Talimogene Laherparepvec in Treating Patients With Non-Muscle Invasive Bladder Transitional Cell Carcinoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of talimogene laherparepvec and to see how well it works in treating patients with non-muscle invasive bladder transitional cell carcinoma. Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may attack specific tumor cells and stop them from growing or kill them.

Official Title
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A Phase I Study of Intravesical Talimogene Laherparepvec for Non-Muscle Invasive Transitional Cell Carcinoma

Conditions
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Stage 0 Bladder Urothelial Carcinoma AJCC v6 and v7, Stage 0a Bladder Urothelial Carcinoma AJCC v6 and v7, Stage 0is Bladder Urothelial Carcinoma AJCC v6 and v7, Stage I Bladder Urothelial Carcinoma AJCC v6 and v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Biological: Talimogene Laherparepvec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically document transitional cell carcinoma with the presence of any of the following stages: carcinoma in situ (CIS), high-grade Ta, or any grade T1, detectable at the time of study accrual; combinations of the aforementioned stages are acceptable; subjects with mixed histology are required to have a dominant transitional cell carcinoma (TCC) pattern Failure of prior intravesical treatment(s), one of which must include a course of BCG; failure is defined as evidence of TCC on cystoscopic examination and biopsy or cystoscopic examination and urine cytology at least 6 weeks from completion of last treatment Patient is either ineligible for or declines radical cystectomy; the investigator must explain that a delay in cystectomy may increase the patient?s chance of disease progression Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 Ability to understand and willingness to sign written informed consent Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5 x institutional upper limit of normal (ULN) and total bilirubin < 1.5 x institutional ULN Absolut neutrophil count (ANC) > 1500/uL Platelets >= 75,000/uL Hemoglobin > 8 mg/dL without need for hematopoetic growth factor or transfusion support Estimated glomerular filtration rate (GFR) > 30 ml/min Serum creatinine less than 1.5 x upper limit of normal (ULN), OR 24-hour creatinine clearance = or 60 mL/min for subject with creatinine levels more than 1.5 x ULN; (Note: creatinine clearance need not be determined if the baseline serum creatinine is within normal limits; creatinine clearance should be determined per institutional standard) Prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT) =< 1.5 x ULN No known history of human immunodeficiency virus (HIV) 1/2, human T-lymphotropic virus (HTLV)-I/II No currently active hepatitis B or C Males with partners of childbearing potential, must agree for the duration of the treatment with talimogene laherparepvec and continuing for 3 months after the last tumor injection of talimogene laherparepvec to either: Abstain from sexual activity Use highly effective barrier protection (latex condom) Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment; if urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required If a pregnancy occurs, the study doctor must be notified; the study doctor should notify the study sponsor as well as Amgen of the pregnancy, discuss any follow-up with the subject (and/or his partner), and ask for information on the pregnancy outcome; the patient should be asked if she wishes to consent to follow up through the Amgen pregnancy surveillance program If the female partner is already pregnant when the male subject begins treatment with talimogene laherparepvec, he must refrain from any sort of sexual activity that could expose his partner or the unborn baby to talimogene laherparepvec through semen, or wear a latex condom during sexual activity while receiving treatment with talimogene laherparepvec and for at least 3 months after the last talimogene laherparepvec administration Exclusion Criteria: Any subjects with muscle-invasive TCC (stages T2 - T4) OR any known TCC of the ureter or renal pelvis are not allowed Any history of metastatic TCC; subjects with suspected malignant lymphadenopathy in the abdomen or pelvis are not allowed Known active central nervous system (CNS) metastases; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids > 10 mg/day of prednisone or equivalent; the exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability Patients whom, in the opinion of the treating urologic oncologist, should undergo cystectomy due to high-risk features Intravesical chemo- or biologic therapy within 6 weeks of first treatment Prior systemic chemotherapy for transitional cell carcinoma of the bladder; subjects who have received prior intravesical chemotherapy are allowed if completed 28 days prior to cycle 1 day Prior radiation therapy for TCC History or evidence of active autoimmune disease, requiring systemic steroid therapy within 28 days of study screening or other systemic immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) or anticipated requirement for systemic immunosuppressive medications during the trial Patients on inhaled or topical steroids are eligible Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the principal investigator Replacement therapy (e.g., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment Major surgery (requiring the use of a general anesthetic) within 4 weeks of study enrollment with the exception of transurethral resection of bladder tumor (TURBT) Concurrent use of investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to talimogene laherparepvec Malignancies other than urothelial cancer (UC) within 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated with curative intent and absence of PSA relapse, or ductal carcinoma in situ of the breast treated surgically with curative intent) or incidental prostate cancer Patients are considered to be free of active malignancy if they have completed therapy and have a < 30% risk of relapse Uncontrolled cystitis, gross hematuria, bladder pain, or bladder spasms, other uncontrolled concurrent illness, or any underlying medical condition, including any underlying conditions resulting in chronic immunosuppression which in the Investigator?s opinion will make the administration of talimogene laherparepvec hazardous, or obscure the interpretation of adverse events Currently known active infection with HIV, hepatitis B or C virus Clinically significant obstructive airway disease Active HSV infection requiring treatment, or requiring intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g. acyclovir) Pregnant or nursing women are excluded Female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of talimogene laherparepvec Received live vaccine within 28 days prior to enrollment Active herpetic skin lesions or prior complications of herpetic infection (e.g., herpetic keratitis or encephalitis) Previous treatment with talimogene laherparepvec or any other oncolytic virus

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (talimogene laherparepvec)<br>Patients receive talimogene laherparepvec intravesically (10ml of 10^6 PFU/mL) on days 1, 8, 15, 22, 29, and 36 or days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Talimogene Laherparepvec<br>* Given intravesically<br>* Other names: T-VEC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-related toxicities according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (Dose escalation) | The distribution for the maximum observed grade for each adverse event will be tabulated and reported with 95% confidence interval. | Up to 2 years | 
| Pathologic T0 rate (Dose expansion) | Point estimates and 95% confidence intervals will be obtained for each dose level of talimogene laherparepvec. Will be estimated for the expansion cohort and compared with the null hypothesis rate separately by using one-sample proportion test. | At 6 months | 
| Relapse-free survival rate (Dose expansion) | Point estimates and 95% confidence intervals will be obtained for each dose level of talimogene laherparepvec. Will be estimated for the expansion cohort and compared with the null hypothesis rate separately by using one-sample proportion test. | From study start until recurrence of disease or death from any cause, assessed at 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in antigen presenting cell (APC) within bladder tumor tissue by immunohistochemical (IHC) assessment | APC infiltration (CD68+, CD11c+, or CD83+) will be assessed by IHC staining, and quantitated by the number of APCs/um^2. Therefore, the number of APCs will be normalized per unit area. APC will be enumerated from 3 tissue regions: tumor/benign tissue interface (from here on referred to as the ?tumor interface?), tumor center, and benign glands | Baseline up to 2 years | 
| Change in circulating immune cells following intravesical talimogene laherparepvec, by flow cytometric assessment | Flow cytometry will be performed in both pre- and post-treatment peripheral blood mononuclear cells to determine the change in T cell activation (both regulatory T cells and T effector cells) after intravesical talimogene laherparepvec therapy. Descriptive statistics for continuous measurements will be used to summarize the changes. | Baseline up to 2 years | 
| Change in T cell and other immune cell infiltration within bladder tumor tissue by IHC assessment | T cell tumor infiltration (of selected T cell subsets) will be scored by IHC assessment, and scored by the number of T cells/um^2. Therefore, the number of T cells will be normalized per unit area. T cell-infiltration for both the pre- treatment diagnostic biopsy specimen and the post-treatment specimen will be quantitated in this fashion. Separate scores will be reported for further characterization of T cell infiltration for tumor interface, tumor center, and benign tissue. | Baseline up to 2 years | 
| Herpes simplex virus (HSV) status assessed by rate of HSV seroconversion in patients who were previously HSV-seronegative and relationship between HSV status and immunologic infiltration within tumor | In patients who were previously HSV-seronegative, the proportion of patients with HSV seroconversion will be reported, with 95% confidence intervals. The relationship between APC infiltration and baseline HSV status will be reported as a binary outcome: positive or negative. Patients with baseline HSV negative status who experience seroconversion will be assessed by the chi-square test separately. | Up to day 43 | 
| Viral replication as measured by viral titers | Viral replication will be assessed by urinary viral titers drawn and assessed by polymerase chain reaction and cellular based assays as previously described. These assays will be performed prior to each dose, as well as at +1 hour (h), +2 h, +24 h and +168 h, with a window of 6 hours for the +24 and +168 h to accommodate for logistical issues patients returning to the clinic. Results will be summarized descriptively as change from baseline using appropriate statistical methods. | Up to 2 years |