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

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ClinicalTrials.gov Identifier: NCT02307487
Recruitment Status : Completed
First Posted : December 4, 2014
Last Update Posted : June 16, 2017
Sponsor:
Information provided by (Responsible Party):
UroGen Pharma Ltd.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Bladder Cancer Neoplasms Urinary Bladder Diseases Urologic Diseases Drug: 120 mg MMC in 90ml gel Drug: 140 mg MMC in 90ml gel Drug: 160 mg MMC in 90ml gel Drug: 120 mg MMC in 60ml gel Drug: 140 mg MMC in 60ml gel Drug: 160 mg MMC in 60ml gel Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : December 2014
Actual Primary Completion Date : April 2016
Actual Study Completion Date : June 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort A2
120 mg MMC in 90ml gel
Drug: 120 mg MMC in 90ml gel
120 mg of Mitomycin C mixed with 90 ml UroGen's TC-3 gel
Other Name: Mitomycin C

Experimental: Cohort B2
140 mg MMC in 90ml gel
Drug: 140 mg MMC in 90ml gel
140 mg of Mitomycin C mixed with 90 ml UroGen's TC-3 gel
Other Name: Mitomycin C

Experimental: Cohort C2
160 mg MMC in 90ml gel
Drug: 160 mg MMC in 90ml gel
160 mg of Mitomycin C mixed with 90 ml UroGen's TC-3 gel
Other Name: Mitomycin C

Experimental: Cohort A
120 mg MMC in 60ml gel
Drug: 120 mg MMC in 60ml gel
120 mg of Mitomycin C mixed with 60 ml UroGen's TC-3 gel
Other Name: Mitomycin C

Experimental: Cohort B
140 mg MMC in 60ml gel
Drug: 140 mg MMC in 60ml gel
140 mg of Mitomycin C mixed with 60 ml UroGen's TC-3 gel
Other Name: Mitomycin C

Experimental: Cohort C
160 mg MMC in 60ml gel
Drug: 160 mg MMC in 60ml gel
160 mg of Mitomycin C mixed with 60 ml UroGen's TC-3 gel
Other Name: Mitomycin C




Primary Outcome Measures :
  1. Rate of Adverse Events (AE) findings considered to be dose limiting according to the CTCAE V 4.0 [ Time Frame: 6 weeks ]
  2. Vital signs findings considered to be dose limiting according to the CTCAE V 4.0 [ Time Frame: 6 weeks ]
  3. Clinical evaluation findings considered to be dose limiting according to the CTCAE V 4.0 [ Time Frame: 6 weeks ]
  4. Lab results considered to be dose limiting according to the CTCAE V 4.0 [ Time Frame: 6 weeks ]

Secondary Outcome Measures :
  1. Rates of all adverse events or clinically relevant physical examination [ Time Frame: 15 months ]
  2. Vital signs and laboratory findings [ Time Frame: 15 months ]
  3. MMC maximum plasma concentration and concentration time curve during 6 hr post instillation [ Time Frame: 15 months ]
  4. Duration of MMC retention in the bladder as detected by urine MMC levels post instillation (6-7 hours) [ Time Frame: 15 months ]

Other Outcome Measures:
  1. Rate of patients with Complete Response (CR) to treatment [ Time Frame: 8-10 weeks post treatment ]
    Complete Response (CR) rate defined as percent of patients with CR at the Primary Disease Evaluation (PDE) Visit

  2. Rate of patients with durable Complete Response (CR) to treatment [ Time Frame: 3, 6, 9 and 12 months post 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient is 18 years of age or older.
  • Patient has signed Informed Consent Form and is willing and able to abide by the protocol.
  • Patients diagnosed with Low Grade (LG) or High grade (HG) NMIBC.
  • No active urinary tract infection as confirmed by urine culture.
  • If the patient is a female of childbearing potential, she is using two acceptable & effective methods of contraception, until 6 months post treatment
  • A negative serum pregnancy test at screening for female patient with childbearing potential
  • If the patient is a male he should use a condom during intercourse, for at least 48 hours post each instillation.
  • If the patient is a male that has a partner that is a female of childbearing potential, he should be advised to use two acceptable & effective methods of contraception until 6 months post treatment.

Exclusion Criteria:

  • Tumor located in prostatic urethra (for male patient) or in the bladder diverticulum.
  • Prior or required pelvic radiotherapy.
  • Systemic chemotherapy within 1 year prior the screening.
  • Pregnant or breastfeeding female patient.
  • Treatment of bladder cancer with BCG within the last 12 months prior to screening visit . Exception: For patient that had BCG treatment within 6-12 months prior to screening visit and are not symptomatic, the patient may enroll at the investigator discretion.
  • Treatment (full course) with intravesical chemotherapy within the 3 months, prior to screening visit.
  • Contraindication to MMC treatment as per investigator determination, or known sensitivity to MMC or TC-3 ingredients.
  • The patient has a known current urinary retention which requires intermittent catheterization to empty the bladder.
  • The patient has a bleeding disorder or a screening platelet count <100X109/L.
  • The patient has screening hemoglobin <10g/dL OR white blood cells < 4000 mm3.
  • GFR<30
  • Hepatic values exceeding 2 times the upper normal limit.
  • The patient has a concurrent severe and/or uncontrolled medical condition (e.g., uncontrolled diabetes, compensated congestive heart failure [NYHA III and over], myocardial infarction within 6 months of screening visit, unstable or uncontrolled hypertension or an active uncontrolled infection) or psychiatric disease, which could compromise participation, compliance with scheduled visits, and/or completion of the study in the opinion of the investigator.
  • The patient has a documented severe vesico-ureteral reflux or has an in-dwelling ureteral stent.
  • The patient participated in an investigational interventional study within the past 90 days, prior to screening visit.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02307487


Locations
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Israel
Wolfson Medical Center of Holon, Department of Urology
Holon, Israel
Meir Medical Center
Kfar Saba, Israel
Sponsors and Collaborators
UroGen Pharma Ltd.
Investigators
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Study Director: Ifat Klein, PhD UroGen Pharma
Additional Information:
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Responsible Party: UroGen Pharma Ltd.
ClinicalTrials.gov Identifier: NCT02307487    
Other Study ID Numbers: TC-BC-10
First Posted: December 4, 2014    Key Record Dates
Last Update Posted: June 16, 2017
Last Verified: June 2017
Keywords provided by UroGen Pharma Ltd.:
TC-3 Gel
MMC
NMIBC
Non Muscle Invasive Bladder Cancer
Hydrogel Reverse thermal gelation
Drug retention
Urinary Bladder Neoplasms
Urologic Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Additional relevant MeSH terms:
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Neoplasms
Urinary Bladder Neoplasms
Urologic Diseases
Urinary Bladder Diseases
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Mitomycins
Mitomycin
Antibiotics, Antineoplastic
Antineoplastic Agents
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors