Clinical trial NCT02722538: Safety and Tolerability of GemRIS 225 mg in Subjects With Muscle-Invasive Bladder Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Urinary Bladder Cancer
Lead sponsor: Taris Biomedical LLC
Sponsor class: INDUSTRY
First posted: 2016-03-30
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants with treatment emergent adverse events (TEAEs) coded with MedDRA and graded for severity with CTCAE v4.0
timeFrame: Maximum 132 days
Secondary outcomes:
measure: Number of participants who are tolerant of TAR-200 indwelling
timeFrame: From Day 0 up to Day 7
measure: Percentage of participants who are tolerant of TAR-200 indwelling
timeFrame: From Day 0 up to Day 7
measure: Number of participants who are tolerant of TAR-200 indwelling
timeFrame: From Day 21 up to Day 28
measure: Percentage of participants who are tolerant of TAR-200 indwelling
timeFrame: From Day 21 up to Day 28
measure: Cmax, plasma dFdU
timeFrame: From Day 0 up to Day 28
measure: Tmax, plasma dFdU
timeFrame: From Day 0 up to Day 28
measure: Cavg, plasma dFdU
timeFrame: From Day 0 up to Day 28
measure: Cmax, plasma dFdC
timeFrame: From Day 0 up to Day 28
measure: Tmax, plasma dFdC
timeFrame: From Day 0 up to Day 28
measure: Cavg, plasma dFdC
timeFrame: From Day 0 up to Day 28
measure: Cmax, urine dFdU (Arm 1 only)
timeFrame: From Day 0 up to Day 28
measure: Tmax, urine dFdU (Arm 1 only)
timeFrame: From Day 0 up to Day 28
measure: Cavg, urine dFdU (Arm 1 only)
timeFrame: From Day 0 up to Day 28
measure: Cmax, urine dFdC (Arm 1 only)
timeFrame: From Day 0 up to Day 28
measure: Tmax, urine dFdC (Arm 1 only)
timeFrame: From Day 0 up to Day 28
measure: Cavg, urine dFdC (Arm 1 only)
timeFrame: From Day 0 up to Day 28
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (AKT) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD31) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (Ki67) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (TUNEL) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD4) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD8) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (PD-L1) (Arm 1)
timeFrame: Anti-tumor analysis will occur at study visit Day 28.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (AKT) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD31) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (Ki67) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (TUNEL) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD4) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (CD8) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
measure: Preliminary anti-tumor effects assessed in tumor material (post-treatment) for immunohistochemical tissue biomarkers of drug-induced cell death (PD-L1) (Arm 2)
timeFrame: Anti-tumor analysis will occur at study visit Day 42.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California Norris Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Nijmegen
country: Netherlands
facility: Radboudumc
Study officials:
affiliation: University of Southern California
name: Siamak Daneshmand, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Daneshmand S, Brummelhuis ISG, Pohar KS, Steinberg GD, Aron M, Cutie CJ, Keegan KA, Maffeo JC, Reynolds DL, Raybold B, Chau A, Witjes JA. The safety, tolerability, and efficacy of a neoadjuvant gemcitabine intravesical drug delivery system (TAR-200) in muscle-invasive bladder cancer patients: a phase I trial. Urol Oncol. 2022 Jul;40(7):344.e1-344.e9. doi: 10.1016/j.urolonc.2022.02.009. Epub 2022 Apr 14.