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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02177695
Recruitment Status : Completed
First Posted : June 30, 2014
Results First Posted : January 3, 2022
Last Update Posted : May 25, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
SWOG Cancer Research Network

Study Description
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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.

Condition or disease Intervention/treatment Phase
Bladder Cancer Drug: Gemcitabine Drug: Cisplatin Drug: Methotrexate Drug: Vinblastine Drug: Doxorubicin Drug: Filgrastim Phase 2

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).
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 237 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer
Actual Study Start Date : August 28, 2014
Actual Primary Completion Date : February 2020
Actual Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Gemcitabine & Cisplatin
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
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.
Other Name: Gemzar

Drug: Cisplatin

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.

Other Name: Platinol
Experimental: Dose Dense MVAC
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

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.

Other Name: Platinol

Drug: Methotrexate
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.
Other Name: Trexall

Drug: Vinblastine
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.
Other Name: Velban

Drug: Doxorubicin
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.
Other Name: Adriamycin

Drug: Filgrastim
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.
Other Name: Neupogen


Outcome Measures
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Primary Outcome Measures :
  1. Assessment of Whether the Treatment-specific COXEN Score is Prognostic of pT0 Rate [ Time Frame: Up to 5 years post registration ]

    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.

  2. Assessment of Whether the Treatment-specific COXEN Score is Prognostic of ≤ pT1 Rate [ Time Frame: up to 5 years post-registration ]

    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.

  3. Assessment of COXEN Score as a Predictive Factor Distinguishing Between GC and ddMVAC [ Time Frame: up to 5 years post-registration ]

    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.

  4. Correlation Between GC-and ddMVAC-COXEN Score [ Time Frame: up to 5 years post-registration ]

    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.


Secondary Outcome Measures :
  1. 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) [ Time Frame: Up to 5 years post registration ]
    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.

  2. Overall Survival [ Time Frame: Up to 5 years post registration ]
    Duration from date of randomization to date of death from any cause.

  3. Pathologic T0 Rate Evaluation: Gemcitabine+Cisplatin (GC) Versus Dose-dense Methotrexate, Vinblastin, Doxorubicin, and Cisplatin (DDMVAC) [ Time Frame: Up to 5 years post-registration ]
    Pathologic complete response rate at the time of cystectomy following GC or DDMVAC treatment

  4. Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Duration of treatment and follow up until death or 5 years post registration ]

    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



Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02177695


Locations
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Sponsors and Collaborators
SWOG Cancer Research Network
National Cancer Institute (NCI)
Investigators
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Study Chair: Thomas W. Flaig, M.D. University of Colorado, Denver
  Study Documents (Full-Text)

Documents provided by SWOG Cancer Research Network:
Study Protocol, Statistical Analysis Plan, and Informed Consent Form  [PDF] July 15, 2019

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: SWOG Cancer Research Network
ClinicalTrials.gov Identifier: NCT02177695    
Other Study ID Numbers: S1314
S1314 ( Other Identifier: SWOG )
NCI-2014-00850 ( Other Identifier: National Cancer Institute )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: June 30, 2014    Key Record Dates
Results First Posted: January 3, 2022
Last Update Posted: May 25, 2023
Last Verified: May 2023
Keywords provided by SWOG Cancer Research Network:
Bladder Cancer
Neoadjuvant Chemotherapy
Coexpression Extrapolation
 COXEN
S1314
SWOG
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Urinary Bladder Diseases
Urologic Diseases
Male Urogenital Diseases
Gemcitabine
Doxorubicin
Methotrexate
Vinblastine
 Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Dermatologic Agents
Folic Acid Antagonists
Immunosuppressive Agents