Efficacy Study of Recombinant Adenovirus for Non Muscle Invasive Bladder Cancer (BOND)
|Transitional Cell Carcinoma Bladder Cancer Carcinoma in Situ Carcinoma in Situ Concurrent With Papillary Tumors||Biological: CG0070 adenovirus vector Other: Control Arm: Quadruple Choice||Phase 2 Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||An Integrated Phase II/III, Open Label, Randomized and Controlled Study of the Safety and Efficacy of CG0070 Adenovirus Vector Expressing GM-CSF in Patients With Non-Muscle Invasive Bladder Cancer With Carcinoma In Situ Disease Who Have Failed BCG|
- Complete Response Proportion (CR) [ Time Frame: 9 months (Phase II) ]'CR' Proportion is confirmed by negative biopsy, cystoscopy, cytology weekly times 2 with the first assessment three months after first intravesical treatment and then assessed again at 9 month. Two consecutive positive urine cytologies to confirm a persistent or recurrent disease if visual and biopsy is negative. Random biopsy mandatory at the first assessment in the trigone, bladder dome, right, left , anterior and posterior of the bladder wall.
- Durable Complete Response Proportion (DCR) [ Time Frame: 15 months (Phase III) ]DCR proportion of DCR lasting 12 months or longer will be conducted after a follow up period of 15 months for each patient. The first complete response assessment will be at 3 month.
- Progression rate to muscle invasive disease [ Time Frame: Throughout the study with expected average of 12 months ]The Progression rate to muscle invasive disease rate is based on analysis from comparing disease status at the time of enrollment versus disease status (for those patients with muscle invasion) at the time of cystectomy or TURBT
- Complete Response Survival [ Time Frame: 15 months ]The Complete Response Survival time to events of patients who have achieved a complete response at the 3 month assessment will be compared with a log rank test.
- Safety [ Time Frame: Expected average of two years throughout the study ]The number and percentage of patients experiencing one or more adverse events will be summarized by relationship to study drug, and severity.
- Cystectomy Free Survival [ Time Frame: 15 month ]The Cystectomy Free Survival time to events of patients will be compared with a log rank test.
|Study Start Date:||March 2014|
|Estimated Study Completion Date:||June 2019|
|Estimated Primary Completion Date:||November 2018 (Final data collection date for primary outcome measure)|
Experimental: CG0070 oncolytic virus
Interventions: CG0070 oncolytic virus intravesical instillations weekly X6 with each instillation lasting 45 minutes after prior transduction agent of DDM intravesically for 15 minutes
Biological: CG0070 adenovirus vector
CG0070 adenoviral vector with GM-CSF expression given intravesically 1x10e12 viral particles for each instillations, weekly times six
Active Comparator: Chemotherapy or Interferon
Quadruple Choice as interventions
Other: Control Arm: Quadruple Choice
Quadruple Choice Treatment Options:
I. Mitomycin C II. Interferon III. Valrubicin IV. Gemcitabine
After the phase I/II CG0070 trial review, it became apparent that the use of CG0070 oncolytic vaccine as an intravesical agent for oncolytic lysis of tumor cells, together with the transcription of GM-CSF on site, may have distinct advantages. This first study showed excellent tumor response rates of 48-77% depending on the dose schedule administered. All of these patients had residual non-muscle invasive bladder cancer who have previously failed BCG therapy at the time of treatment.
With the addition of a transduction agent such as DDM, the intravesical instillation of CG0070 enabled uniform distribution of viral particles and exposure to the tumor during those 30-60 minutes instillations as contrast to the intra-tumor injection, intra-arterial or intravenous injection of viral particles in other oncolytic viral trials. Some or most of these delivering methodologies have obvious intrinsic imperfections and potential toxicity. This unique opportunity of an relatively easy intravesical tumor exposure is difficult to duplicate in other solid tumor models.
The replication of CG0070 in the majority of patients during the first phase I/II trial indicated tumor lysis with release of tumor specific or tumor associated antigens that have been stably expressed, in abundant quantities during tumor cell death. Release of tumor antigens have been the key elements, together with sufficient on-site GM-CSF, in stimulating strong cross-presentation and confirmation signals to the antigen presenting cells such as dendritic cells interacting with CD4+ and CD8+ T cells. This concept of a "real time" vaccine like regimen is expected to compare favorably with other forms of cancer immunotherapy treatment such as BCG in this patient population.
It is with this thought that CG0070 may find a success in this setting because of a reasonably and proven complete response rate in residual and failed BCG bladder cancer patients in the first phase I/II study (some cases with only one instillation). Of importance as well, is the demonstration in the study data of a strong GM-CSF expression during its replication phase. Those patients with carcinoma in situ disease and those with RB pathway dysfunction were particularly responsive.
It is therefore, desirable to formulate a protocol to encompass the specialty of this oncolytic vaccine and the unique intravesical delivery to prove the efficacy by a randomized controlled study. This opportunity allows a study on the CG0070's beneficial effects, if any, on the standard of care for carcinoma in situ non muscle invasive bladder cancer patients after they failed BCG therapy. The prognosis of this group presently depends mainly on early radical cystectomy, which carries a high morbidity and decrease of quality of life generally viewed as unacceptable for this group of older patients.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01438112
|United States, Arizona|
|Phoenix, Arizona, United States, 85032-2129|
|United States, California|
|University of California, San Diego- Moores Cancer Center|
|La Jolla, California, United States, 92093|
|UCLA Institute of Urological Oncology|
|Los Angeles, California, United States, 90024|
|University of California, Davis- Cancer Center|
|Sacramento, California, United States, 95817|
|United States, Illinois|
|University of Chicago, Department of Surgery, Section of Urology|
|Chicago, Illinois, United States, 60637|
|United States, North Carolina|
|Wake Forest University Health Sciences|
|Winston-Salem, North Carolina, United States, 27157|
|United States, Tennessee|
|Vanderbilt University Medical Center Department of Urologic Surgery|
|Nashville, Tennessee, United States, 37232|
|Study Chair:||Alex W Yeung, MBBS||Cold Genesys, Inc.|