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.
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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
237
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.
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.
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.
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.
Time frame: 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.
Time frame: 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.
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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.
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.
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.
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Fairbanks Memorial Hospital
Fairbanks, Alaska, United States
University of Arizona Cancer Center at Saint Joseph's
Phoenix, Arizona, United States
University of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
The University of Arizona Medical Center-University Campus
Tucson, Arizona, United States
Yuma Cancer Center
Yuma, Arizona, United States
Fowler Family Center for Cancer Care
Jonesboro, Arkansas, United States
AIS Cancer Center at San Joaquin Community Hospital
Bakersfield, California, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
...and 556 more locations
Time frame: 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.
Time frame: up to 5 years post-registration
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.
Time frame: Up to 5 years post registration
Value of Gene Expression Profiling in Predicting Overall Survival (OS)
5-year OS curve was estimated using the Kaplan-Meier method. Included all COXEN evaluable participants regardless of arm assignment. The report groups were favorable vs. unfavorable COXEN status.
Time frame: 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
Time frame: 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
Time frame: Duration of treatment and follow up until death or 5 years post registration