Efficacy Study of Recombinant Adenovirus for Non Muscle Invasive Bladder Cancer (BOND)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Cold Genesys, Inc.
Sponsor:
Information provided by (Responsible Party):
Cold Genesys, Inc.
ClinicalTrials.gov Identifier:
NCT01438112
First received: September 19, 2011
Last updated: June 18, 2014
Last verified: June 2014

September 19, 2011
June 18, 2014
March 2014
November 2018   (final data collection date for primary outcome measure)
  • Complete Response Proportion (CR) [ Time Frame: 9 months (Phase II) ] [ Designated as safety issue: No ]
    '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 consectutive 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) ] [ Designated as safety issue: No ]
    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.
  • Durable Complete Response Rate [ Time Frame: 6 months (Phase II) ] [ Designated as safety issue: No ]
    The 6 months durable complete response rate will be measured by complete response lasting 6 months or longer with negative cytology, cystoscopy, and biopsy. Durable Complete Response Rate at 6 months [Time Frame: 6 months following first treatment] [Designated as safety issue: No]
  • Disease Free Survival w/o Cystectomy [ Time Frame: 18 months (Phase III) ] [ Designated as safety issue: No ]
    The 18 months disease free survival rate w/o cystectomy will be measured by patients who exhibit a complete response lasting 18 month or longer confirmed by negative cytology, cystoscopy, and biopsy.• Disease Free Survival Rate ("DFS") w/o Cystectomy at 18 months [Time Frame: 18 months post randomization] [Designated as a safety issue: No]
Complete list of historical versions of study NCT01438112 on ClinicalTrials.gov Archive Site
  • Progression rate to muscle invasive disease [ Time Frame: Throughout the study with expected average of 12 months ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    The Cystectomy Free Survival time to events of patients will be compared with a log rank test.
  • Progression to muscle invasive disease rate [ Time Frame: Throughout the study with expected average of 12 months ] [ Designated as safety issue: No ]
    The Progression 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.
  • 18 month Disease Free Survival Rate [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    The 18 month disease free survival rate will be based on the proportion of patients who are classified as alive and without documented disease at this time point compared with the control arm
  • Safety / Tolerability [ Time Frame: Expected average of two years throughout the study ] [ Designated as safety issue: Yes ]
    The number and percentage of patients experiencing one or more adverse events will be summarized by relationship to study drug, and severity.
  • Cystectomy Rate [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    The Cystectomy rate is defined as patients who have undergone radical cystectomy for whatever reason.
  • pRb Positive Complete Response Rate [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    The complete response rate in patients determined to be positive for Rb pathway deficiencies using pRb IHC
Not Provided
Not Provided
 
Efficacy Study of Recombinant Adenovirus for Non Muscle Invasive Bladder Cancer
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

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Transitional Cell Carcinoma
  • Bladder Cancer
  • Carcinoma in Situ
  • Carcinoma in Situ Concurrent With Papillary Tumors
  • Biological: CG0070 adenovirus vector
    CG0070 adenoviral vector with GM-CSF expression given intravesically 1x10e12 viral particles for each instillations, weekly times six
    Other Names:
    • oncolytic virus
    • CG0070
    • GM-CSF expression
    • adenoviral vector
  • Other: Control Arm: Quadruple Choice

    Quadruple Choice Treatment Options:

    I. Mitomycin C II. Interferon III. Valrubicin IV. Gemcitabine

    Other Names:
    • Mitomycin C
    • Interferon
    • Valrubicin
    • Gemcitabine
  • 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
    Intervention: Biological: CG0070 adenovirus vector
  • Active Comparator: Chemotherapy or Interferon

    Quadruple Choice as interventions

    1. Mitomycin C
    2. Interferon
    3. Valrubicin
    4. Gemcitabine
    Intervention: Other: Control Arm: Quadruple Choice
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
222
June 2019
November 2018   (final data collection date for primary outcome measure)

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
Both
18 Years and older
No
Contact: Alex W Yeung, MBBS 949.200.7680 alex.yeung@coldgenesys.net
Contact: Paul DeRidder, MD 714-345-5887 p.deridder@coldgenesys.net
United States
 
NCT01438112
12154
Yes
Cold Genesys, Inc.
Cold Genesys, Inc.
Not Provided
Study Chair: Alex W Yeung, MBBS Cold Genesys, Inc.
Cold Genesys, Inc.
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP