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.
Brief Title
S1314, Co-expression Extrapolation (COXEN) Program to Predict Chemotherapy Response in Patients With Bladder Cancer
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).
Categories
Completion Date
Completion Date Type
Actual
Conditions
Bladder Cancer
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.
* 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.
Inclusion 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
* 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
Gender
All
Gender Based
false
Keywords
Bladder Cancer
Neoadjuvant Chemotherapy
Coexpression Extrapolation
COXEN
S1314
SWOG
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02177695
Org Class
Network
Org Full Name
SWOG Cancer Research Network
Org Study Id
S1314
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer
Primary Outcomes
Outcome Description
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.
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.
Outcome Measure
Assessment of Whether the Treatment-specific COXEN Score is Prognostic of pT0 Rate
Outcome Time Frame
Up to 5 years post registration
Outcome Description
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.
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.
Outcome Measure
Assessment of Whether the Treatment-specific COXEN Score is Prognostic of ≤ pT1 Rate
Outcome Time Frame
up to 5 years post-registration
Outcome Description
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.
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.
Outcome Measure
Assessment of COXEN Score as a Predictive Factor Distinguishing Between GC and ddMVAC
Outcome Time Frame
up to 5 years post-registration
Outcome Description
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.
___________________________________________________________________________________________________________________ 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.
Outcome Measure
Correlation Between GC-and ddMVAC-COXEN Score
Outcome Time Frame
up to 5 years post-registration
Secondary Ids
Secondary Id
S1314
Secondary Id
NCI-2014-00850
Secondary Id
U10CA180888
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Up to 5 years post registration
Outcome Measure
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)
Outcome Description
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.
Outcome Time Frame
Up to 5 years post registration
Outcome Measure
Value of Gene Expression Profiling in Predicting Overall Survival (OS)
Outcome Description
Pathologic complete response rate at the time of cystectomy following GC or DDMVAC treatment
Outcome Time Frame
Up to 5 years post-registration
Outcome Measure
Pathologic T0 Rate Evaluation: Gemcitabine+Cisplatin (GC) Versus Dose-dense Methotrexate, Vinblastin, Doxorubicin, and Cisplatin (DDMVAC)
Outcome Description
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
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
Outcome Time Frame
Duration of treatment and follow up until death or 5 years post registration
Outcome Measure
Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Benjamin Gartrell
Investigator Email
bgartrel@montefiore.org
Investigator Phone
718-405-8404