Clinical Trials

The James Cancer Center Columbus, OH

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Gene Expression Profiling in Predicting Chemotherapy Response in Patients with Localized, Muscle-Invasive Bladder Cancer

Protocol: SWOG-S1314

Full Title

A Randomized Phase II Study Of Co-Expression Extrapolation (COXEN) With Neoadjuvant Chemotherapy For Localized, Muscle-Invasive Bladder Cancer

Purpose

This randomized phase II trial studies how well looking at genes using a type of gene expression profiling called COXEN (co-expression extrapolation) works in predicting response to chemotherapy in patients with bladder cancer that has spread to the muscle of the bladder. Drugs used in chemotherapy, such as methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Colony-stimulating factors, such as filgrastim and pegfilgrastim may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Gene expression profiling measures genetic information in various types of cells. Studying genes that affect how well patients respond to treatment may help doctors learn whether genetic information can be used in predicting treatment response and may help doctors plan the best treatment.

Study Objective

PRIMARY OBJECTIVES:

I. To characterize the relationship of dose-dense methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin (DDMVAC)- and gemcitabine hydrochloride + cisplatin (GC)-specific COXEN scores in terms of complete pathologic response (pT0) rate at cystectomy in patients treated with neoadjuvant chemotherapy.

SECONDARY OBJECTIVES:

I. To assess, in a hypothesis generating fashion, the ability of COXEN to select for an individual chemotherapy regimen (GC versus DDMVAC).

II. To assess the value of gene expression profiling in predicting overall survival (OS) in bladder cancer patients treated with neoadjuvant chemotherapy.

III. To assess the difference in pT0 rate between the 21-day GC and 14-day DDMVAC arms, regardless of gene expression.

IV. To assess the safety and tolerability of 21-day GC and 14-day DDMVAC chemotherapy when given in the neoadjuvant setting for bladder cancer.

TERTIARY OBJECTIVES:

I. To assess whether the COXEN gene expression profiles of ultra-pure circulating tumor cells (upCTCs) predict response (T0) to neoadjuvant chemotherapy at cystectomy

II.To assess other translational endpoints via gene expression, tissue microarray, micro ribonucleic acid (RNA), single nucleotide polymorphism (SNP) and genetic profiling data collected in the neoadjuvant bladder cancer setting.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride intravenously (IV) over 1 hour on days 1 and 8 and cisplatin IV over 1 hour on day 1. Select patients receive pegfilgrastim subcutaneously (SC) on day 9 or filgrastim SC or IV on days 9-13. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive methotrexate IV over 3 minutes on day 1 and vinblastine sulfate IV over 3 minutes, doxorubicin hydrochloride IV over 5 minutes, and cisplatin IV over 1 hour on day 1 or 2. Patients also receive filgrastim SC or IV on days 3-7 or pegfilgrastim SC on day 2 or 3. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Within 70 days from the last dose of chemotherapy, patients undergo radical cystectomy.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

Are you eligible?

Inclusion Criteria:

Patients must have histologically proven urothelial carcinoma of the bladder; those with mixed histology, including a component of urothelial carcinoma, are eligible; pure small cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma are excluded

Patients must have stage cT2-T4a N0 M0 disease; clinical T stage is based on the transurethral resection of bladder tumor (TURBT) sample and imaging studies; patients must undergo cystoscopy and TURBT as part of the staging procedure within 56 days prior to registration; to exclude non-bulky/low-risk tumors and ensure adequate tissue for assessment, subjects must have documented muscle invasion with at least one of the following:

Disease measuring at least 5 mm on cross-sectional imaging or by endoscopic assessment; bladder thickening on imaging without definable tumor is not adequate; pathology verification of >= 0.5 cm of viable tumor (longest diameter) from the biopsy sample and represented on the submitted slides is also acceptable

The presence of tumor-associated hydronephrosis

Patients must have staging scans with abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (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

Patients must have a Zubrod performance status of 0 or 1

Patients must not have received previous systemic cytotoxic chemotherapy for urothelial carcinoma

Patients must not have received previous systemic anthracycline (intravesical anthracycline is allowed)

Patients must not have peripheral neuropathy >= grade 2

Patients must not have presence of class III or IV heart failure, according to New York Heart Association classifications, or a known left ventricular ejection fraction of less than 50%; Note: left ventricular ejection fraction (LVEF) evaluation by echocardiogram or multi-gated acquisition scan (MUGA) is not required prior to registration

Patients must not have a clinically relevant hearing impairment > grade 2

Calculated creatinine clearance >= 60 mL/min; the serum creatinine value used in the calculation must have been obtained within 28 days prior to registration; use the modified Cockcroft-Gault formula

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (or =< 2.5 x ULN with Gilbert’s disease)

Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2 x institutional ULN

Absolute neutrophil count (ANC) >= 1,500/mcL

Hemoglobin >= 9 g/dL

Platelets >= 100,000/mcL

Patients must not be known to have hypersensitivity to cisplatin, gemcitabine (gemcitabine hydrochloride), doxorubicin (doxorubicin hydrochloride), vinblastine (vinblastine sulfate), methotrexate or filgrastim/pegfilgrastim

Patients must not have any incidence of or uncontrolled medical illness (e.g. active cardiac symptoms, active systemic infection, etc.) that would limit the patient’s ability to participate in the protocol

Prestudy history and physical must be obtained within 28 days prior to registration

Patients must not be pregnant or nursing; women/men of reproductive potential must agree to use an effective contraceptive method during and for 6 months after completing protocol treatment; a negative pregnancy test is required within 7 days prior to registration; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

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; patients with localized prostate cancer who are being followed by an active surveillance program are also eligible

Patients 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 of formal-fixed paraffin embedded (FFPE) tissue, with 2 (5 micron) slides at the start and end of the 20 slides, for a total of 22 unstained slides; the diagnostic TURBT sample must have been obtained within 56 days prior to registration; all sections should be placed on "plus" slides, as is the standard procedure in most pathology units

Patients must consent, if residual tumor is present at the time of cystectomy, to the submission of 20 (10 micron) unstained slides with 2 (5 micron) slides at the start and stop of the series (total of 22 unstained slides)

Patients must consent to have voided urine (40-50 mL) submitted prior to initiating chemotherapy (pre-treatment) and after chemotherapy prior to surgery (post-treatment)

Patients must consent to whole blood (2 x 10 mL) submitted prior to initiating chemotherapy

Patients must agree to participate in the translational medicine studies

Patients must be offered the opportunity to participate in the ultra pure Circulating Tumor Cells (upCTCs) study

Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent prior to any study-related procedures in accordance with institutional and federal guidelines

As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of Institutional Review Board approval for this study has been entered in the system

Bladder Cancer Genitourinary Cancers