study of intratumoral reolysin® in combination with gemcitabine and cisplatin as neoadjuvant therapy in muscle-invasive transitional cell carcinoma of the bladder

Conditions: Muscle-invasive Transitional Cell Carcinoma of the Bladder

Summary: the purpose of this study is to investigate the safety and efficacy of intratumoral reolysin® therapy alone and in combination with standard neoadjuvant gemcitabine and cisplatin in muscle-invasive bladder cancer.

reovirus serotype 3 - dearing strain (reolysin®) is a naturally occurring, ubiquitous, non-enveloped human reovirus. reovirus has been shown to replicate selectively in ras-transformed cells causing cell lysis. activating mutations in ras or mutations in oncogenes signaling through the ras pathway may occur in as many as 80% of human tumors. the specificity of the reovirus for ras-transformed cells, coupled with its relatively nonpathogenic nature in humans, makes it an attractive anti-cancer therapy candidate. this is an open-label study of intratumoral reolysin® in combination with standard of care neoadjuvant cisplatin/gemcitabine in patients with histologically and clinically confirmed muscle-invasive bladder cancer (t2-4) with or without pelvic lymph node involvement (n1-2) in stage iii and iv with no distant metastases (m0) and no prior systemic therapy for bladder cancer. treatment with intratumoral reolysin® and chemotherapy is planned for 3 cycles followed by radical cystectomy or until unacceptable toxicity or another discontinuation criterion is met. two sequential treatment cohorts will be enrolled. patients in cohort 1 will receive intratumoral reolysin® on cycle 1 day 1, then 7-14 days later patients will receive intratumoral reolysin® on cycle 2 day 1 plus intravenous neoadjuvant chemotherapy for 2 cycles (every 3 weeks) starting from cycle 2 day 2 followed by radical cystectomy. three patients will be enrolled in this cohort. if there is a dose limiting toxicity the cohort will be expanded to an additional 3 patients. upon completion of cohort 1, cohort 2 will be open to enrollment of 3 patients to receive 3 cycles of standard neoadjuvant chemotherapy on day 1 and day 8 of each cycle and intratumoral reolysin® on day 2 of each cycle (every 3 weeks). if there is a dose limiting toxicity the cohort will be expanded to an additional 3 patients. an expansion cohort will follow with up to 12 patients to be enrolled following either cohort 1 or cohort 2 treatment regimen based on the results of cohort 1 and cohort 2.

Eligibility criteria:
inclusion criteria: * histologically and clinically confirmed muscle-invasive bladder cancer (t2-4) with or without pelvic lymph nodes involvement (n1-2) in stage iii and iv (m0). * ecog performance status ≤2. * adequate liver function with a bilirubin within normal limits. transaminases up to 3 x uln (grade 1) and alkaline phosphatase may be up to 2.5 x uln (grade 1). * adequate bone marrow function, as defined by neutrophils count of ≥1,500/mm3, and platelet count ≥100,000/ mm3. * adequate renal function (serum creatinine ≤1.5 times the uln). * negative pregnancy test and reliable and appropriate contraceptive method during the study for a woman of childbearing potential. all female patients of childbearing age and all male patients with partners of childbearing age should use a reliable method of contraception, such as the barrier method, throughout the study and for 60 days after last treatment. * informed of the investigational nature of this study and must sign a written informed consent in accordance with institutional and federal guidelines. exclusion criteria: * received any prior therapy for invasive bladder cancer including surgery, radiation therapy, chemotherapy or any other systemic anti-cancer therapy (prior intravesical therapy for non-invasive bladder cancer is acceptable including intravesical bcg and/or mitomycin and interferon). * evidence of lymph nodes or other metastatic disease beyond the pelvis (n3 and/or m1). * pre-existing immunosuppressive or connective tissue disorders that require immune suppressive drugs. * history of hiv or active hepatitis. * any serious concurrent illness including; but not limited to, unstable angina pectoris, uncompensated congestive cardiac failure; myocardial infarct in the previous 6 months; cardiac arrhythmias or psychiatric illness that would limit compliance with study requirements. * pregnant or lactating. * a history of hypersensitivity to gemcitabine and cisplatin or any component of the formulation. * a prior malignancy, other than non-melanoma skin cancer, unless they have completed therapy at least 5 years prior to start of study and have no evidence of recurrent or residual disease. * unwilling or unable to sign informed consent document. * in social situations that would limit compliance with study requirements.

Keywords: bladder cancer reolysin® gemcitabine cisplatin reovirus oncolytic virus