Study of Intratumoral REOLYSIN® in Combination With Gemcitabine and Cisplatin as Neoadjuvant Therapy in Muscle-invasive Transitional Cell Carcinoma of the Bladder

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1b Study of Intratumoral REOLYSIN® in Combination With Gemcitabine and Cisplatin as Neoadjuvant Therapy in Muscle-invasive Transitional Cell Carcinoma of the Bladder

Conditions
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Muscle-invasive Transitional Cell Carcinoma of the Bladder

Intervention / Treatment
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* Biological: REOLYSIN®
* Drug: Gemcitabine
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: REOLYSIN®|3 cycles (each cycle = 21 days). Cohort 1: 3x10E10 TCID50 intratumoral via cystoscopy on Day 1 of each cycle. Cohort 2: 3x10E10 TCID50 intratumoral via cystoscopy on Day 2 of each cycle.|
|Drug: Gemcitabine|3 cycles (each cycle = 21 days). Cohort 1: 1000mg/m2 intravenously on Day 2 and Day 9 of Cycle 2 and Cycle 3. Cohort 2: 1000mg/m2 intravenously on Day 1 and Day 8 of each cycle.|
|Drug: Cisplatin|3 cycles (each cycle = 21 days). Cohort 1: 70 mg/m2 intravenously on Day 2 of Cycle 2 and Cycle 3. Cohort 2: 70 mg/m2 intravenously on Day 1 of each cycle.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Nature, frequency, severity and timing of Adverse Events. | During treatment and up to 28 days after treatment | 
| Pre- and post-treatment biopsies will be evaluated for tumor viability, percentage of necrosis, reovirus replication and tumor infiltration of immune cells and expression of PD-1 and PD-L1 |  | Assessed at surgery conducted following 3 3-week study treatment cycles | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure (TTF) |  | By medical chart review until disease reoccurrence or 2 years from surgery, whichever occurs first first. | 
| Disease Free Survival (DFS) |  | By medical chart review until disease reoccurrence or death or 2 years from surgery, whichever occurs first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bladder, Cancer, REOLYSIN®, Gemcitabine, Cisplatin, Reovirus, Oncolytic virus