Efficacy Study of Recombinant Adenovirus for Non Muscle Invasive Bladder Cancer

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