Change in study design

The use of a designed viral vector that can destroy cancer cells while leaving normal cells largely unharmed. The virus also stimulates an immunological response by producing a special factor (GM-CSF) to attract and promote the development of dendritic and T effector cells. It forms the hypothesis that this regimen may be used for people who have failed current forms of treatment and are recommended for cystectomy. It is with hope that this novel therapy will be able to delay or potentially avoid cystectomy for this patient population. Bladder instillation of this agent causes little long lasting side effects and may drastically improve the stimulation of the immune system for local cancer cell death as well as destroying those tumor cells that may have travelled to regional lymph nodes or distant organs.

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.

Inclusion Criteria:

1. Patients must be considered high risk, with pathologically confirmed high grade disease (HG) WHO 2004
2. Patients must have pathologically-proven unresectable, primary, secondary or concurrent carcinoma in situ disease, defined by having either Ta and/or T1 with CIS, or CIS
3. Patients must have no evidence of muscle invasive disease
4. Patient need to sign a specific informed consent acknowledging that a delay of cystectomy may lead to an increase chance of progression and/or metastasis with serious or sometimes fatal consequences.
5. Patients must have received at least two or more prior courses of intravesical therapy. BCG must have been one of the prior therapies administered. Patients can have either failed BCG induction therapy within a six month period or have been successfully treated with BCG, but subsequently found to have recurrence. The standard course of intravesical therapy must include six weekly treatments (allowable range of instillations per course is 4-9). The second course of BCG can consist of three weekly treatments
6. 18 years of age or older
7. Residual disease at accrual
8. Pathologically diagnosed transitional cell (urothelial) bladder cancer (further details in 10.) patients where radical cystectomy with curative intent is indicated for superficial bladder cancer that is resistant to treatment.
9. Patients must be able to enter into the study within five weeks of their most recent diagnostic procedure, which is usually a diagnostic biopsy, a transurethral resection of bladder tumor (TURBT) procedure or other diagnostic scanning such as CT and PET procedures.
10. Histopathologically confirmed, transitional cell (urothelial) carcinoma. Urothelial tumors with mixed histology (but with <50% variant) are eligible.
11. No evidence of urethral or renal pelvis TCC by upper tract radiological imaging (e.g., intravenous pyelogram, CT urogram, or retrograde pyelogram) within the past 2 years.
12. Eastern Cooperative Oncology Group (ECOG) performance status <2.
13. Not pregnant or lactating
14. Patients with child bearing potential must agree to use adequate contraception
15. Agree to study specific informed consent and HIPAA authorization for release of personal health information
16. Adequate baseline CBC, renal and hepatic function. Renal parameters as detailed above. Absolute lymphocyte count ≥ 1,000/μL before all doses of CG0070
17. Patient to provide a tumor specimen for determination of RB pathway status

Exclusion Criteria:

1. Previous systemic chemotherapy or radiation for bladder cancer. Note: Prior immunotherapy or intravesical (administered within the bladder) chemotherapy for superficial disease is acceptable
2. No bladder cancer residual disease, such as patients that are rendered disease free by TURBT
3. History of anaphylactic reaction following exposure to humanized or human therapeutic monoclonal antibodies, hypersensitivity to GM-CSF or yeast derived products, clinically meaningful allergic reactions or any known hypersensitivity or prior reaction to any of the formulation excipients in the study drugs.
4. Known infection with HIV, HBV or HCV.
5. Anticipated use of chemotherapy, radiotherapy, or other immunotherapy not specified in the study protocol while on study
6. Any underlying medical condition that, in the Investigator's opinion, will make the administration of study vaccine hazardous to the patient, would obscure the interpretation of adverse events, or surgical resection. Anticipated use of chemotherapy, radiotherapy, or other immunotherapy not specified in the study protocol while on study
7. Systemic treatment on any investigational clinical trial within 28 days prior to registration.
8. Concurrent treatment with immunosuppressive or immunomodulatory agents, including any systemic steroid (exception: inhaled or topically applied steroids, and acute and chronic standard dose NSAIDs, are permitted). Use of a short course (i.e., ≤ 1 day) of a glucocorticoid is acceptable to prevent a reaction to the IV contrast used for CT scans.
9. Immunosuppressive therapy, including: cyclosporine, antithymocyte globulin, or tacrolimus within 3 months of study entry.
10. History of prior experimental cancer vaccine treatment (e.g., dendritic cell therapy, heat shock vaccine)
11. History of partial cystectomy in the setting of bladder cancer primary tumor.
12. History of anaphylactic reaction following exposure to humanized or human therapeutic monoclonal antibodies, hypersensitivity to GM-CSF or yeast derived products, clinically meaningful allergic reactions or any known hypersensitivity or prior reaction to any of the formulation excipients in the study drugs.
13. History of stage III or greater cancer, excluding urothelial cancer. Basal or squamous cell skin cancers must have been adequately treated and the subject must be disease-free at the time of registration. Subjects with a history of stage I or II cancer, must have been adequately treated and have been disease-free for ≥ 3 years at the time of registration.
14. Concomitant active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis)
15. Progressive viral or bacterial infection
16. All infections must be resolved and the patient must remain afebrile for seven days without antibiotics prior to being placed on study
17. Any underlying medical condition that, in the Investigator's opinion, will make the administration of study vaccine hazardous to the patient, would obscure the interpretation of adverse events, or not permit adequate surgical resection.
18. Unwilling or unable to comply with the protocol or cooperate fully with the investigator and site personnel