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

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

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).

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:

  1. Hemoglobin ≥ 9.0 g/dL
  2. Absolute neutrophil count (ANC) ≥ 1,500/mm3
  3. Platelet count ≥ 100,000/mm3
  4. Total bilirubin ≤ 1.5xULN (upper limit of normal)
  5. Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤ 2.5xULN
  6. 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.