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Non-Muscle Invasive Bladder Neoplasms

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Mitomycins

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Group A: 20 mg MMC mixed with 60cc TC-3 hydrogel. (n=8)

• Group B: 40 mg MMC mixed with 60cc TC-3 hydrogel (n=8)

• Group C: 80 mg MMC mixed with 60cc TC-3 hydrogel (n=8)

TC-3 hydrogel

This study is a prospective randomized open labeled dose ranging comparative study. Twenty four (24) patients with NMIBC who meet the inclusion/exclusion criteria will be recruited for the study following the initial diagnostic cystoscopy.

The investigators believe that this study is of importance on several aspects:

1. It evaluates a new mode of bladder instillation that may bypass the drawbacks of the current instillation mode.
2. If proved effective, this mode of treatment might save the need for TURBT performance and serve as a new mode of tumor ablation.
3. Even if proved partially effective, this mode of treatment will diminish tumors size and/or number, thus enable a more limited TURBT procedure.
4. This mode of treatment will enable immediate medical attendance to the patient's tumor recurrence without the waiting period (resulting from queues in the medical centers) for TURBT. This might improve the patient's prognostic outcome.
5. If this experimental treatment will prove to have a better ablative effect in comparison to the standard of care known in the art, this could be translated to a better prophylactic effect of tumor recurrence.
6. Finding the minimal, yet optimal, effective dose for tumor ablation and tumor recurrence prevention will enable us to reduce adverse effects of higher drug dosage.

Non-muscle-Invasive Bladder cancer is mainly treated by tumor resection (Trans Urethral Resection - TUR), followed by series of intravesical instillations of prophylactic chemotherapeutic drugs such as Mitomycin C (MMC) or BCG. Unfortunately, this treatment approach is limited due to rapid dilution of the chemotherapeutic drug by the incoming urine and clearance by urination.

TheraCoat's core technology is based on a reverse thermal biodegradable gel (TC-3 Gel) (low viscosity at cold temperature (5°C) and gel appearance at body temperature)for drug retention in the urinary bladder.

Prior to instillation, the TC-3 Gel, in its liquid state, is mixed with MMC and instilled into the bladder by a standard catheter. Once inside the bladder, the gel solidifies and forms a drug reservoir. Upon contact with urine, the gel dissolves, release the drug slowly and is finally cleared out from the bladder.

Intravesical MMC instillation using TheraCoat's gel is expected to increase treatment efficiency due to prolongation of treatment duration and consequently improving bladder exposure to MMC.

Treatment Protocol - Immediately following baseline cystoscopy and tumor diagnosis and patient undergoes 6 weekly instillations followed by 2-4 weeks healing period.

1st Follow-Up Visit (Pre-Scheduled TURBT Visit): The patient will undergo a second cystoscopy to compare to baseline status. The patient will be followed-up for a period of 1 year as follows: 3,6,9,12 months.

A Prospective Open Label Comparative Dose Ranging Study Evaluating the Effect of Pre-TURBT Intravesical Instillation of Mitomycin C (MMC) Mixed With TC-3 Gel in Patients With Non Muscle Invasive Bladder Cancer (NMIBC)

Comparison of the cystoscopic and pathological effect of pre-TURBT instillations between the 3 different dosages of MMC mixed with TC-3 Hydro-gel groups on bladder lesion(s).

Comparison of one year tumor recurrence rate between the 3 treatment groups

Demonstration that blood levels of MMC following Pre-TURBT TC-3 gel-MMC instillation are below the toxic level (400ng/ml) known in the art for IV MMC administration

Cystoscopic and pathological effect (evaluated during TUR-BT visit) of pre-TURBT intravesical instillations with 20,40,80 mg of MMC mixed with 60cc TC-3 Hydrogel on bladder lesion(s) of NMIBC patients.

Demonstration of Pre-TURBT TC-3 gel-MMC instillation safety and adverse event rate.Adverse events will be defined as any adverse change in health or side effect that occurs in the clinical trial participant while the patient is receiving the treatment or until the completion of the post-treatment follow-up cystoscopy.

UroGen Pharma Ltd.

120 mg of Mitomycin C mixed with 90 ml UroGen's TC-3 gel

120 mg MMC in 90ml gel

140 mg of Mitomycin C mixed with 90 ml UroGen's TC-3 gel

140 mg MMC in 90ml gel

160 mg of Mitomycin C mixed with 90 ml UroGen's TC-3 gel

160 mg MMC in 90ml gel

120 mg of Mitomycin C mixed with 60 ml UroGen's TC-3 gel

120 mg MMC in 60ml gel

140 mg of Mitomycin C mixed with 60 ml UroGen's TC-3 gel

140 mg MMC in 60ml gel

160 mg of Mitomycin C mixed with 60 ml UroGen's TC-3 gel

160 mg MMC in 60ml gel

Ifat Klein, PhD

A prospective, open label, modified 3+3 dose escalation study. This dose-escalation study is designed to carefully assess the safety of successive cohorts of patients (3 patients/cohort), each cohort treated with a fixed dose of TC-3 and MMC Intravesical instillations.

A prospective, open label, modified 3+3 dose escalation study. This dose-escalation study is designed to carefully assess the safety of successive cohorts of patients. A total of 10 patients will be treated in the first cohort with 120mg MMC-TC-3 Gel unless DLT is reached in more than 1/3 of the patients in the cohort. The next cohorts will have 3 patients/cohort, each cohort treated with a fixed dose of TC-3 and MMC Intravesical instillations. Since data is already available for 40 and 80 mg MMC in TC-3 gel, the initial cohort is 120mg MMC mixed with of 60 mL TC-3. Subsequent cohorts will be given dose levels of 140mg \& 160mg MMC mixed with 60 mL TC-3. Thus, if 160mg MMC mixed in 60ml TC-3 will be found to be safe and tolerable, no higher doses will be further explored at this stage.

If 120 mg MMC in 60 ml TC-gel (2 mg/ml) is found to be intolerable, higher concentrations will not be tested. Instead, a dose of 120 mg in 90 cc TC gel and a subsequent doses of 140 and 160 mg MMC in 90 cc TC gel will be tested in the same dose escalating manner. This will allow testing similar doses at lower concentrations (up to 1.78 mg/ml) but with a longer dwell time due to the larger volume of TC-gel.

Dose escalation is to be halted when the maximum tolerated dose (MTD) will be reached; MTD is defined as one dose level below which dose limited toxicity (DLT) is Any adverse event (AE) related to TC-3+MMC and qualified per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) as grade 3 or 4 will be evaluated by board of 2 independent physicians to determine if it qualifies as DLT based on the known safety profile of MMC. If the NCI grade will not apply, the adverse event to be graded as mild, moderate, or severe.

If one of the three patients in a cohort experienced a DLT, three more patients will be added to the cohort for AE confirmation, only if 3 patients from the given cohort will experienced DLT, the MTD will be reached If no further DLTs are observed in the cohort, the three patients will be enrolled in the next successive cohort.

Safety of Pre-TURBT Intravesical Instillation of Escalating Doses of TC-3 Gel and MMC in NMIBC Patients

Evaluation of the Safety of Pre-TURBT Intravesical Instillation of Escalating Doses of TC-3 Gel Mixed With Mitomycin C (MMC) in Non-muscle Invasive Bladder Cancer (NMIBC) Patients

Complete Response (CR) rate defined as percent of patients with CR at the Primary Disease Evaluation (PDE) Visit

Durable Complete Response (CR) rate defined as percent of patients who continue to display CR at 3, 6, 9 and 12 months following the last treatment.

TC-3 gel mixed with Mitomycin C (MMC) Six weekly intravesical instillations of 40 ml of TC-3 gel mixed with 40 mg MMC will be instilled using catheter.

TC-3 gel mixed with Mitomycin C (MMC) Six weekly intravesical instillations of 40 ml of TC-3 gel mixed with 80 mg MMC will be instilled using catheter.

A reverse thermal biodegradable gel (TC-3) (low viscosity at 5°C gel appearance at body temperature) for drug retention in the urinary bladder.

40 mg MMC in 40 mL TC-3.

80 mg MMC in 40 mL TC-3.

Sudhir Rawal, MD

The purpose of this study is to evaluate the clinical response of the tumors within the bladder of recurrent NMIBC patients to Mitomycin-C embedded in UroGen Pharma's (known at that time as TheraCoat Ltd.) TC-3 Sterile Hydrogel (TC-3) and to evaluate the patency of ureters 6 hr post instillation.

An open label, successive dose escalation trial in subjects with Non Muscle Invasive Bladder Cancer (NMIBC), designed to evaluate the clinical response of low-intermediate risk tumors within the bladder to Mitomycin-C embedded in TC-3 Sterile Hydrogel (TC-3), administered intravesically, prior to TURBT in NMIBC subjects.

Eligible subjects with NMIBC will be recruited to the trial following the initial diagnostic cystoscopy. During the diagnostic cystoscopy, the number of tumor lesions, their size and location will be documented and recorded with video or photo cystoscopy.

A baseline cystoscopy will be conducted in all subjects for the evaluation of number of tumors and their diameters, and for mapping of their location. Baseline blood samples for liver and renal functions, as well as for complete blood count (CBC) and coagulation tests will be drawn prior to instillation to ensure eligibility and to serve as a reference point for systemic safety follow-up.

A future TURBT has been planned for 8-10 weeks post screening. Enrolled subjects will be treated successively with 40mg MMC in 40 mL TC-3 (the first 6 subjects) and with 80 mg MMC in 40 mL TC-3 (the following 12 subjects). At treatment session initiation, an 18-20 Fr two-way catheter will be inserted into the subject's bladder in order to completely empty the bladder of urine. Thereafter, a volume of 40 mL of cooled TC-3 mixed with 40 mg or 80 mg of MMC will be instilled through the catheter into the bladder of the subject. The catheter will then be ligated for twenty minutes, after which it will be drawn out of the bladder and the subject was will be allowed to urinate freely.

The subjects will undergo six weekly bladder instillations according to their assigned treatment of either 40 mg MMC (Group A) or 80 mg MMC (Group B) in 40 mL of TC-3. Following completion of instillation treatment series, there will be a 2-4 weeks healing period prior to next follow up visit (overall 10-12 weeks post screening). During 2-4 weeks follow-up (FU) visit, the lesions' status will be examined under cystoscopy. For subjects who will appear to have complete response (CR), this will be confirmed based on histological results. For subjects that will not be classified as having CR, decision about performance of TURBT or giving additional treatment will be at the PI's discretion.

Following 2-4 week FU visit, subjects will be managed according to their local standard guidelines. All patients will attempt to be followed up for 12 months following 2-4 weeks FU within the trial. These visits will be documented and data regarding recurrence and progression will be collected. Moreover, biopsy slides prior (when available), and following treatment will be collected and analyzed by an independent uro-pathologist.

Pilot Study to Evaluate the Clinical Response to Mitomycin-C in Hydrogel (TC-3) Administered Intravesically in NMIBC Patients

Evaluation of the Clinical Response of Mitomycin-C (MMC) Embedded in Hydrogel (TC-3) in Comparison to Mitomycin C in Saline, When Administered Intravesically, Pre-TURBT in Non Muscle Invasive Bladder Cancer (NMIBC) Patients. Muscle Invasive Bladder Cancer (NMIBC) Patients

Subjects' satisfaction with the treatment will be measured using an 8-item satisfaction questionnaire

Cystoscopic and pathological effect of pre-TURBT intravesical instillations with 40 or 80 mg of MMC mixed with 40cc TC-3 Hydrogel on bladder lesion(s) of NMIBC patients

Information of whether anesthesia was used during the treatment will be collected

Blood and urine tests (including urine culture test) be be collected

The degree of pain subject felt at the time the drug will be injected to the bladder will be collected (VAS)

Data regarding gel clearance and adverse urinary patency post instillation will be obtained based on the "post instillation telephone follow-up" set of questions.

Lesion mass will consider the number and size of the papillary lesion, and will be described at Screening and in 2-4 weeks follow-up visit

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Prospective Open Label Comparative Dose Ranging Study Evaluating the Effect of Pre-TURBT Intravesical Instillation of Mitomycin C (MMC) Mixed With TC-3 Gel in Patients With Non Muscle Invasive Bladder Cancer (NMIBC)	NCT01799499	Non Muscle Inva...	TC-3 hydrogel TC-3 hydrogel TC-3 hydrogel	21 Years -	UroGen Pharma Ltd.
Safety of Pre-TURBT Intravesical Instillation of Escalating Doses of TC-3 Gel and MMC in NMIBC Patients	NCT02307487	Bladder Cancer Neoplasms Urinary Bladder... Urologic Diseas...	120 mg MMC in 9... 140 mg MMC in 9... 160 mg MMC in 9... 120 mg MMC in 6... 140 mg MMC in 6... 160 mg MMC in 6...	18 Years -	UroGen Pharma Ltd.
Pilot Study to Evaluate the Clinical Response to Mitomycin-C in Hydrogel (TC-3) Administered Intravesically in NMIBC Patients	NCT02891460	Urinary Bladder... Urologic Neopla... Neoplasms Urinary Bladder... Urologic Diseas...	40 mg MMC in 40... 80 mg MMC in 40...	18 Years -	UroGen Pharma Ltd.

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