Safety and Tolerability of GemRIS 225 mg in Subjects With Muscle-Invasive Bladder Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if TAR-200, an investigational drug-delivery system, is safe and tolerable in patients with muscle-invasive bladder cancer (MIBC) between diagnosis and radical cystectomy (RC).

Official Title
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A Phase 1b, Multicenter, Open Label Study Evaluating Safety, Tolerability and Preliminary Efficacy of GemRIS 225 mg in Subjects With Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Conditions
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Urinary Bladder Cancer

Intervention / Treatment
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* Drug: Gemcitabine-Releasing Intravesical System (GemRIS)/TAR-200


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological proof of muscle-invasive transitional cell carcinoma of the bladder (stage II-III). Subjects with evidence of metastatic nodal disease to the obuturator or presacral lymph nodes only may be included (N1 M0). Subjects with any degree of fixation of the pelvic sidewall are not eligible. In Arm 1, subjects must have residual visible tumor following TURBT. In Arm 2, subjects must be fully resected (i.e., no visible tumor or as little tumor as possible) after restaging TURBT 2-6 weeks prior to Study Day 0. Adequate bone marrow, liver, and renal function, as assessed by the following requirements conducted within 21 days prior to dosing: Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1,500/mm3 Platelet count ≥ 100,000/mm3 Total bilirubin ≤ 1.5xULN (upper limit of normal) Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5xULN Glomerular Filtration Rate (GFR) ≥ 30% (≥ 30 ml/min/1.73 m2) Subjects must be willing to undergo a cystoscopy on study for investigational product removal. Eligible for and willing to undergo RC per the attending urologist. Subjects must be deemed ineligible for cisplatin-based combination chemotherapy by the attending medical oncologist. Subjects medically eligible for neoadjuvant cisplatin-based combination chemotherapy who refuse this therapeutic option and understand the risks and benefits of doing so. Prior radiation therapy is allowed provided that no radiation therapy was administered to the urinary bladder. Written informed consent and Health Insurance Portability and Accountability Act of 1966 (HIPAA) authorization for release of personal health information. Age > 18 years at the time of consent. Exclusion Criteria: Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome. Prior systemic chemotherapy for transitional cell carcinoma of the bladder. Any other prior systemic chemotherapy for a non-urothelial carcinoma must have been completed > 5 years prior to initiation of study. Previous exposure to gemcitabine instillations. Currently receiving other intravesical chemotherapy. Concurrent clinically significant infections as determined by the treating investigator. Presence of any bladder or urethral anatomic feature that in the opinion of the investigator may prevent the safe placement, indwelling use or removal of TAR-200. Documented history of vesicoureteral reflux or the presence of an indwelling ureteral stent or nephrostomy tube at the time of screening. Pelvic radiotherapy administered within less than 6 months prior to enrollment. Subjects who received radiotherapy ≥ 6 months prior to enrollment must demonstrate no cystoscopic evidence or symptoms of radiation cystitis. Bladder Post-Void Residual Volume (PVR) of > 250-mL. Active, uncontrolled urogenital bacterial, viral or fungal infections, including urinary tract infection that in the opinion of the investigator, contraindicates participation. Skin/nail fungal infections are not exclusionary. Subjects with active shingles (varicella zoster infection) will be excluded from the study. History or presence of any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, gynecological, endocrine, immunological, dermatological, neurological or psychiatric disease or disorder that, in the opinion of the investigator, contraindicates participation. History of diagnosis of neurogenic bladder. Concomitant immunosuppressive medications, such as methotrexate or TNF inhibitors, within 2 weeks of Study Day 0, exclusive of steroid doses ≤ 5 mg daily. Difficulty providing blood samples. Unwilling or unable to provide informed consent or comply with the requirements of this protocol, including the presence of any condition (physical, mental or social) that is likely to affect the subject's return for scheduled visits and follow-up. Other unspecified reasons that, in the opinion of the investigator or TARIS, make the subject unsuitable for enrollment.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Residual Tumor following TURBT<br>TAR-200 is placed into the bladder through an inserter on Study Day 0 and is removed on Study Day 7. TAR-200 releases gemcitabine gradually during the 7 day indwelling time. A second TAR-200 is placed in the bladder on Study Day 21 and is removed on Study Day 28, which is the day of the Radical Cystectomy (RC). | Drug: Gemcitabine-Releasing Intravesical System (GemRIS)/TAR-200<br>* TAR-200 is a passive, nonresorbable gemcitabine-releasing intravesical drug delivery system, regulated as a drug, whose primary mode of action is the controlled release of gemcitabine into the bladder over a 7-day period.<br>|
| Experimental: No Residual Tumor Following TURBT<br>TAR-200 is placed into the bladder through an inserter on Study Day 0 and is removed on Study Day 7. TAR-200 releases gemcitabine gradually during the 7 day indwelling time. A second TAR-200 is placed in the bladder on Study Day 21 and is removed on Study Day 28, which is the day of the Radical Cystectomy (RC). | Drug: Gemcitabine-Releasing Intravesical System (GemRIS)/TAR-200<br>* TAR-200 is a passive, nonresorbable gemcitabine-releasing intravesical drug delivery system, regulated as a drug, whose primary mode of action is the controlled release of gemcitabine into the bladder over a 7-day period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment emergent adverse events (TEAEs) coded with MedDRA and graded for severity with CTCAE v4.0 |  | Maximum 132 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who are tolerant of TAR-200 indwelling |  | From Day 0 up to Day 7 | 
| Percentage of participants who are tolerant of TAR-200 indwelling |  | From Day 0 up to Day 7 | 
| Number of participants who are tolerant of TAR-200 indwelling |  | From Day 21 up to Day 28 | 
| Percentage of participants who are tolerant of TAR-200 indwelling |  | From Day 21 up to Day 28 | 
| Cmax, plasma dFdU | Analysis of Cmax (maximum concentration achieved over time) of diflourodeoxyuridine (dFdU) in plasma. | From Day 0 up to Day 28 | 
| Tmax, plasma dFdU | Analysis of Tmax (Day at which maximum concentration was achieved) of diflourodeoxyuridine (dFdU) in plasma. | From Day 0 up to Day 28 | 
| Cavg, plasma dFdU | Analysis of Descriptive statistics (e.g. sample size, mean and median, quartiles, minimum and maximum and box plots) of the concentration of diflourodeoxyuridine (dFdU) in plasma | From Day 0 up to Day 28 | 
| Cmax, plasma dFdC | Analysis of Cmax (maximum concentration achieved over time) of gemcitabine (deoxydifluorocytidine hydrochloride - dFdC) in plasma | From Day 0 up to Day 28 | 
| Tmax, plasma dFdC | Analysis of Tmax (Day at which maximum concentration was achieved) of gemcitabine (deoxydifluorocytidine hydrochloride - dFdC) in plasma | From Day 0 up to Day 28 | 
| Cavg, plasma dFdC | Analysis of Descriptive statistics (e.g. sample size, mean and median, quartiles, minimum and maximum and box plots) of the concentration of gemcitabine (deoxydifluorocytidine hydrochloride - dFdC) in plasma | From Day 0 up to Day 28 | 
| Cmax, urine dFdU (Arm 1 only) | Analysis of Cmax (maximum concentration achieved over time) of diflourodeoxyuridine (dFdU) in urine | From Day 0 up to Day 28 | 
| Tmax, urine dFdU (Arm 1 only) | Analysis of Cmax (maximum concentration achieved over time) of diflourodeoxyuridine (dFdU) in urine | From Day 0 up to Day 28 | 
| Cavg, urine dFdU (Arm 1 only) | Analysis of Descriptive statistics (e.g. sample size, mean and median, quartiles, minimum and maximum and box plots) of the concentration of diflourodeoxyuridine (dFdU) in urine | From Day 0 up to Day 28 | 
| Cmax, urine dFdC (Arm 1 only) | Analysis of Cmax (maximum concentration achieved over time) of gemcitabine (deoxydifluorocytidine hydrochloride - dFdC) in urine | From Day 0 up to Day 28 | 
| Tmax, urine dFdC (Arm 1 only) | Analysis of Tmax (Day at which maximum concentration was achieved) of gemcitabine (deoxydifluorocytidine hydrochloride - dFdC) in urine | From Day 0 up to Day 28 | 
| Cavg, urine dFdC (Arm 1 only) | Analysis of Descriptive statistics (e.g. sample size, mean and median, quartiles, minimum and maximum and box plots) of the concentration of gemcitabine (deoxydifluorocytidine hydrochloride - dFdC) in urine. | From Day 0 up to Day 28 | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (AKT) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD31) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (Ki67) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (TUNEL) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD4) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD8) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (PD-L1) (Arm 1) |  | Anti-tumor analysis will occur at study visit Day 28. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (AKT) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD31) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (Ki67) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (TUNEL) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD4) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD8) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. | 
| Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (PD-L1) (Arm 2) |  | Anti-tumor analysis will occur at study visit Day 42. |