COXEN score is a predictive factor distinguishing between these two chemotherapy regimens. . By evaluating the correlation between the GC- and the DDMVAC-COXEN score. | up to 5 years post-registration | 
| Assessment of COXEN Score as a Predictive Factor Distinguishing Between GC and ddMVAC | To assess in a hypothesis generating fashion, the ability of COXEN to select for an individual chemotherapy regimen (GC vs DDMVAC) P-values are reported as a measure of whether COXEN can select between GC/DDMVAC and to determine the significance of interactions between treatment specific COXEN scores and treatment arms in models predicting either pT0 or <= pT1. Interactions with p-values > 0.05 are interpreted as not significant. ________ The relationship of dose-dense methotrexate, vinblastin, doxorubicin, and cisplatin (DDMVAC)- and gemcitabine+cisplatin (GC)- specific CO-eXpression ExtrapolatioN (COXEN) scores This will be done in two ways: By assessing whether the treatment-specific COXEN score is prognostic of pT0 rate or ≤ pT1 in this patient population and to assess in a preliminary fashion whether the COXEN score is a predictive factor distinguishing between these two chemotherapy regimens. . By evaluating the correlation between the GC- and the DDMVAC-COXEN score. | up to 5 years post-registration | 
| Correlation Between GC-and ddMVAC-COXEN Score | The Pearson and Spearman correlation coefficients for GC-and ddMVAC-COXEN score were calculated and are reported below. ___________________________________________________________________________________________________________________ The relationship of dose-dense methotrexate, vinblastin, doxorubicin, and cisplatin (DDMVAC)- and gemcitabine+cisplatin (GC)- specific CO-eXpression ExtrapolatioN (COXEN) scores This will be done in two ways: By assessing whether the treatment-specific COXEN score is prognostic of pT0 rate or ≤ pT1 in this patient population and to assess in a preliminary fashion whether the COXEN score is a predictive factor distinguishing between these two chemotherapy regimens. . By evaluating the correlation between the GC- and the DDMVAC-COXEN score. | up to 5 years post-registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predictability of the CO-eXpression ExtrapolatioN (COXEN) Score to Direct Which of the Two Regimens the Patient Should Receive: Gemcitabine+Cisplatin (GC) Versus Dose-dense Methotrexate, Vinblastin, Doxorubicin, and Cisplatin (DDMVAC) | In addition to stratification factors and dichotomous COXEN GEM score, an indicator for treatment arm and the interaction of treatment arm with COXEN GEM score was also included in a logistic regression model. A significant interaction would suggest that the respective COXEN GEM score was able to differentiate whether a patient was more likely to respond to one chemotherapy regimen over another. *note that this is the same objective at Primary Outcome #3 above - this was erroneously listed twice in the protocol. | Up to 5 years post registration | 
| Overall Survival | Duration from date of randomization to date of death from any cause. | Up to 5 years post registration | 
| Pathologic T0 Rate Evaluation: Gemcitabine+Cisplatin (GC) Versus Dose-dense Methotrexate, Vinblastin, Doxorubicin, and Cisplatin (DDMVAC) | Pathologic complete response rate at the time of cystectomy following GC or DDMVAC treatment | Up to 5 years post-registration | 
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. Grade 3 is less severe than Grade 5. Grade 3 - Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL* (bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden). Grade 4 - Life-threatening consequences; urgent intervention indicated. Grade 5 - Death related to AE *ADL- Activities of Daily Living | Duration of treatment and follow up until death or 5 years post registration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bladder Cancer, Neoadjuvant Chemotherapy, Coexpression Extrapolation, COXEN, S1314, SWOG