Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title A Randomized Phase II Study of Co-Expression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder Cancer
IRB S1314
CC 14-1443
Hospital Florida Weston, Hillcrest, Main Campus, Mansfield, North Coast Cancer, Wooster
Phase Phase 2
Disease Bladder
Description
Primary Objective- To characterize the relationship of DDMVAC- and GC-specific COXEN scores in terms of pT0 rate at cystectomy in patients treated with neoadjuvant chemotherapy. 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.
- To assess, in a hypothesis generating fashion, the ability of COXEN to select for an individual chemotherapy regimen (GC versus DDMVAC).
- To assess the value of gene expression profiling in predicting overall survival (OS) in bladder cancer patients treated with neoadjuvant chemotherapy.
- To assess the difference in pT0 rate between the 21-day GC and 14-day DDMVAC arms, regardless of gene expression.
- To assess the safety and tolerability of 21-day GC and 14-day DDMVAC chemotherapy when given in the neoadjuvant setting for bladder cancer.
- To assess whether the COXEN gene expression profiles of ultra-pure circulating tumor cells (upCTCs) predict response (T0) to neoadjuvant chemotherapy at cystectomy.
- To assess other translational endpoints (as outlined in Section 18.3) via gene expression, tissue microarray, microRNA, SNP and genetic profiling data collected in the neoadjuvant bladder cancer setting. (The pre-chemotherapy TURBT sample and the post-chemotherapy cystectomy samples will be tested for mRNA, genetic, SNP, and microRNA expression. Additionally, blood, urine and tissue for tissue microarray will be obtained.)
Inclusion Criteria
Disease Related Criteria- Patients must have histologically proven urothelial carcinoma of the bladder. Those with mixed histology, including a component of urothelial carcinoma, are eligible. 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 TURBT sample and imaging studies. Patients must undergo cystoscopy and TURBT as part of the staging procedure (detailed in Section 4.0) 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 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.
- Patients must have a Zubrod performance status of 0 or 1 (see Section 10.4).
- Patients must be 18 years of age or older.
- 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 (see Appendix 18.2), or a known left ventricular ejection fraction of less than 50%. Note: 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.
- Patients must have adequate renal function as evidenced by 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 below: Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x [creatinine (mg/dl)]
- Patients must have adequate hepatic function as evidenced by total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (or ≤ 2.5 x ULN with Gilbert's disease), SGOT (AST) and SGPT (ALT) ≤ 2 x institutional ULN. These results must be obtained within 28 days prior to registration.
- Patients must have adequate hematologic function as evidenced by absolute neutrophil count (ANC) ≥ 1,500/μL, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/μL. These results must be obtained within 28 days prior to registration.
- Patients must not be known to have hypersensitivity to cisplatin, gemcitabine, doxorubicin, vinblastine, 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 due to the potential teratogenic side effects of the protocol treatment. 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 (either serum or urine) 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 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 outlined in Section 18.3.
- 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 OPEN registration process (see Section 13.4 for OPEN access instructions) 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.
