Safety and Efficacy of CG0070 Oncolytic Virus Regimen in Patients With High Grade Non-Muscle Invasive Bladder Cancer

The plan is to study the safety and efficacy of CG0070 in high-grade NMIBC patients who
failed BCG therapy. Most patients with NMIBCis (Cis, Cis with Ta and/or T1, high grade Ta or
T1 with frequent or uncontrolled recurrences) who have failed BCG intravesical therapy
(standard of care) usually have no other choice but to proceed to cystectomy. Cystectomy is a
surgery associated with major morbidity, mortality and quality of life issues. Morbidity and
long term tedious medical care will be for the rest of the patient's life span. Most patients
at this stage do not show signs of disease progression into the muscle layer or of
metastasis, making surgery a very difficult decision. CG0070, if successful in this trial,
will serve to provide a therapeutic alternative for this patient population in need. For the
present study, Cis or Cis with Ta and/or T1 patients can only be enrolled if they have failed
the BOND study and are medically unfit for surgery. Furthermore, patients with high grade Ta
or T1 disease who have failed both BCG and chemotherapy treatments are also prone to disease
progression. Since these patients are not eligible to be enrolled in the BOND trial, the
present study will serve as an alternative to access CG0070 experimental treatment.

Inclusion Criteria:

- • Patients must have pathologically confirmed high grade disease (HG), as defined by
the 2004 WHO classification system

- Patients must have no evidence of muscle invasive disease

- Patient must fall under one of the following criteria:

1. Patients who were first enrolled in the BOND protocol but have failed to
achieve a complete response or have relapsed following a complete response
at 3 months after receiving control treatments

2. OR patients who were first enrolled in the BOND protocol but have relapsed
following a complete response lasting over a year after receiving CG0070
treatments

3. OR patients who have Ta/T1 high grade, refused cystectomy and are CG0070
naïve

4. OR patients from the exBOND protocol who experienced a tumor relapse with no
disease progression after sustaining 12 months or longer complete response
duration

- For Cis patients or Cis with Ta and/or T1 only:

1. Tumor must be considered unresectable or with residual disease.

2. Patients must be declared as medically unfit for cystectomy.

3. No disease progression from disease status at the beginning of the BOND
trial.

- For Ta/T1 HG Patients:

1. They must have also received at least one prior course of BCG therapy per
the recommended schedules. 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 BCG therapy must include at least six weekly treatments
(allowable range of instillations per course is 4-9) within a six-month
period

2. They must have received 2 or more intravesical chemotherapy regimens other
than BCG

3. They must have relapsed within 6 months of their last treatment

- 18 years of age or older

- Radical cystectomy has been declined by the patient in a signed special section
of the informed consent, whereby there is a clear explanation by the investigator
to the subject that a delay of cystectomy may increase his/her chance of disease
progression, the results of which may lead to serious and life threatening
consequences.

- 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.

- Histopathologically confirmed, transitional cell (urothelial) carcinoma.
Urothelial tumors with mixed histology (but with <50% variant) are eligible.

- Eastern Cooperative Oncology Group (ECOG) performance status <2.

- Not pregnant or lactating

- Patients with child bearing potential must agree to use adequate contraception

- Agree to study specific informed consent and HIPAA authorization for release of
personal health information

- Adequate baseline CBC, renal and hepatic function. Parameters described as
.WBC>3000 cells/mm3, ANC>1,000 cells/mm3, hemoglobin>10g/dL, and platelet count
>100,000 cells/mm3

- Adequate renal function: serum creatinine <2.0mg/dL

- Bilirubin, AST and ALT not more than 2 x Upper Limits of Normal

- PT/INR, PTT, and fibrinogen within institutional normal limits

- Absolute lymphocyte count ≥ 800/μL before the first dose of CG0070

Exclusion Criteria:

- Previous systemic chemotherapy or radiation for bladder cancer. Note: Prior
immunotherapy or intravesical (administered within the bladder) chemotherapy for
superficial disease is acceptable

- 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.

- Known infection with HIV, HBV or HCV.

- Anticipated use of chemotherapy, radiotherapy, or other immunotherapy not
specified in the study protocol while on study

- Any underlying medical condition that, in the Investigator's opinion, will make
the administration of study vector hazardous to the patient, would obscure the
interpretation of adverse events, or not permit adequate surgical resection.

- Systemic treatment on any investigational clinical trial within 28 days prior to
registration.

- 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.

- Immunosuppressive therapy, including: cyclosporine, antithymocyte globulin, or
tacrolimus within 3 months of study entry.

- History of prior experimental cancer vaccine treatment (e.g., dendritic cell
therapy, heat shock vaccine)

- 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.

- Progressive viral or bacterial infection

o All infections must be resolved and the patient must remain afebrile for seven
days without antibiotics prior to being placed on study

- Unwilling or unable to comply with the protocol or cooperate fully with the
investigator and site personnel

- Evidence of disease progression compared to disease status before BOND protocol
for NMIBCis patients.

- Patient have relapsed less than 1 year after or who are refractory to treatment
with CG0070.

- Cis, and Cis with Ta and/or T1 patients who are medically fit for cystectomy.