trial title a phase 3
untitled h2

MitoGel™ (UGN-101) on Ablation of Upper Urinary Tract Urothelial Carcinoma Protocol ID: TC-UT-03-P
Country: USA
trial title a phase 3
1. statement of compliance

The trial will be conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection of Human Patients (21 CFR Part 50), and the Clinical Terms of Award. All personnel involved in the conduct of this trial have completed human patients' protection training.
trial title a phase 3
2. confidentiality statement

The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential
trial title a phase 3
3. investigator's statement and signature

The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local legal and regulatory requirements and applicable US federal regulations, local regulations and ICH guidelines. Principal Site Investigator:
trial title a phase 3
principal site investigator

_________________ ___________________ __________________ ______________  
| Name/Title   | Site name   | Signature   | Date   |
|--------------|-------------|-------------|--------|  
| Effective Date: 18-Jun-2018                  |                                                                        |    |
|----------------------------------------------|------------------------------------------------------------------------|----|
| Table of Contents 1. Statement of Compliance | 1                                                                      |    |
| 2.                                           | Confidentiality Statement                                              | 1  |
| 3.                                           | Investigator's Statement and Signature Page                            | 2  |
| 4.                                           | Abbreviation List                                                      | 6  |
| 5.                                           | Protocol Synopsis                                                      | 8  |
| 6.                                           | Key Roles and Contact Information                                      | 17 |
| 7.                                           | Introduction and Background                                            | 18 |
| 7.1.                                         | Upper tract urothelial carcinoma (UTUC)                                | 18 |
| 7.2.                                         | Current treatment:                                                     | 18 |
| 7.3.                                         | Investigational Product: MitoGel™ (TC-3 and MMC)                       | 21 |
| 7.4.                                         | Justification of Trial Design                                          | 24 |
| 7.5.                                         | Potential Risks and Benefits                                           | 26 |
| 8.                                           | Trial Objectives                                                       | 27 |
| 8.1.                                         | Safety                                                                 | 27 |
| 8.2.                                         | Primary Efficacy                                                       | 28 |
| 8.3.                                         | Key Secondary Efficacy                                                 | 28 |
| 8.4.                                         | Secondary Efficacy                                                     | 28 |
| 9.                                           | Trial Endpoints                                                        | 28 |
| 9.1.                                         | Safety Endpoints                                                       | 28 |
| 9.2.                                         | Efficacy Endpoints                                                     | 28 |
| 9.3.                                         | Trial Design                                                           | 30 |
| 9.4.                                         | Evaluation plan at PDE                                                 | 32 |
| 9.5.                                         | Evaluation plan at follow-up                                           | 33 |
| 9.6.                                         | Central Lab Pathologist                                                | 34 |
| 10.                                          | Trial Population and Eligibility Criteria                              | 34 |
| 10.1.                                        | Inclusion Criteria                                                     | 34 |
| 10.2.                                        | Exclusion Criteria                                                     | 36 |
| 11.                                          | Investigational product (IP) - MitoGel™ Kit                            | 38 |
| 11.1.                                        | MitoGel™ Kit Packaging and Labeling                                    | 38 |
| 11.2.                                        | Investigational Product Acquisition, Dispatch, and Storage             | 41 |
| 11.3.                                        | MitoGelTM Admixture Dosage, Preparation, Dispensing and Administration | 43 |
| 11.4.                                        | IP Accountability                                                      | 46 |
| 11.5.                                        | Replacement of Unusable MitoGel™ Kits                                  | 47 |
| 11.6.                                        | Assessment of IP compliance                                            | 47 |
| 11.7.                                        | Destruction of IP                                                      | 47 |
| 12.                                          | Safety Evaluation                                                      | 48 |
| 12.1.                                        | Safety Assessment Prior and During the Treatment Period:               | 48 |
| 12.2.                                        | Telephone Contact 24–32 Hours Post-treatment                           | 49 |
| 12.3.                                        | VAS Questionnaire - Pain Assessment During Treatment                   | 49 |
| 12.4.                                        | Tests for Assessment of Safety                                         | 49 |
| 13.                                          | Trial Conduct and Procedures                                           | 50 |
| 13.1.                                        | Patient Eligibility Review and Enrolment to the Trial                  | 50 |
| 13.2.                                        | Screening Visit (V0): -4 to -1 weeks                                   | 51 |
| 13.3.                                        | Treatment Visits                                                       | 54 |
| 13.4.                                        | LAB 1 (V7) & LAB 2 (V8):                                               | 63 |
| 13.5.                                        | Primary Disease Evaluation Visit (PDE, V9)                             | 64 |
| 13.6.                                        | CR Patients Maintenance Instillations (Maintenance Visits)             | 65 |
| 13.7.                                        | Follow-up Visits (V12, V15, V18, V21)                                  | 65 |
| 13.8.                                        | Unscheduled Visit                                                      | 66 |
| 13.9.                                        | Treatment Discontinuation                                              | 66 |
| Document State: Effective (Controlled)       | Page 3 of 130                                                          |    |  
  
| Effective Date: 18-Jun-2018            |                                                                           |     |
|----------------------------------------|---------------------------------------------------------------------------|-----|
| 14.                                    | Schedule of Events                                                        | 68  |
| 14.1.                                  | Part I - All Patients - Up to PDE Visit                                   | 68  |
| 15.                                    | Evaluation of Response                                                    | 75  |
| 15.1.                                  | Tumor Measurements and Classification of Partial Response (PR)            | 75  |
| 15.2.                                  | Assessment of UC Tumor Progression                                        | 76  |
| 15.3.                                  | Assessment of UC Tumor Recurrence                                         | 76  |
| 15.4.                                  | Pathological Evaluation:                                                  | 77  |
| 16.                                    | Trial Flow-Chart Per Patient                                              | 78  |
| 17.                                    | Patients Withdrawal From Treatment or/and Follow Up, and Trial Completion | 79  |
| 17.1.                                  | Criteria for Patient withdrawal from MitoGel Treatment:                   | 79  |
| 17.2.                                  | Definition of Trial Completion                                            | 81  |
| 17.3.                                  | Replacement of Individual Patients                                        | 81  |
| 18.                                    | Statistical Methodology                                                   | 81  |
| 18.1.                                  | Significance Level                                                        | 82  |
| 18.2.                                  | Sample Size Rationale                                                     | 82  |
| 18.3.                                  | Futility Analysis                                                         | 83  |
| 18.4.                                  | Analysis Sets                                                             | 83  |
| 18.5.                                  | Patient Disposition                                                       | 85  |
| 18.6.                                  | Demographic and Baseline Characteristics                                  | 85  |
| 18.7.                                  | Efficacy Analyses                                                         | 85  |
| 18.8.                                  | Evaluation of Safety                                                      | 88  |
| 19.                                    | Management of Adverse Events                                              | 91  |
| 19.1.                                  | Definitions                                                               | 91  |
| 19.2.                                  | Reporting procedures                                                      | 93  |
| 19.3.                                  | Data Monitoring Committee (DMC)                                           | 97  |
| 20.                                    | Concomitant Medications                                                   | 98  |
| 21.                                    | Ethical Considerations and Confidentiality                                | 98  |
| 21.1.                                  | Informed Consent                                                          | 98  |
| 21.2.                                  | Ethics Committee and Competent Authorities                                | 99  |
| 22.                                    | Quality Control and Quality Assurance:                                    | 100 |
| 22.1.                                  | Source Documentation                                                      | 100 |
| 22.2.                                  | Record Retention                                                          | 101 |
| 22.3.                                  | Clinical Monitoring                                                       | 101 |
| 22.4.                                  | Protocol Deviations                                                       | 102 |
| 22.5.                                  | Audit and Inspection                                                      | 102 |
| 23.                                    | Trial Systems                                                             | 103 |
| 23.1.                                  | Data Collection and Management Responsibilities                           | 103 |
| 23.2.                                  | Procedures & Timelines for Data Capturing                                 | 103 |
| 23.3.                                  | Acknowledgment of MitoGel™ Kit Shipment Receipt                           | 105 |
| 23.4.                                  | System for Images Upload                                                  | 105 |
| 24.                                    | Trial Completion/Termination                                              | 105 |
| 24.1.                                  | Trial Completion                                                          | 105 |
| 24.2.                                  | Trial Termination                                                         | 105 |
| 25.                                    | Changes in the Conduct of the Trial:                                      | 106 |
| 25.1.                                  | Protocol Amendments                                                       | 106 |
| 26.                                    | Study Leadership                                                          | 106 |
| 27.                                    | Administrative and Regulatory Details                                     | 107 |
| 27.1.                                  | Registration of Clinical Studies and Disclosure of Results                | 107 |
| 27.2.                                  | Ownership of Data                                                         | 107 |
| 27.3.                                  | Conflict of Interest Policy                                               | 107 |
| 27.4.                                  | Final Report and Publication of the Results                               | 107 |
| Document State: Effective (Controlled) | Page 4 of 130                                                             |     |  
  
| 27.5.                                                                                                                                                                                                                                  | Finance and Insurance   | 108   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-------|
| 28.                                                                                                                                                                                                                                    | Bibliography:           | 109   |
| Appendix I: Clinical Evaluation                                                                                                                                                                                                        | 116                     |       |
| Appendix II: Vital Signs                                                                                                                                                                                                               | 117                     |       |
| Appendix III: Required Lab Tests                                                                                                                                                                                                       | 118                     |       |
| Appendix IV: Questions 24–32 hours Post Treatment Visit                                                                                                                                                                                | 119                     |       |
| Appendix V: Karnofsky & ECOG Scores (Oken et al, 1982)                                                                                                                                                                                 | 120                     |       |
| Appendix VI: Recommended Antimicrobial Prophylaxis for Urologic Procedure                                                                                                                                                              | 121                     |       |
| Appendix VII: Collection and Handling of Plasma Samples for MMC Pharmacokinetics 122 Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction Grades 123 Appendix IX: Protocol Amendment Version 6.0 - Summary of Changes 124 |                         |       |  
  
4. Abbreviation List  
  
| ADL   | Activities of Daily Living                     |
|-------|------------------------------------------------|
| ADR   | Adverse drug reaction                          |
| AE    | Adverse Event                                  |
| ALP   | Alkaline Phosphatase                           |
| ALT   | Alanine Aminotransferase                       |
| AST   | Aspartate Aminotransferase                     |
| BCG   | Bacille de Calmette et Guérin                  |
| CBC   | Complete Blood Count                           |
| CFR   | Code of Federal Regulations                    |
| CI    | Confidence Interval                            |
| CIS   | Carcinoma In Situ                              |
| CR    | Complete response                              |
| CRF   | Case Report Form                               |
| CT    | Computed Tomography                            |
| CTCAE | Common Terminology Criteria for Adverse Events |
| DMC   | Data Monitoring Committee                      |
| EC    | Ethical Committee                              |
| ECOG  | Eastern Cooperative Oncology Group             |
| EDC   | Electronic Data Capturing system               |
| eGFR  | Estimated Glomerular Filtration Rate           |
| FDA   | Food and Drug Administration                   |
| FU    | Follow Up                                      |
| FPI   | First Patient In                               |
| g     | Gram                                           |
| GCP   | Good Clinical Practice                         |
| GMP   | Good Manufacturing Practice                    |
| HG    | High Grade                                     |
| ICF   | Informed Consent Form                          |
| ICH   | International Conference on Harmonisation      |
| IFP   | Instructions for Pharmacy                      |
| IFU   | Instructions for Use                           |
| IP    | Investigational Product                        |
| IRB   | Institutional Review Board                     |
| LG    | Low Grade                                      |
| LPO   | Last Patient Out                               |
| mg    | Milligram                                      |
| mL    | Milliliter                                     |  
| Effective Date: 18-Jun-2018   |                                                                                          |
|-------------------------------|------------------------------------------------------------------------------------------|
| mITT                          | Modified Intent-to-Treat                                                                 |
| MitoGel™                      | MitoGel™ Admixture, of TC-3 Hydrogel Mixed with  Mitomycin C, using the Kit's components |
| MMC                           | Mitomycin C                                                                              |
| NCI                           | National Cancer Institute                                                                |
| NDD                           | No detectable Disease                                                                    |
| NMIBC                         | Non Muscle Invasive Bladder Cancer                                                       |
| NR                            | No Response                                                                              |
| NSP                           | Nephron-Sparing Procedures                                                               |
| ORR                           | Objective Response Rate                                                                  |
| PCS                           | Potentially Clinically Significant                                                       |
| PDE                           | Primary Disease Evaluation                                                               |
| PG                            | Performance goal                                                                         |
| PK                            | Pharmacokinetics                                                                         |
| PQC                           | product quality complaint                                                                |
| PR                            | Partial Response                                                                         |
| PP                            | Per Protocol                                                                             |
| RNU                           | Radical nephro-ureterectomy                                                              |
| SAE                           | Serious Adverse Event                                                                    |
| SE                            | Safety Evaluation                                                                        |
| SGOT                          | Serum Glutamic Oxaloacetic Transaminase                                                  |
| SGPT                          | Serum Glutamic Pyruvic Transaminase                                                      |
| SOC                           | Standard of Care                                                                         |
| SUSAR                         | Suspected Unexpected Serious Adverse Events  Response                                    |
| TC-3                          | TC-3 Sterile Hydrogel by UroGen Pharma Ltd.                                              |
| TEAE                          | Treatment Emergent Adverse Events                                                        |
| TNM                           | Tumor Node Metastases                                                                    |
| TURBT                         | Transurethral Resection of Bladder Tumor                                                 |
| UADR                          | Unexpected Adverse Drug Reaction                                                         |
| UC                            | Urothelial carcinoma                                                                     |
| ULN                           | Upper limit of normal                                                                    |
| URS                           | Ureteroscopy                                                                             |
| UPJ                           | Ureteropelvic Junction                                                                   |
| UUT                           | Upper Urinary Tract                                                                      |
| UTI                           | Urinary tract infection                                                                  |
| UTUC                          | Upper Tract Urothelial Carcinoma                                                         |
| WFI                           | Water for Injection                                                                      |  
  
| 5.                    | Protocol Synopsis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|-----------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Trial Title           | A Phase 3 Multicenter Trial Evaluating the Efficacy  and Safety of MitoGel™ (UGN-101) on Ablation of  Upper Urinary Tract Urothelial Carcinoma                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| Protocol              | TC-UT-03                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Number Clinical Phase | Phase III and Phase IIIb                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Investigationa        | MitoGel™ Kit                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| l Product Route of    | Instillation to the Upper Urinary Tract (UUT)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Delivery Indication   | Treatment for Upper Tract Urothelial Carcinoma (UTUC)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| Sponsor               | UroGen Pharma Ltd. 9 Ha'Ta'asiya St., Ra'anana, Israel                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Trial Centers         | Approximately 45 medical centers across the United States, Canada, Europe  and Israel.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Trial                 | Safety:   To evaluate the safety and tolerability of the MitoGel™ Admixture in  UTUC patients.  To assess the pharmacokinetics profile of Mitomycin C (MMC) in  plasma of a sub-group of patients treated with MitoGel™ Admixture.                                                                                                                                                                                                                                                                                                                                                                        |
| Objectives:           | Primary Efficacy Objectives: To evaluate the tumor ablative effect of MitoGel™ Admixture in the UUT  of patients with UTUC at PDE visit. Key Secondary Efficacy Objectives: To evaluate response durability at 12 months for patients showing CR at  PDE.  Secondary Efficacy Objectives:  To evaluate the durability of tumor ablative effect of MitoGel™  Admixture in patients who demonstrated complete response (CR) at the  Primary Disease Evaluation (PDE) Visit, 3, 6 and 9 months following  the PDE visit.  To evaluate the overall clinical benefit to the treatment with MitoGel™  admixture |  
  
  
A Ph-3 Multicenter Trial Evaluating the Efficacy  
and Safety of MitoGel™ - US, IL  
Document Number: CLP-0002344  
Document Version: 6.0  
| Document Version: 6.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                     |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| and Safety of MitoGel™ - US, IL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Effective Date: 18-Jun-2018                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                     |
| Safety                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Study's safety endpoints include:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                     |
| Endpoints                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Frequency (number of events) and incidence (number of patients) of  adverse events. |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Changes from baseline in laboratory values and incidence of  measurements defined as Potentially Clinically Significant (PCS).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                     |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Changes from baseline in vital signs assessments values and incidence of  measurements of Potential Clinical Significance (PCS).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                     |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Clinically relevant Physical examinations findings.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                     |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Changes in concomitant medications (type or dose) from baseline.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                     |
| In addition, pharmacokinetic (PK) profile of the first MMC instillation in the  blood will be examined for the first six patients. In addition,  pharmacokinetic (PK) profile of the first MMC instillation in the blood will  be examined for the first six patients.                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                     |
| Efficacy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Primary Efficacy Endpoint:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                     |
| Endpoints                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Complete Response (CR) defined dichotomously as "Success" if CR was  confirmed at the end of the treatment period (PDE Visit), and "Failure"  otherwise. Key Secondary Efficacy Endpoint: Long term durability of CR: This endpoint is defined only for those patients  demonstrating CR at PDE visit. The endpoint is defined dichotomously as  "Success" if CR was obtained at follow-up Visit 4 (12 months post PDE  visit), and "Failure" otherwise.  Secondary Efficacy Endpoint   Durability of CR defined dichotomously as "Success" if CR was  achieved at PDE visit and remained at follow-up Visit 1, Visit 2 and  Visit 3 (3, 6 and 9 months post PDE), and "Failure" otherwise. This  endpoint is defined only for those patients demonstrating CR at PDE  visit.  Partial response at PDE visit will be defined dichotomously, similarly to  the primary efficacy endpoint. For subjects with partial response at PDE  visit, originally planned and actual treatments will be compared. |                                                                                     |
| Trial Design Trial TC-UT-03 is a prospective, open label, single-arm trial, designed to assess the efficacy,  safety, and tolerability of treatment with MitoGel™ instilled in the upper urinary tract of  patients with non-invasive low-grade (LG), UTUC. Upon signing of informed consent, the patients will undergo a screening visit for eligibility  evaluation. Eligible patients will be treated with MitoGel™ once weekly for a total of 6 times;  in a retrograde fashion. Patients who demonstrate CR (based on the central lab evaluation and  URS) will be treated with MitoGel™ once monthly as a maintenance therapy for a total of 11 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                     |  
  
Page 9 of 130  
instillations or up to the first recurrence, whichever comes first. Instillation through a nephrostomy tube may be an option if necessary upon advising with the principle coordinating investigator. Determination of the eligibility of all patients and admission into the trial will be decided upon a case-by-case basis in consultation with the trial principal coordinating investigator Dr. Seth Lerner . The sponsor will send a final approval for patient enrollment to the site. General description of trial visits  
| Visit                                    | Timeline                                                                      |
|------------------------------------------|-------------------------------------------------------------------------------|
| Screening (V0)                           | Up to 4 weeks prior to treatment                                              |
| Instillations 1-6 (V1-V6)                | Once weekly for 6 weeks                                                       |
| Safety Labs (V7-V8)                      | One week and 3 weeks post last instillation                                   |
| Primary disease evaluation (PDE)         | 5±1 weeks following the last instillation visit                               |
| (V9) Maintenance Instillations (V10-V20) | Within 2-3 weeks following PDE visit, 11 monthly  administration of MitoGelTM |
| Follow up visits (FU 1-4) (V12,          | 3, 6, 9, and 12 months following the PDE visit.                               |
| V15, V18, V21)                           |                                                                               |  
  
Investigational product: The MMC concentration of MitoGel™ to be used in this trial will be 4 mg MMC per 1 mL of TC-3 gel. The volume of the MitoGel™ to be instilled into the patient pyelocalyceal system will be individualized and will be based on volumetric measurements of the pyelocalyceal system using pyelography (average of 3 measurements) and will not exceed 15 mL (a maximum dose of 60 mg). The pyelography procedure can be done at any time before the first treatment. The volume of MitoGel™ instilled will be 100%  
  
 of the measured pyelocalyceal volume or 15 mL (whichever is lower).  
Instillations process: Prior to every instillation the patient will be prescribed with sodium bicarbonate and will be instructed to consume 1.3 g of sodium bicarbonate the night prior to treatment, the morning of, and 30 min. prior to the treatment the patient will be also prescribed with a prophylaxis antibiotic to be taken to cover each treatment according to the AUA antimicrobial prophylaxis recommendations. Prophylactic anti-allergic treatment will be given per PI discretion. Recommended regimen– Anti-histaminic agents to be taken the day before instillation, on the day of instillation and 1-3 days after the instillation. Changes in such regimen may occur per the site principal investigator medical judgment. Diazepam (5-10 mg) (or any other relaxation pill) will be given before instillations according to the PI discretion to reduce the anxiety. PK evaluation will take place in a subset of patient (N=6) who provided an informed consent. Blood samples will be collected at 0 (pre-dose) and 30 min, 1, 2, 3, 4, 5, and 6 hours post first MitoGel™ instillation. Patients' safety will be monitored through the entire study by recording Adverse Events (AEs) throughout the study by:
Frequency (number of events) and incidence (number of patients) of adverse events Changes from baseline in laboratory values and incidence of measurements defined as Potentially Clinically Significant (PCS).  
Changes from baseline in vital signs assessments values and incidence of measurements of Potential Clinical Significance (PCS).  
Clinically relevant Physical examinations findings Five (5) weeks (± 1 w) following the last treatment, the PDE Visit, during which safety and efficacy will be assessed, will take place. During this visit, UT wash urine cytology will be carried out followed by URS which enables to assess visually the ablative effect of the MitoGel™. In case of remaining lesions, biopsy or brush biopsy shall be taken if applicable. Patient demonstrating CR at PDE will undergo monthly maintenance instillations of MitoGel™ up to 11 months post PDE. Safety follow-up for these patients will be done until one month post last instillation or at the end of the follow-up period in FU visit 12, which is the earlier. For patients who did not demonstrate Complete Response, to the extent that it is possible, all remaining tumors lesions will be biopsied. Based upon PI discretion the patients shall undergo any additional surgical or other treatment which might be deemed necessary to the patient health. The tumor lesion location, size and grade, as well as the surgical procedure or treatment provided to treat the remaining disease will be documented. Efficacy will be assessed by the rate of CR at PDE, i.e., 5 weeks (±1 week) after last MitoGel™ treatment. The durability of response will be assessed primarily by the rate of CR at 3 months after PDE and then every 3 months up to a one year post PDE visit.  
  
 During the FU period, disease recurrence and or progression, the type of intervention, and histopathological (where applicable) will be recorded.  
DMC-An independent Data Monitoring Committee (DMC) has been assigned to this trial.  
Accumulating safety, tolerability and efficacy data will be monitored periodically by the DMC according to a pre-specified process and frequency detailed in the DMC charter. In addition, a steering committee has been assigned to this trial. In case need arises, Ad hoc DMC meetings will be initiated by the steering committee. Every effort will be made to reach a consensus within the Data Monitoring Committee and with the principal coordinating investigator. In case of disagreement on recommended modifications to the protocol, the Steering Committee will make the final decision.
trial title a phase 3
follow up data will be

| long term safety and efficacy of the investigational product. Number of  74 patients Patients Planned trial  FPI to Last Patient Out (LPO): Approximately 34 months; period Treatment  Total: Approximately 14-16 months, per patient: and follow up  1-3 weeks screening period, 6 weeks treatment period, 5 weeks posttreatment to PDE, up to 12 months Follow Up (FU) period from the PDE  including a maintenance therapy of a single instillation once monthly up to  11 months FU. duration per  patient Trial  Adults patients with LG, non-invasive UTUC in renal pelvis and calyces  above the UPJ (Ureteropelvic Junction) population Inclusion  1. Patient has signed Informed Consent Form and is willing and able to  comply with all requirements of the protocol. 2. Patient is at least 18 years of age. 3. Naive or recurrent patients with LG, non-invasive UTUC in the  pyelocalyceal system. 4. Patient has at least one (1) measurable papillary LG tumor, evaluated  visually, ≤ 15 mm. The largest lesion should not exceed 15mm. 5. Biopsy taken from one or more tumors located above the ureteropelvic  junction (UPJ) showing LG urothelial carcinoma. Diagnosed not more  than 2 months prior to the screening. 6. Patient should have at least one remaining papillary LG tumor evaluated  visually with a diameter of at least 5 mm. 7. Wash urine cytology sampled from the pyelocalyceal system  Criteria:   |
|---|  
A Ph-3 Multicenter Trial Evaluating the Efficacy  
and Safety of MitoGel™ - US, IL  
Document Number: CLP-0002344  
Document Version: 6.0  
| Effective Date: 18-Jun-2018                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                        |                                                                                                                                    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|
| documenting the absence of HG urothelial cancer, diagnosed not more  than 2 months prior to the screening.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                        |                                                                                                                                    |
| 8.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Patients with bilateral LG UTUC may be enrolled if at least one side  meets the inclusion criteria for the trial and if the other kidney does not  require further treatments (The other kidney can be treated prior to the  beginning of the study).§ |                                                                                                                                    |
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Patients with ECOG (Eastern Cooperative Oncology Group)  performance status <3 (with Karnofsky >40).                                                                                                                                                   |                                                                                                                                    |
| 10. Patients with life expectancy greater than 24 months at time of  screening. 11. Patients must have adequate organ and bone marrow function as  determined by routine laboratory tests as below: Patients must have  adequate organ and bone marrow function as determined by routine  laboratory tests as below:  Leukocytes ≥3,000/μL (≥3×109/L),  Absolute neutrophil count ≥1,500/μL (≥1.5×109/L),  Platelets ≥100,000/μL (≥100×109/L),  Hemoglobin ≥9.0 mg/dL,   Total bilirubin ≤1.5 upper limit of normal (ULN),  AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal (ULN),  ALP ≤2.5 × institutional ULN, and  Estimated glomerular filtration rate (eGFR) ≥30 mL/min.   In rare instances, the Principal Investigator may enroll patients whose  laboratory screening values do not conform exactly to the levels  outlined above but who, in the judgement of the local PI, the DMC  and the coordinating PI can be safely and ethically treated on  protocol.  12. Patient has no active urinary tract infection (UTI) as confirmed by urine  culture or urinalysis*. 13. Female Patients of childbearing potential**, must have a negative serum  pregnancy test at screening and must agree to use two acceptable &  effective methods of contraception***, until 6 months post treatment.  14. All sexually active male patients must agree to use a condom during  intercourse, for at least 48 hours post each instillation. 15. Male patients who have a partner that is a female of childbearing  potential must agree to use two acceptable & effective methods of  contraception until 6 months post treatment.  16. Patients must not have any other medical condition(s) that make(s) their  participation in the study unadvisable in the opinion of the investigator. (§ *; **; ***; see end of Exclusion Criteria) |                                                                                                                                                                                                                                                        |                                                                                                                                    |
| Exclusion                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 1.                                                                                                                                                                                                                                                     | Patient received BCG treatment for UC during the 6 months prior to  Visit 1. Document State: Effective (Controlled) Page 13 of 130 |
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A Ph-3 Multicenter Trial Evaluating the Efficacy  
and Safety of MitoGel™ - US, IL  
Document Number: CLP-0002344  
Document Version: 6.0  
| Document Version: 6.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                   |                                                                                                                                          |
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| and Safety of MitoGel™ - US, IL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Effective Date: 18-Jun-2018                                                                                                                                                                                                                                                       |                                                                                                                                          |
| Criteria:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 2.                                                                                                                                                                                                                                                                                | The patient has untreated concurrent urothelial cancer in other locations  other than the target area (unless treated during screening). |
| 3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Carcinoma in situ (CIS) in the past in the urinary tract.                                                                                                                                                                                                                         |                                                                                                                                          |
| 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Patient has a history of invasive urothelial carcinoma during the past 5  (Five) years.                                                                                                                                                                                           |                                                                                                                                          |
| 5.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Patient has a history of high grade papillary urothelial carcinoma in the  urinary tract during the past 2 (Two) years.                                                                                                                                                           |                                                                                                                                          |
| 6.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Patient is actively being treated or intends to be treated with systemic  chemotherapy during the duration of the trial.                                                                                                                                                          |                                                                                                                                          |
| 7.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Any other malignancy diagnosed within 2 years of trial entry with the  exception of: a. Basal or squamous cell skin cancers, or  b. Noninvasive cancer of the cervix, or  c. Any other cancer deemed to be of low-risk for progression or patient  morbidity during trial period. |                                                                                                                                          |
| 8.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Patient with urinary obstruction in a case of retrograde administration or  administration not feasible via nephrostomy tube.                                                                                                                                                     |                                                                                                                                          |
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Inability to deliver the investigational drug to the pyelocalyceal system.                                                                                                                                                                                                        |                                                                                                                                          |
| 10. Patient has any other medical or mental condition(s) that make(s) his/her  participation in the trial unadvisable in the opinion of the treating  urologist.  11. Patient has contraindication to MMC treatment, or known sensitivity to  MMC. 12. Patient has an intractable bleeding disorder (e.g., coagulation factors  deficiencies, Von Willebrand Disease). 13. Patient is currently receiving any other investigational agents or has  participated in a research protocol involving administration of an  investigational product within the past 30 days prior to Visit 1. 14. Patient previously treated with MitoGel™ for UTUC. 15. Pregnant (positive serum pregnancy test), planning to become pregnant  during the trial period, breast-feeding, or of childbearing potential and  not practicing reliable contraception***. 16. Patient is non-responder to Mitomycin C as a chemical ablation agent for  urothelial carcinoma. This criterion relevant only to patient who already  participated in another UroGen's studies or any other relevant studies  with chemical ablation efficacy endpoint.  § If both upper tracts meet inclusion criteria, the treating urologist in  consultation with the sponsor can decide which side is to be treated  within the trial. The other side should be treated as per standard of care,  however if the other kidney treatment includes an intravesical  instillations, the patient is not eligible. In any case, the other kidney must  be free of cancer before the first instillation on the side to be treated in  the clinical trial. Document State: Effective (Controlled) Page 14 of 130 |                                                                                                                                                                                                                                                                                   |                                                                                                                                          |
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A Ph-3 Multicenter Trial Evaluating the Efficacy  
and Safety of MitoGel™ - US, IL  
Document Number: CLP-0002344  
Document Version: 6.0  
| and Safety of MitoGel™ - US, IL                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Effective Date: 18-Jun-2018                                                                                                                                                                                                                                                                                         |                                                                    |
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| *                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | In case of a symptomatic UTI the patient will be treated with a full  course of antibiotics, and the instillation will be postponed until  resolution. In the case of asymptomatic bacteriuria, the use of  prophylactic antibiotics and postponement of the treatment is left to the  discretion of the PI.        |                                                                    |
| ** Women of non-childbearing potential:  1. At least 12 months since the last menses, or 2. Without uterus and/or both ovaries, or 3. Has been surgically sterile for at least 6 months prior to trial drug  administration. *** Acceptable methods of birth control which are considered to have a  low failure rate (i.e., less than 1% per year) when used consistently and  correctly, such as implants, injectable, combined (estrogen/progesterone)  oral contraceptives, intrauterine devices (IUDs-only hormonal), condoms  with spermicide, sexual abstinence or vasectomized partner. |                                                                                                                                                                                                                                                                                                                     |                                                                    |
| Statistical                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Approximately 83 patients will be recruited to provide at least 74 evaluable  patients. While no interim efficacy analysis is planned:                                                                                                                                                                              |                                                                    |
| Methodology                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                    | A futility analysis is planned after 20 subjects have reached PDE, |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | The DMC will periodically review safety and efficacy data and will, if  appropriate, recommend earlier submission to FDA in the case where it  has concluded that safety and efficacy have been demonstrated. If this  were to occur, the study would nevertheless continue while FDA  evaluates the data provided. |                                                                    |
| Sample Size Rationale: A total of approximately 83 subjects are planned to provide at least 74 who  are evaluable that will provide 88.5% power to demonstrate the  hypothesized CR rate of 30% is higher than the performance goal of 15%.  Power is estimated using an exact binomial hypothesis testing with twosided Alpha=0.05.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                     |                                                                    |  
  
  
| Effective Date: 18-Jun-2018   |
|-------------------------------|
| Primary Efficacy Analysis: The primary efficacy analysis will test the following hypotheses in ITT,  using an exact binomial hypothesis testing: H0: CRrate ≤15% H1: CRrate >15%  Key Secondary Efficacy Analysis: The key secondary efficacy analysis will test the following hypotheses in the  CR analysis set of subjects demonstrating CR at PDE, using exact binomial  testing: H0: Durable CR at 12-months ≤ 40% H1: Durable CR at 12 months > 40% In addition, durability of CR will be analyzed continuously using KaplanMeier curve. Interim Analysis A futility analysis will be conducted after N = 20 evaluable subjects have  provided primary efficacy data. Results of the analysis will be provided to  the DMC. The DMC will forward its recommendations following DMC  meetings to the steering committee, which will than make the final  determination on trial continuation.                               |  
  
6. Key Roles and Contact Information
trial title a phase 3
sponsor

UroGen Pharma Ltd. 9 Ha'Ta'asiya., POB 2397 Ra'anana, 4365405, Israel info@urogen.com Tel: +972-9-770-7600 Fax: +972-77-4171410 Trial Manager  
 Medical Monitor /  
 Pharmacovigilance Officer Medical Director Quality Assurance Principal Coordinating Investigator Dr. Seth Paul Lerner Site: Baylor College of Medicine M.C. Houston, Texas 77030, USA Office Phone:
Data Management & Statistics  
  
Primary Central Pathology and Cytology Reviewer  
  
Secondary Central Pathology and Cytology Reviewer  
  
Pharmacokinetics Central Lab
trial title a phase 3
7. introduction and background

7.1. Upper Tract Urothelial Carcinoma (Utuc)  
Upper tract urothelial carcinomas (UTUCs) are malignant changes of the transitional urothelial cells lining of the upper urinary tract. UTUC are uncommon and account for only 5%–10% of urothelial carcinomas (UCs) [Browne, 2005; Rouprêt, 2013; Hurwitz, 2014], and the estimated annual incidence of UTUCs in western countries is about two new cases per 100,000 inhabitants. UTUC is found in the renal pelvis (in about two-thirds of the cases) and the ureter (in about one-third of the cases) [Jarrard, 2012]. Concurrent bladder cancer is present in approximately 17% of cases of UTUC. In 22%–47% of UTUC patients, recurrence occurs in the bladder, whereas recurrence in the contralateral upper tract is observed in 2%–6% [Rouprêt, 2013].  
About 60% of UTUCs are invasive at diagnosis, with a peak incidence in people in their 70s and 80s, and prevalence is 3 times higher in men than in women. [Rouprêt, 2013].  
The most common symptom of UTUC is microscopic or gross hematuria (70%–80%),
while flank pain occurs in 20%–40% of cases, and a lumbar mass is present in 10%–20% [Hall, 1998: Rouprêt, 2013].  
Screening and diagnosis of UTUC consists of upper tract urinary cytology, various imaging assessment methods, and ureteroscopy [Grossfeld, 2001, Rouprêt, 2013, Hurwitz 2014]. Urinary cytology correlates with the presence of urothelial carcinoma, but does not accurately predict the stage or grade of these respective tumors [Messer, 2011; Sverrisson, 2014]. Flexible ureteroscopy can assess the tumor, obtain tumor biopsy, and determine tumor grade in 95% of cases [Tavora, 2009; Rouprêt, 2013]. Multi-Detector Computed Tomographic Urography (MDCTU) is the gold standard for exploration of the upper urinary tract and has high sensitivity in the detection of small renal lesions [Scolieri, 2000].
trial title a phase 3
7.2. current treatment 7.2.1. surgical

Radical nephro-ureterectomy (RNU) with excision of bladder cuff (through either open or laparoscopic access) is the gold standard of care for upper tract urothelial cancer in patients with a normally functioning contralateral kidney [Lughezzani, 2010; Rouprêt, 2011; Cutress, 2012; Rouprêt, 2013]. RNU is indicated in cases of:
Upper ureteral and renal pelvic tumors, Infiltrating tumor on imaging,  
  
  
High-grade tumor, and Multifocality (with two functional kidneys).
trial title a phase 3
7.2.2. nephron-sparing procedures (nsp)

Conservative surgery, or first-line nephron-sparing procedures (NSP) for low-risk UTUCs allows preservation of the upper urinary and renal unit while sparing the patient the morbidity associated with open radical surgery. Conservative management of UTUCs can be considered in imperative cases (renal insufficiency or solitary functional kidney) or in elective cases (when the contralateral kidney is functional) for LG, low-stage tumors [O'Malley, 2009; Volanis, 2012; Cutress, 2012; Rouprêt, 2014]. Combining ureteroscopic biopsy grade, diagnostic imaging findings, and urinary cytology may help decision making on radical RNU versus NSP [Rouprêt, 2011; Rouprêt, 2014]. Recent recommendations have established selection criteria for NSP (i.e., LG biopsy, unifocal tumor <1 cm in diameter, complete resection possible, no evidence of parenchymal invasion on imagery, patients informed of and committed to the need for closer surveillance). Advances in imaging techniques, practice of systematic ureteroscopic biopsies, and development of preoperative prediction tools also allow for a better selection of candidates who would benefit from NSP [Colin, 2013]. Disease recurrence has been shown to be common after NSP (ranging between 26%–90%), which mandates a regular, close, lifelong follow-up of the upper urinary tract [Pak, 2009; Cutress, 2012; Colin, 2013; Kalaitzis, 2013]. The challenge of high recurrence rate and the (low) potential for progression following NSP often requires patients to undergo multiple resection procedures. Thus, in addition to clinical characteristics, the motivation, comprehension, and compliance of the patients are required [Cutress, 2012; Colin, 2013; Kalaitzis, 2013; Rouprêt, 2007; Rouprêt, 2013]. Nevertheless, as clinical stage and tumor grade are prognostic factors for recurrence and survival [Rouprêt, 2007], choosing the correct patient population for this treatment will increase the chances of treatment success and reduce the risk.  
In a retrospective review of a cohort of 57 patients treated conservatively and followed for a minimum of 2 years, the recurrence rate was 89.5%, with a mean of 5.5 recurrences per patient [Pak, 2009; Park, 2013). The average number of procedures per patient was 10.1, over a range of 5 to 41 months. The most conservative estimate of overall survival for UTUC treated with the current paradigm is 35%, for a cohort with an average age of 74 years with 35 months of follow-up, with progression of the UTUC as the cause of death in approximately 50% of the  
  
 patients [Krambeck, 2007). There are few reports that have evaluated the quality of life (QOL) in patients with UTUC, but it is apparent that patients with non-muscle invasive bladder cancer who were undergoing repeated transurethral resections had lower general health perceptions than normal cohorts [Yoshimura, 2005). It seems that in patients with LG, small-sized tumors have equal endpoints following endoscopic treatment as compared to RNU, with the advantages of minimal morbidity and preservation of renal parenchyma following endoscopic management [Singh, 2011; Rouprêt, 2013]. To date, however, only a few studies have reported long-term endpoints after NSP in UTUCs and strong data are lacking to assess definitively the cancer control allowed by this therapeutic strategy [Colin, 2013]. As it seems that a tumor-free status can be achieved only rarely, therapy for urothelial cancer in the upper urinary tract represents a significant unmet medical need [Volanis, 2012; Grasso, 2012; Kalaitzis, 2013].
trial title a phase 3
7.2.3. chemotherapy

Transitional cell tumors of both the upper and lower urinary tract are considered to be chemo-sensitive tumors. Intravesical Mitomycin C (MMC) therapy for lower urinary tract (bladder) transitional cell carcinoma has been used for more than two decades, as adjuvant therapy. Its use in upper tract (renal pelvis and ureter) transitional cell carcinoma has showed promise in terms of both efficacy and safety, but the number of published studies is limited, due to low incidence and prevalence of this type of tumor [Keeley, 1997].  
A variety of adjuvant topical chemotherapy studies demonstrated ability to reduce the risk of tumor recurrence in the UUT and in the bladder following UTUC operative treatments (both RNU and NSP). The optimal use of adjuvant chemotherapy, using MMC, Bacillus Calmette- Guérin vaccine (BCG), or cisplatin, is not defined yet [Elliott, 1996; Martinez-Pineiro, 1996; Sakamoto, 2001; Matin, 2010; O'brien, 2011; Kim, 2013; Rouprêt, 2013]. In addition, only a few neo-adjuvant systemic chemotherapy studies have been published to date, and they demonstrated some complete response (chemical ablation), a significant rate of down-staging, and significantly higher survival rates than surgery without neo-adjuvant chemotherapy [Matin 2010, Rouprêt 2013, Porten 2014]. Thus, the cumulative data provide justification for the additional clinical trials using improved adjuvant and neo-adjuvant chemotherapy strategies [Rouprêt, 2013; Audenet, 2013b].  
Difficulties in administering and maintaining MMC or other topical chemotherapeutic agents for sufficient time to the upper tract have limited their use for chemo-ablative purpose in patients with UTUC [O'Donoghue, 2004]. The improved efficacy of MMC following the  
  
  
increase in exposure time was established by numerous *in-vitro* models, *in-vivo* clinical studies, and computer simulations [De Bruijn, 1992; Sadeghi, 1998; Au, 2002]. Therefore, providing a means to prolong the duration of MMC intravesical treatment is imperative for enhancing the anti-tumor effect of the instilled MMC.  
Mitomycin C is inactivated by acid urine (Au et al. 2001). Therefore, the patients in this study will receive 1.3 gr of sodium bicarbonate 3 times prior to every instillation for alkalization of urine.
trial title a phase 3
7.3. investigational product mitogel™️ (tc-3

The investigational product is presented in MitoGel™ Kit comprising MMC for injection drug product (the active component), and TC-3 Sterile Hydrogel.  
MitoGel™ is initially prepared as a cooled liquid preparation; as a reverse thermal hydrogel, MitoGel™ subsequently solidifies at body temperature at the site of instillation in vivo, leading to the formation of a MMC containing gel-depot. As a result, the MitoGel™ provides prolonged exposure of UTUC tumors to MMC. Accordingly, MitoGel™ is envisioned to act as a chemoablative therapeutic product in the setting of UTUC. Studies reported in the literature indicate a direct correlation between anti-tumor activity and instilled MMC concentration and dwelling (exposure) time on treatment effectiveness [Deb, 2001; Eastham, 1993; Schmittgen, 1991; Wang, 2013].  
Prolongation of the MMC exposure time is expected to increase the drug efficacy over time while maintaining similar or lower systemic peak exposure, and therefore a good safety profile is expected. *In-vitro* models, *in-vivo* studies, clinical trials, and computer simulations have shown that enhancement of MMC activity may be achieved by increasing MMC dwelling time and drug concentration in the target tissue [Barlogie, 1980; De Bruijn, 1992; Nozue, 1995; Ozawa, 1998; Perry, 1992; Sadeghi, 1998; Schmittgen, 1991; Slee, 1986; Walker, 1986].  
Furthermore, owing to the nature of the TC-3 component of the MitoGel™, mixing with the drug and instillation via a standard ureteral catheter is relatively straightforward, as the unique thermo-sensitive properties enable it to convert from a liquid state when chilled, throughout the mixing with the drug and the instillation, into a semi-solid gel at body temperature inside the target organ.  
Following instillation of MitoGel™, MMC is efficiently released from TC-3 when the  
  
gel is dissolved by the urine [TheraCoat, 2014a, Report No. TAS-4M-P-A-133, Rev 3].  
 Preliminary studies provide in-vitro and in-vivo data that support the use of this formulation of sustained-release MMC. The release profile of MMC from MitoGel™ was evaluated in invitro studies.  
. The results of safety and performance tests reveal that TC-3 is biocompatible, poses no deleterious effect on the urothelium and does not obstruct ureters or urethra upon instillation and the subsequent solidification of the gel.  
Preclinical studies demonstrating low MMC plasma levels, well below the toxicity level, support the systemic safety of upper-tract instillation of MitoGel™. In a GLP toxicology study ( ), six weekly instillations of mL MitoGel™ to the upper urinary tract of at a total MMC dose of up to mg MMC (concentration of mg/mL) were not associated with any mortality, clinical findings, changes in body weights, ECG intervals or meaningful changes hematologic, coagulation, serum chemistry , urinalysis or urine chemistry endpoints, at any collection interval, up to and including the 4 weeks recovery period at the end of the instillation period.  
Analysis of plasma samples found that following retrograde instillation of MitoGel™,
systemic exposure (AUC0-10hr) and Cmax values of MMC increased with increasing dose in an approximately dose proportional manner on Days 1 (1st instillation) and 36 (last instillation). It should be noted that systemic exposure levels were significantly below report levels known to cause myelosuppression (threshold of 400 ng/mL).  
Macroscopic findings in the ureter of mild to moderate swelling/thickening and/or irregular surface were noted at necropsy following the last instillation in a dose dependent pattern. These corresponded to microscopic findings of edema and/or urothelial vacuolation. Four weeks following the last instillation, findings of mild swelling/thickening of the ureter were rare.  
Microscopic findings noted in the kidney were confined to the pelvis, involving the urothelium and submucosa. These findings included urothelial vacuolation, urothelial hypertrophy, and erosion; while edema, mixed leukocyte infiltrates, and hemorrhage were primarily found in the submucosa. Similar microscopic findings were noted mostly in the proximal ureter. The findings were similar in nature to the findings described in the literature for intravesicular MMC treatment. Microscopic findings trended towards resolution over the  
  
 recovery period, with decreased severity and incidence after the recovery phase. The microscopic findings were considered to be non-adverse, given the generally limited severity, the progression towards recovery, the lack of associated clinical or clinical pathology findings, the lack of systemic changes, and the localized nature of the microscopic findings.  
Based upon the results of this study, six weekly repeated administrations of MitoGel at a concentration of mg/mL ( mg MMC) was found to produce no adverse effects. Taken together, TC-3 Sterile Hydrogel appears to provide a safe drug retention and delivery system for MMC in the upper urinary tract.  
While MMC has been studied extensively and is routinely used in clinical practice for intracavital (as well as systemic) administration, the human experience with MitoGel™ is limited. As of July 2016, MitoGel™ has been used as compassionate use treatment in 18 patients for whom the remaining treatment alternative was removal of the affected kidney. Out of 18 recruited patients, 14 were classified as LG. To date, of the 14 LG UTUC patients (our target patient population for the pivotal trial), we noticed the following results:
- Eleven patients completed the 6 weekly instillations (the anticipated protocol in the planned pivotal trial)
- 10 patients were evaluable (one patient was only partially evaluable)
- Of these 10 patients, all patients have responded; 7 having reported complete responses
(CR) and 3 with partial responses (PR)
- 2 out of the 3 PR's were treated with low MMC concentration formulation of MitoGel
- Response durability evaluation is ongoing and encouraging The most commonly reported adverse events by patients was flank pain (n=6) or "fullness" sensation (5 patients) during the instillation procedure or during the period immediately following the instillation. These adverse events are believed to be associated with the instillation of the gel or insertion of the ureter catheter, and were generally mild or moderate and resolved without treatment. Three patients had acute Pyelonephritis (one of them with aggravation of chronic renal failure) which resolved following IV antibiotics. This event is a known and accepted AE in cases of upper tract manipulations. Other events reported which are believed to be related, or partially related to the MMC component of the investigational product is allergic reaction to Mitomycin, involving palmar and arm rash and pruritus (n=1), and cheek blush and swelling (n=1) and post instillation short single or recurrent febrile event (n=3), Nausea was reported in four patients and can be related either to upper tract manipulations or to  
  
 MMC itself. In addition, pancytopenia was evident in two patients: The first being an elderly previously polycythemic patient who received Hydrae (a myelosuppressant) concomitantly with the investigational product and the second patient underwent the following in the same treatment session: TURBT, immediate MMC instillation to the bladder and upper tract instillation with MitoGel which probably led to enhanced systemic absorption of MMC. Weakness, fatigue and dizziness could also be related to MMC component of MitoGel as well as a single case of bladder inflammation and upper tract inflammation. Both of which completely resolved.  
MMC mixed with TC-3 has also been studied as an ablative intravesical treatment in Non-
Muscle Invasive Bladder Cancer (NMIBC). While the different anatomy of the UUT may pose new challenges, the clinical data from the bladder instillations is relevant to support safety and efficacy of MMC in the upper tract, as it consists of a similar epithelial tissue and can provide some information with regard to the expected adverse events
trial title a phase 3
7.4. justification of trial design

The present trial is designed to evaluate the efficacy and safety of MitoGel™ administered to the UUT in patients with LG-UTUC.  
Only a few trials were performed with chemotherapy and endoscopic management in UTUC, and the trials differed one from each other in eligibility criteria, treatment specificities and results [Cutress, 2012; Ristau, 2012; Audenet, 2013a]. However, it can be collectively concluded that favorable population that benefit from elective endoscopic management have non-invasive LG disease characteristics [Cutress, 2012; Rouprêt, 2013]. Therefore, we chose to have naive or recurrent patients with LG, non-invasive UTUC, as the target population for this trial.  
There are only few publications on instillation of MMC as either adjuvant or neo-adjuvant therapy in the upper urinary tract [Hellenthal, 2009; O'Brien, 2011]. In the literature, the total dose for MMC instillation in the UUT ranges from 20 to 60 mg (with concentrations generally ranging from 1-2 mg/mL) [Keeley, 1997; Nepple, 2009; Aboumarzouk, 2013; Wang, 2013; Hurwitz, 2014].  
More data is available on instillation of MMC as adjuvant therapy for urothelial cancer of the bladder. Given the similarity of the disease and urothelial lining throughout the urinary tract, the experience with MMC in the bladder is informative and can be used to determine the  
  
 concentration of instillation in the UUT.  
The FDA has granted an orphan designation for MitoGel for "treatment of upper tract urothelial carcinoma (UTUC)". To date, UroGen have conducted over 250 instillations in the upper tract of , at three dose concentrations i.e., mg, mg and mg per mL, of the product in a GLP toxicology study evaluating the safety of the MitoGel™, simulating the intended regimen in the clinic at higher concentration, with each undergo 6 weekly instillations. This GLP regulated toxicity study was conducted in support of the IND
submission to the agency.  
The study concluded that even at the high concentration used, which are double than the one proposed in the clinical settings ( mg of MMC per mL of gel in the GLP study vs. 4mg of MMC per mL of gel in the human study) no toxicity has been observed (systemic or local).  
The dose selected for the UTUC patients in the phase 3 study is 4mg of MMC per mL of gel, to allow a safety margin, which was accepted by the FDA during pre-IND discussions.  
This safety data together with the clinical experience of using MitoGel™ in human subjects (over 60 instillations in 18 subjects collected from the Expanded Access Program) was found acceptable by the FDA in order to move forward with this study.  
In the current trial, the total dose to be instilled in patients will not exceed 60 mg MMC.  
The concentration of MMC in MitoGel™ will be 4 mg MMC/1 mL TC-3. This is similar to the dosage of MMC used for intravesical instillations and in post/peri-operative instillations in the UUT [Mohamed, 2011 (Smith's Textbook of Endourology, 2011 see page 291)]. Due to the inter-individual variability in the anatomy and volume of renal pelvis and calyces, the volume of the MitoGel™ for the instillation will be determined for each patient individually by the investigator. This will be based on volumetric estimation using retrograde pyelography for injecting the contrast agent (maximal volume required to fill the pyelocalyceal space). Based on clinical experience from the Expanded Access Program treatment in UTUC patients, it is estimated that between 5 and 15 mL of MitoGel™ should be sufficient for filling and even distribution of the gel within the renal pelvis and calyces.
trial title a phase 3
7.4.1. justification of single arm

This treatment protocol addresses an unmet medical need for an orphan indication. The standard treatment for UTUC requires either nephroureterectomy or endoscopic surgical resection. In this protocol the utilizing of a primarily non-surgical approach to the management  
  
 of UTUC is explored. In pre-IND discussions, the FDA has agreed with the single arm design of this trial. There is no comparable non-surgical "ablative" therapy to which MitoGel™ can be compared. In addition, MitoGel™ is indicated as a nephron sparing approach for patients who are currently candidates for RNU, therefore, neither equivalent control nor placebo arms are applicable or may be considered due to unethical reasons.
trial title a phase 3
7.4.2. justification of the trial

The primary efficacy endpoint is the rate of complete response (CR); i.e., a complete ablation of tumor lesions as a response to the chemotherapy treatment, which will be assessed during the primary disease evaluation (PDE) Visit. The PDE will occur at the pre-scheduled visit for endoscopic management treatment, set for 5 weeks following the last instillation (altogether, approximately 3 months from baseline). As tumors are not expected to disappear spontaneously, response can be attributed to the treatment, making the rate of CR an appropriate endpoint for a trial lacking a placebo control arm. For confirmation of therapeutic benefit, durability of ablation at 3 months post PDE has been chosen as a secondary endpoint. This time-point was chosen because recurrence within 3 months post-surgical removal of bladder lesions has been previously associated with the efficiency of the surgical procedure indicative of incomplete removal of the lesions rather than true recurrence. Therefore, a "second look" (clinical evaluation) at 3 months post Transurethral Resection of Bladder Tumor (TURBT), for example, is recommended in the guidelines [Kapoor, 2013; Rouprêt, 2013]. Durable CR at Month 3 post PDE in this trial will be taken to indicate a complete ablation of the tumor(s) and is thus expected to be indicative of the efficiency of the new treatment offered and a confirmation of efficacy. Accumulating evidence of recurrence rate and of time for recurrence post retrograde management varies significantly between different publications [Kapoor, 2013; Rouprêt, 2013]. In this trial, we will follow recurrence rate and time for 12 months post PDE, as exploratory endpoints.
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7.5. potential risks and benefits

Although literature review did not demonstrate any side effects associated with the systemic absorption when MMC was administered topically, bone marrow toxicity
(thrombocytopenia and leukopenia) and renal toxicity are considered possible risks for the  
  
 patients. The CBC, renal, and liver blood function will be checked regularly during the trial.
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allergic response to mmc

MMC (Kyowa) bladder instillations have been shown to cause allergic reactions in various toxicities in treated patients. Toxicities were found to be manageable most of the time by treating the patients with antihistamine drugs prior to and after the treatment. Allergic response will be closely monitored during the trial.
trial title a phase 3
cystitis

Cystitis and other bladder irritation symptoms secondary to UUT instillation of MMC may develop. Urine tests, including urine culture and urinalysis, will be checked regularly during the trial.
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uti and pyelonephritis

Aiming to minimize the risk for Urinary Tract Infections (UTI), especially Acute Pyelonephritis, anti-microbial prophylaxis should be prescribed according to the AUA Best Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxis (See Appendix VI);
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onset of renal insufficiency or

Although uncommon, treatment may cause impairment of renal function. Renal functions test will be checked regularly during the trial.
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7.5.2. potential benefits

This trial is potentially beneficial in several aspects:
It will evaluate a new mode of UTUC treatment, MitoGel™ for local therapy, that may prevail the drawbacks of the current UTUC topical treatment, It may entail good safety profile of MitoGel™ in UTUC patients.
trial title a phase 3
8. trial objectives 8.1. safety

To evaluate the safety and tolerability of the MitoGel™ Admixture in UTUC patients. To assess the pharmacokinetics profile of Mitomycin C (MMC) in plasma of a subgroup of patients treated with MitoGel™ Admixture.
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8.2. primary efficacy

To evaluate the tumor ablative effect of MitoGel™ Admixture in UTUC patients at PDE
visit.
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8.3. key secondary efficacy

To evaluate response durability at 12-months follow-up for subjects showing CR at PDE
visit
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8.4. secondary efficacy

To evaluate the durability of tumor ablative effect of MitoGel™ Admixture in patients who demonstrated complete response (CR) at the Primary Disease Evaluation (PDE) Visit, 3, 6 and 9 months following the PDE visit.  
To evaluate the overall clinical benefit to treatment with MitoGel™ admixture
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9. trial endpoints 9.1. safety

Study's safety endpoints include:
Adverse events and serious adverse events occurring at any time during the study, Laboratory tests, Physical and urology oriented examinations, Vital signs.  
In addition, pharmacokinetic (PK) profile of the first MMC instillation in the blood will be examined for the first six patients.
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9.2. efficacy endpoints 9.2.1. primary

Study's primary endpoint is Complete Response (CR) at the end of the treatment period
(PDE Visit). CR is defined dichotomously as "Success" if CR was confirmed at PDE visit (or relevant follow-up; see Figure 1 below), and "Failure" otherwise. There are a number of diagnostic scenarios for CR, which are described in the following figure.  
  
Gray boxes present final outcome S* = Success F** = Failure ^ = repeat cytology at 13 weeks, when subject returns for first post PDE instillation
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key secondary efficacy endpoint 9.2.2.

Long Term Durability of CR: This endpoint is defined only for those patients demonstrating CR at PDE visit. The endpoint is defined dichotomously as "Success" if CR was obtained at follow-up Visit 4 (12 months post PDE visit), and "Failure" otherwise.  
Figure 1:  Method for Determining Complete Response
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9.2.3. secondary efficacy endpoints

Durability of CR defined dichotomously as "Success" if CR was achieved at PDE visit and remained at follow-up Visit 1, Visit 2 and Visit 3 (3, 6 and 9 months post PDE
visit), and "Failure" otherwise. This endpoint is defined only for those patients demonstrating CR at PDE visit.  
Partial response at PDE visit will be defined dichotomously, similarly to the primary efficacy endpoint. For subjects with partial response at PDE visit, originally planned and actual treatments will be compared.
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9.3. trial design

The current trial is a prospective, open-label, single-arm phase III trial, designed to assess efficacy tolerability and safety of MitoGel™ treatment administered to the upper urinary tract.  
Upon signing of informed consent, the patients will undergo a screening visit for eligibility evaluation. Eligible patients with confirmed LG non-invasive UTUC will be treated with 6 once-weekly instillations of MitoGel™ in a retrograde fashion. Instillation through a nephrostomy tube may be an option, if necessary upon advising with the principle coordinating investigator.  
Determination of the eligibility of the entire patients and admission into the trial will be decided upon a case-by-case basis in consultation with the trial principle coordinating investigator (Dr. Seth Lerner). Patient relevant data will be sent by email to the Sponsor and images will be uploaded to a secure portal ( ). The patient's medical history, concomitant medications, pyelography imaging of the pyelocalyceal system anatomy, URS photos when available, local pathology and cytology results and all other relevant clinical records will be sent in un-identified manner. The entire patient information should be sent to the Sponsor no later than 7 working days from the screening visit and earlier if possible.  
The final eligibility will be approved by email from the sponsor to the site.  
MitoGel™ Admixture concentration to be used in this trial will be 4mg MMC per 1mL of TC-3 gel.  
The volume of the MitoGel™ Admixture to be instilled will be individualized, based on the volumetric estimation of the pyelocalyceal space using retrograde (antegrade if required) pyelography. To increase accuracy, an average of three (3) measurements will be the reference in case the number contains decimal fraction it should be round to the closest whole number. The pyelography procedure can be done at any time before the first instillation and in  
  
 accordance with the method of administration selected by the investigator. The measurements will be documented in each patient's study file and the volume required to fill the UUT will be recorded.  
Prior to every instillation, the treating investigator/designee must review the pyelocalyceal volume measurement recorded in the patient file and complete the designated MitoGel administration form which is provided by UroGen, with the required volume for instillation. The volume will be verified by site team observer. Both treating urologist and the observer will sign the administration form, thus confirming the correct volume will be instilled.  
Thereafter, the treating investigator/designee will withdraw the exact volume required into the syringe.  
Once instillation is completed, the investigator /designee who performed the instillation will complete the actual volume instilled and sign the administration form. The administration form will be filed in the study patient file. These steps will be repeated at each administration.  
Administration of MitoGelTM Admixture to the upper urinary tract shall be carried out while the patient is in Trendelenburg position and lies down on the side that is being treated to the extent that it is possible.  
Patients should remain in the clinic/hospital for at least 6 hours observation period following the first instillation procedure.  
Placement of a ureteral catheter for instillation of MitoGel™ should be performed as follow: 1. Cystoscopy should be performed in order to obtain screening of the urethra and the bladder for abnormal findings, 2. advance guidewire through the cystoscope working channel via the ureter to the renal pelvis, 3. anchor the guidewire in the renal pelvis and remove the cystoscope, 4. advance the ureteral catheter over the guidewire to the preferable location in the renal pelvis and take photos to document the location of the catheter tip. Preferable location will be considered as the place where the flow from the catheter tip of the investigational product will enable best coverage of MitoGelTM in the renal pelvis and the calyces. Fluoroscopy should be used to ensure proper placement of the catheter within the renal pelvis prior to instillation.  
The ablative effect of the MitoGel™ will be evaluated at the pre-scheduled ureteroscopy
(URS) (on PDE visit), performed 5 weeks after the last instillation. Response will be determined based on upper tract wash urine cytology followed by visual evaluation using  
  
 video-ureteroscopy (appearance, number, size, and location of the lesions), and histopathology of remaining lesions. A biopsy shall be performed for all remaining lesions where it is technically feasible. Cytology and histophathology slides will be reviewed by the local and the central pathology lab. The determination of degree of response and durability of complete response for trial analysis purposes will be based on the local lab readings.  
An independent Data Monitoring Committee (DMC) is assigned for this trial. Accumulated safety, tolerability, and efficacy data will be monitored periodically by the DMC according to the schedule and scope defined in the DMC charter. The DMC is established according to the FDA's Guidance (Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees; 2006).  
A trial steering committee is also assigned for this trial. In case of need the steering committee will initiate Ad hoc DMC meetings, and will review the DMC recommendations.  
A futility analysis will be conducted after N = 20 evaluable subjects have provided primary efficacy data. Results of the analysis will be provided to the data monitoring committee (DMC). The DMC will forward to the steering committee its recommendations and the steering committee will make the final determination regarding trial continuation. The accumulated study data at this stage will be shared with the FDA for the decision of study continuation and/or adaptation. Study will continue to enroll subjects as per study plan while discussions Agency is taking place.  
Safety will be determined based on physical examination, blood tests, vital signs, and a record of AEs. Any unexpected AE related to MitoGel™ and qualified per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) as grade 3 or 4 will be evaluated by the sponsor medical team and steering committee, see AE grading terminology in Appendix VIII: CTACAE 4.03 Severity Grades, and Allergic Reaction Grades.  
9.4. **Evaluation plan at PDE**
Tumor response to treatment will be evaluated during the PDE visit occurring 5 weeks after the last treatment. Please refer to Section 15 for a detailed description of response evaluation criteria:
Complete Response (CR) is defined as No Detectable Disease (NDD) and will be assessed visually during ureteroscopy (URS) and by upper tract washing urine cytology.
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9.4.1. cr patients maintenance instillations

A maintenance treatment will start immediately after the local lab confirms that patient's cytology is negative for cancer, and no longer than 2-3 weeks post PDE, unless there is a medical condition which require to postpone the treatment. In these cases, the first maintenance instillation should be delayed until recovery.  
Maintenance Regimen- MitoGel™ Admixture will be given once monthly (±2 week)
until one month prior to last FU visit within the study (i.e., until Month 11 post PDE).  
Safety assessment - During maintenance treatment at each instillation the patients will have performed in the hospital local lab, safety lab tests, physical examination and vital signs per protocol (see Appendix I - Appendix III). For patients who drop out of the study safety will be assessed according to the SOC.
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9.5. evaluation plan at follow-up

Patients will be followed-up for twelve months (12) or until disease recurrent or progression.  
Patient will be given the maintenance treatment with the study IP during the follow-up period, meaning that the same safety assessment will be done as written in the above section.  
Three (3) months after PDE, the first follow-up (FU) visit will be conducted. During this visit, follow-up data on disease outcome will be collected.  
Additional follow-up data on disease outcome will be collected for up to 12 months after PDE.  
Follow up data may be collected up to 3 years from PDE visit for all patients to evaluate long term safety and efficacy of the investigational product.  
Disease outcome to be recorded will include the following:
o Recurrence.  
o Progression defined as either change in stage according to the Tumor-Node-
Metastases (TNM) classification, or grade according to the 2004 WHO classification of tumors.  
Any intervention conducted to treat the UTUC will be recorded. AEs will be recorded according to the rules described in Section 19.
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9.6. central lab pathologist

Biopsy and UUT cytology slides will be sent to the central lab pathologist at the screening visit. Biopsy slides from PDE and FU visits will be sent to the central lab pathologist according to the findings of this visit. Cytology slides will be sent to the central lab in any of the above visits.
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9.6.1. general process & timelines

In case of low grade patient by local pathologist, and confirmation of eligibility by the investigator, biopsy and cytology slides should be shipped to the central lab no longer than 14 working days following the screening visit and after the site has received the eligibility confirmation by the Sponsor. Central lab results are expected to be emailed to the site and UroGen within no longer than 4 working days. The central lab should send the slides back to the site within 3 weeks of receipt. In case of contradiction between local diagnosis and central lab diagnosis, here are the steps to be taken:
1. *Study coordinator to forward the central lab report to the local pathologist* requesting repeated review.  
2. *Central lab findings provided to both physician and local pathologist* 3. Any change in physician diagnosis or treatment as a result of central lab findings will be recorded. At the same time, primary analysis will be based on initial determination based on site's local lab.  
In any case it is at the local PI judgment if to treat the patient within the study
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10. trial population and eligibility

Patients with LG, non-invasive UTUC lesions in the renal pelvis and calyces above the UPJ as determined by local lab.  
10.1. Inclusion Criteria 1. Patient has signed Informed Consent Form and is willing and able to comply with all requirements of the protocol.  
2. Patient is at least 18 years of age. 3. Naive or recurrent patients with LG, non-invasive UTUC in the pyelocalyceal system.  
4. Patient has at least one (1) measurable papillary LG tumor, evaluated visually, ≤ 15 mm.  
  
  
The largest lesion should not exceed 15mm.  
5. Biopsy taken from one or more tumors located above the ureteropelvic junction (UPJ)
showing LG urothelial carcinoma. Diagnosed not more than 2 months prior to the screening.  
6. Patient should have at least one remaining papillary LG tumor evaluated visually with a diameter of at least 5 mm.  
7. Wash urine cytology sampled from the pyelocalyceal system documenting the absence of HG urothelial cancer, diagnosed not more than 2 months prior to the screening 8. Patients with bilateral LG UTUC may be enrolled if at least one side meets the inclusion criteria for the trial and if the other kidney does not require further treatments (The other kidney can be treated prior to the beginning of the study).§
9. Patients with ECOG (Eastern Cooperative Oncology Group) performance status <3 (with Karnofsky >40).  
10. Patients with life expectancy greater than 24 months at time of screening. 11. Patients must have adequate organ and bone marrow function as determined by routine laboratory tests as below:
Leukocytes ≥3,000/μL (≥3×109/L), Absolute neutrophil count ≥1,500/μL (≥1.5×109/L),
Platelets ≥100,000/μL (≥100×109/L),
Hemoglobin ≥9.0 mg/dL,
Total bilirubin ≤1.5 upper limit of normal (ULN), AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal (ULN),
ALP ≤2.5 × institutional ULN,
Estimated glomerular filtration rate (eGFR) ≥30 mL/min, and In rare instances, the Principal Investigator may enroll patients whose laboratory screening values do not conform exactly to the levels outlined above but who, in the judgement of the local PI, the DMC and the coordinating PI, can be safely and ethically treated on protocol.  
12. Patient has no active urinary tract infection (UTI) as confirmed by urine culture or urinalysis*.  
13. Female Patients of childbearing potential**, must have a negative serum pregnancy test at screening and must agree to use two acceptable & effective methods of contraception***, until 6 months post treatment.  
14. All sexually active male patients must agree to use a condom during intercourse, for at least  
  
  
48 hours post each instillation.  
15. Male patients who have a partner that is a female of childbearing potential must agree to use two acceptable & effective methods of contraception until 6 months post treatment.  
16. Patients must not have any other medical condition(s) that make(s) their participation in the study unadvisable in the opinion of the investigator.  
(§ *; **; ***; see end of Exclusion Criteria)
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10.2. exclusion criteria

1. Patient received BCG treatment for UC during the 6 months prior to Visit 1.  
2. The patient has untreated concurrent urothelial cancer in other locations other than the target area (unless treated during screening)
3. Carcinoma in situ (CIS) in the past in the urinary tract. 4. Patient has a history of invasive urothelial carcinoma during the past 5 (Five) years. 5. Patient has a history of high grade papillary urothelial carcinoma in the urinary tract during the past 2 (Two) years.  
6. Patient is actively being treated or intends to be treated with systemic chemotherapy during the duration of the trial.  
7. Any other malignancy diagnosed within 2 years of trial entry with the exception of:
a. Basal or squamous cell skin cancers, or b. Noninvasive cancer of the cervix, or c. Any other cancer deemed to be of low-risk for progression or patient morbidity during trial period.  
8. Patient with urinary obstruction in a case of retrograde administration or administration not feasible via nephrostomy tube.  
9. Inability to deliver the investigational drug to the pyelocalyceal system. 10. Patient has any other medical or mental condition(s) that make(s) his/her participation in the trial unadvisable in the opinion of the treating urologist.  
11. Patient has contraindication to MMC treatment, or known sensitivity to MMC 12. Patient has an intractable bleeding disorder (e.g., coagulation factors deficiencies, Von Willebrand Disease).  
13. Patient is currently receiving any other investigational agents or has participated in a  
  
  
research protocol involving administration of an investigational product within the past 30 days prior to Visit 1.  
14. Patient previously treated with MitoGel™ for UTUC. 15. Pregnant (positive serum pregnancy test), planning to become pregnant during the trial period, breast-feeding, or of childbearing potential and not practicing reliable contraception***.  
16. Patient is non-responder to Mitomycin C as a chemical ablation agent for urothelial carcinoma. This criterion relevant only to patient who already participated in another UroGen's studies or any other relevant studies with chemical ablation efficacy endpoint.  
§ If both upper tracts meet inclusion criteria, the treating urologist in consultation with the sponsor can decide which side is to be treated within the trial. The other side should be treated as per standard of care, however if the other kidney treatment includes an intravesical instillations, the patient is not eligible. In any case, the other kidney must be free of cancer before the first instillation on the side to be treated in the clinical trial.  
* In case of a symptomatic UTI the patient will be treated with full course of antibiotics and the instillation will be postponed until resolution. In the case of asymptomatic bacteriuria, the use of prophylactic antibiotics and postponement of the treatment is left to the discretion of the PI.  
** Women of non-childbearing potential:
4. At least 12 months since the last menses, or 5. Without uterus and/or both ovaries, or 6. Has been surgically sterile for at least 6 months prior to trial drug administration.  
***Acceptable methods of birth control which are considered to have a low failure rate (i.e.,
less than 1% per year) when used consistently and correctly, such as implants, injectable, combined (estrogen/progesterone) oral contraceptives, intrauterine devices (IUDs-only hormonal), condoms with spermicide, sexual abstinence or vasectomized partner.
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11. investigational product (ip) -

Detailed information about the investigational product is found in the investigator brochure.
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11.1. mitogel™️ kit packaging and

All clinical supplies will be packaged (**Figure 2)**, labeled (**Figure 3-Figure 5**:) and shipped in compliance with cGMP and GDP. All trial provided IP will be appropriately documented (i.e., batch records, Certificate of Analysis, etc.).
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table 1 mitogel™️ kit components

| Component                             | Quantity (per Kit)                                                                 | Function                                            |
|---------------------------------------|------------------------------------------------------------------------------------|-----------------------------------------------------|
| Mitomycin for Injection, USP          | 2  40-mg vials                                                                    | Active Ingredient                                   |
| (vial) * TC-3 Sterile Hydrogel (vial) | 1  20-mL vial                                                                     | Sustained release medium Once Admixture ready to be |
| Blank MitoGel™ Admixture              | completed and affixed on the:                                                      |                                                     |
| 5                                     |                                                                                    |                                                     |
| Labels                                | Vial, Protective Bag, pharmacy  book, patient study file                           |                                                     |
| Light Protective Bag                  | 1                                                                                  | Protects MitoGel from light                         |
| MitoGel™ Admixture Syringe            | 1                                                                                  | To be affixed on the syringe at                     |
| Label                                 | the treatment area.  Instructions for MitoGel                                      |                                                     |
| Instructions for Pharmacy (IFP)       | 1                                                                                  | Admixture Preparation.                              |
| *                                     | USP = United States Pharmacopeia; The MMC is provided as a dry lyophilized powder. |                                                     |  
** The 20 mL of "TC-3 Sterile Hydrogel" is provided in a 25-mL glass vial.  
  
Figure 2: Sample of the Kit Box Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use
trial title a phase 3
mitogel™️ kit

UroGen Pharma Ltd., 9 Ha'Ta'asiya St., Ra'anana, Israel. Tel: +972-77-4171412 For instillation to the upper urinary tracts Each Kit contains Quantity per Kit Manufactured by **Component**
2 x 40 mg vials for UroGen Pharma Ltd. Mitomycin for Injection, USP (vial)  
  
1 for UroGen Pharma Ltd. Preparation Leaflet
5 for UroGen Pharma Ltd. Labels Rx only Storage: Retain the vials in the carton until use. Store the kit at 25°C (77°F), excursion permitted between 15°C (59°F) and 30°C (86°F). Avoid excessive heat (over 40°C, or 104°F). Once prepared as MitoGel™ Admixture, keep in the vial at room temperature and protected from light. Use the Instructions for Pharmacist leaflet while preparing the MitoGel™ Admixture.  
Packed for: UroGen Pharma Ltd. Packed by: Tel:
Kit Batch Number: Mfg Date: Kit serial Number:
* Format presentation. Data will be updated according to batches manufactured.
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figure 3 mitogel kit label

1 x 20 mL vial for UroGen Pharma Ltd. TC-3 Sterile Hydrogel (vial)
Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use  
  
  
Mitomycin for Injection, USP, 40 mg, for instillation to the upper urinary tracts when used in MitoGel™ Admixture Rx only Storage: Retain the vial in the carton. Store dry powder at 25°C (77°F), excursion permitted between 15°C (59°F) and 30°C (86°F), protected from light. Avoid excessive heat (over 40°C, 104°F).  
Mfd for: UroGen Pharma Ltd. 9 Ha'Ta'asiya St. Ra'anana, Israel.  
Tel: +972-77-4171412 Mfd by:  
  
  
Batch Number: Mfg. Date: MMMYYYY
Figure 4: Mitomycin for Injection, USP Label  
  
Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use TC-3 Sterile Hydrogel for instillation to the upper urinary tracts when used in MitoGel™ Admixture Volume: 20mL Storage: Store at 25°C (77°F), excursion permi (86°F). Avoid excessive heat (over 40°C, 104°F).  
Ingredients: Poloxamer P407, hydroxypropyl methylcellulose, polyethylene glycol 400, water for injection.  
Mfd for: UroGen Pharma Ltd. 9 Ha'Ta'asiya St. Ra'anana, Israel.  
  
Mfd by:
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figure 5 tc-3 sterile hydrogel

The components of the MitoGel™ Kit are produced under aseptic conditions and according to current Good Manufacturing Practice (GMP) (European Commission, May 2003 Guidelines) and FDA "Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice", September 2004.  
The MitoGel™ Kit lots used in this trial are tested and their release is supervised and approved by the UroGen QA Department.
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11.2.investigational product acquisition dispatch and

Initial clinical supply shipment will be sent automatically to sites in which the study was approved by their CA/IRB/EC, when the first patient at the site has been enrolled.
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11.2.2. shipment of clinical supplies

The Sponsor/designee will notify the Principal Investigator prior to shipment of drug supplies and other related clinical supplies regarding the anticipated date of their arrival at the pharmacy. Shipment will be sent directly to the delegated personnel at the pharmacy.  
All shipped clinical supplies will be appropriately documented to ensure proper handling in case of emergency.  
Shipment will be sent under controlled conditions. Transportation temperature will be monitored and recorded by temperature-monitoring devices loggers.  
Each shipment of clinical supplies for the trial will contain a certificate of analysis and a shipment certificate detailing the content of shipment.  
The pharmacist or study coordinator (in case of ancillary clinical supplies required for MitoGel instillation procedure) who receive the shipment will review the shipment items against the shipping certificate supplied to assure adequacy of shipment. In addition, the temperature logger will be read and the output will be printed for the pharmacy's records, assuring the shipment has arrived in good condition according to requirements. If all is OK, he/she will confirm receipt in the eCRF system
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11.2.3. mitogeltm kit storage and

The MitoGel™ Kit must be stored under controlled conditions and in accordance with applicable regulatory requirement(s) for cytotoxic substances.  
Retain the vials in the carton until use. Store the kit at 15-25°C (59-77°F). Avoid excessive heat (over 40°C, or 104°F). Once prepared as MitoGelTM Admixture, keep in the vial at room temperature and protect from light.  
The clinical supplies storage area at the site must be monitored by the site staff for temperature consistency with the above instructions. Documentation of temperature monitoring should be maintained at all times until study closure.
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11.2.4. mitogel™️ admixture stability and

Store the vial at 15-250C (59-770F). One hour before administration place in refrigerator, or in any other cooling apparatus at 2-80C (35-460F) to liquefy the MitoGel™ Admixture for the instillation. Keep protected from light. Avoid exposure to excessive heat (over 40°C, or 104°F)
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the mitogel should be instilled

A product quality complaint (PQC) is defined as any suspicion of a product defect related to manufacturing, labeling, or packaging, i.e., any dissatisfaction related to the identity, quality, quantity, durability, or reliability of a product, including but not limited to its labeling or packaging integrity.  
The impacted MitoGelTM Kit or ancillary supplies must be marked "not for use" and quarantined during investigation and until a decision has been made by the sponsor regarding the drug's validity. In case of MitoGel, the quarantined kits should be kept at the required temperature to allow future use if approval is received by quality assurance personnel of the sponsor. Reporting must be done upon first awareness, and the site should await the sponsor's written decision regarding the drug's validity prior to drug dispensing.  
PQC forms will be supplied to the site and pharmacy at trial start. In case of any temperature deviation, either during transport or storage at the pharmacy, or any problem (as specified above) with supplied clinical ancillary supplies (injector, catheters etc.), it is the site investigator's responsibility to assure the completed PQC is sent to the sponsor via email/fax immediately, to allow proper monitoring of complaints relating first, to patients safety, monitoring of site's supplies inventory.
trial title a phase 3
any pqc written report must

Following review of the quality complaint form, the sponsor will send written approval to allow the use of the affected Kit/s, or request for kit destruction. In case a kit should be destroyed, it will be disabled in the system by the site pharmacist or sponsor, and will not be available for dispensing.  
Product quality complaints may have an impact on the safety and efficacy of the product.  
Timely, accurate, and complete reporting and analysis of PQC information from clinical studies  
  
 are crucial for the protection of patients, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC information; all clinical studies conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
trial title a phase 3
11.3. mitogeltm admixture dosage preparation

MitoGel TM Admixture dose will depend on the patient's pelvicalyceal volume. MitoGel TM Admixture concentration will be 4mg/mL (4mg MMC in 1 mL of TC-3).  
Enrolled patients will receive 6 weekly instillations given in a retrograde fashion. CR patients will undergo additional, monthly maintenance instillations of the same concentration, up to 12 months following PDE visit.  
The volume of the MitoGel™ Admixture to be administered and thus, the final dose, will be individualized and will be based on volumetric measurements of the pyelocalyceal system using pyelography. For better accuracy, the volumetric measurement should be repeated 3 times. The volume of MitoGel™ Admixture instilled will be 100% of the measured pyelocalyceal system volume: average of the three measurements. The average of the three measurements is the instillation volume. In case the number contains decimal fraction, please round it as follows:
≥0.5 - round it up to the closest whole number.  
<0.5 - round it down to the closest whole number. The administered volume should be identical to the mean measured volume and will not exceed 15 mL (a maximum total dose of 60 mg MMC), whichever is lower (For detailed instillation instructions please refer to the IFU). The volumetric measurements should be documented in the source data and the CRF
trial title a phase 3
11.3.2. mitogeltm kit dispensing

The investigator or coordinator will be responsible for notifying the responsible person in the pharmacy ahead of time of the participants scheduled instillation visit.  
Prior to every treatment, investigator/coordinator will dispense MitoGel Kit in the EDC  
  
  
system ( ), obtaining the number of MitoGel kit to be withdrawn from the pharmacy stock.  
Withdraw of MitoGel TM Kit from inventory for the preparation of the MitoGel TM
Admixture will be done only after the investigator has provided designated prescription with patient details according to the trial specific supplied prescription, and supplied MitoGel kit number.  
In clinical sites using their own systems for ordering MitoGel Admixture (instead of UroGen supplied prescriptions for the trial) the drug order wording MUST be:
"Please dispense 1 vial of 4mg/ml MitoGel Admixture, according to the IFP" OR "Please dispense at least 17ml of 4mg/ml MitoGel Admixture, according to the IFP" OR In sites where the inclusion of exact volume is mandatory in the drug order the wording will be: "Please dispense 17ml of 4mg/ml MitoGel Admixture".  
The maximal volume to be administered to a patient is 15ml. The drug order should NOT request 15ml of MitoGel since the adjustment for the individualized volume will be done by the clinical team at the treatment center.  
The MitoGel™ Admixture will be dispensed only to authorized site trial personnel.  
Dispensing must be documented in the study accountability log.  
In case the instillation has been cancelled the pharmacist must document in the study accountability log that the Admixture was prepared but not dispensed to the patient.  
In case the instillation was cancelled after MitoGel™ Admixture was dispensed, it is the investigator responsibility to notify the pharmacy about the cancellation.  
Returned MitoGel™ Admixture must not be dispensed again, even to the same patient, and must be destroyed. MitoGel™ Admixture may not be relabeled or reassigned for use to other patients.  
In case MitoGel kit was dispensed in the EDC system but eventually was not opened/not used, and kit was kept at required storage conditions at the pharmacy, the MitoGel kit may be returned to the site stock but ONLY after coordination with Sponsor/Designee.
trial title a phase 3
11.3.3. preparation

MitoGel™ Admixture will be prepared according to the Instructions For Pharmacy (IFP)
document provided in the MitoGel™ Kit.  
When not using the trial-supplied labels, the MitoGelTM Admixture Vial label should  
  
  
contain at the minimum the following information:
<Trial Identifier, preferably TC-UT-03-P>
<Subject Identifier, preferably subject enrollment ID>
"MitoGelTM Admixture 4mg/ml (Mitomycin C 4mg per 1mL)
Kit Batch Number ___________
"For instillation to the upper urinary tract"
"Note: Maximum patient dose is 15mL (60mg) "Storage: Store up to 8 hours at room temperature protected from light"
"Caution: New Drug-Limited by Federal (or United States) Law to Investigational Use" Prep. Date:
Exp. Date and Time:
trial title a phase 3
mitogeltm admixture syringe label

Admixture label for the syringe is provided within the MitoGel kit. It must be used. The pharmacists can either complete or not complete it, but it must be sent to the site along with the Admixture vial. If not completed by the pharmacist, the syringe admixture label should be completed by the person withdrawing admixture from the vial into the syringe and affixed onto the syringe, prior to treatment.
trial title a phase 3
11.3.4. ip administration

MitoGel™ Admixture will be administered by study authorized person as documented in the delegation log and only after proper training was given regarding the instillation procedure.  
The pharmacy will dispense a 17-20 mL MitoGel™ Admixture for every instillation regardless of the individual volume required. Prior to every instillation, the treating investigator/designee must review the pyelocalyceal volume measurement recorded in the patient file and complete the designated MitoGel administration form which is provided by UroGen, with the required volume for instillation. The volume will be verified by site team observer. Both treating investigator/designee and observer will sign the administration form, thus confirming the correct volume will be instilled.  
Thereafter the treating investigator/designee will withdraw the exact volume required into the syringe.  
Once instillation is over, the treating investigator or designee who performed the instillation must complete the actual volume instilled and sign the administration form. The administration form must be filed in the study patient file. These steps MUST be repeated at each instillation.  
The Admixture will be instilled in a retrograde fashion via ureter catheter. In exceptional  
  
  
cases after approval by the trial coordinating PI, instillation through a nephrostomy tube may be conducted.  
Due to the viscose nature of the Admixture the instillation must be done using the designated Injector Device supplied by UroGen. For detailed instillation instructions please refer to the Instructions for Use (IFU) document as well as UroGen's Injector Device Instructions for Use Manuel.
trial title a phase 3
11.3.5. ip instillation schedule

MitoGel™ Admixture will be administered for therapy in the pyelocalyceal system as 6 once-a-week, consecutive instillations, at Weeks 1, 2, 3, 4, 5, and 6. Drug administration will be documented in the patient file, Case Report Forms (CRFs), and in the Drug Administration Records. For CR patients, additional instillations will be administered until 11M FU visit or until tumors' recurrence.
trial title a phase 3
11.4. ip accountability

The investigator is responsible for ensuring that all MitoGel™ Kits received at the site are inventoried and accounted for throughout the trial. The MitoGel™ Kit should be dispensed under the supervision of the investigator or a qualified member of the investigational staff, or by a hospital/clinic pharmacist. The dispensing of a MitoGel™ Admixture to a patient will be documented in the pharmacy drug accountability form or electronic drug accountability logs.  
The MitoGel™ Kit must be handled in strict accordance with the protocol and the container label, and must be stored at the site's secure drug room or Pharmacy at a limitedaccess area under appropriate storage conditions.  
Unused MitoGel™ Kits must be available for verification by the sponsor's site monitor during on-site monitoring visits. The return to the sponsor of unused or expired MitoGel™ Kits will be documented on the drug return form. Destruction of unused MitoGel Kits may be done on-site following written approval by the sponsor. Destruction must be documented in the "IP destruction form".  
Used (Empty) MitoGel TM vial or kit boxes should be discarded after use and will not be reviewed by the sponsor's site monitor.  
The investigator agrees to neither dispense the trial drug from, nor store it at, any site other than the trial sites agreed upon with the sponsor.
trial title a phase 3
11.5. replacement of unusable mitogel™️

Unusable MitoGel™ Kits will be marked "not for use" in pen over the label and stored separately from usable MitoGel™ Kits.  
In addition, unusable kits will be disabled in the EDC. Disabling of the kit will trigger shipment of replacement kit, in case kits are scarce at site.  
Site should also notify of the need for additional MitoGel kits to the site CRA and email the sponsor's operations: .
trial title a phase 3
11.6. assessment of ip compliance

At each treatment visit the actual dose administered will be documented in the Administration Form, which will be filed at the study file, and data recorded in the CRF, thus allowing monitoring of IP compliance.
trial title a phase 3
11.6.1. assessment of the other

At each treatment visit, the site team will check the compliance of the patients taking the bicarbonate and antibiotics and results will be recorded in the patient's file and in the CRF. The sites are requested to document the bicarbonate compliance on the supplied compliance log.  
Anti-histaminic drugs and relaxants are prescribed at the investigator's discretion therefore the data will be reviewed but not assessed for compliance.
trial title a phase 3
11.7. destruction of ip

Used MitoGel™ Kit vials should be discarded locally according to local institution guidelines for cytotoxic waste destruction.  
Unused MitoGel™ Kits must be available for verification by the sponsor's site monitor during on-site monitoring visits and will not be destroyed prior to Sponsor approval. Once destruction is approved, site will destroy the kit locally and will document it in the destruction form and accountability log.  
MitoGel™ Admixture vial and used syringe will be discarded at the clinic/urology department according to local institution guidelines for cytotoxic waste destruction
trial title a phase 3
12. safety evaluation

12.1. Safety Assessment Prior And During The Treatment Period: 12.1.1. Adverse Event Collection  
The patient's condition will be monitored throughout the study. At each visit, adverse events (AEs) will be elicited using a standard non-leading question, such as "How have you felt since the last visit?" In addition, any AE signs or symptoms that are observed will be documented; The AE/safety assessment will be conducted by the investigator or qualified clinical staff. The Investigator or qualified clinical staff will record the AEs on the Adverse Event Log provided in each patient's chart and CRF;
The study period for AEs collection is defined from the ICF signature and up to 30 days following the last administration of investigational product unless the AE is suspected to be related to the study treatment, in such case the AE should be reported regardless to the timelines of the reporting period (refer to section 19.2);
All AEs will be collected as follows:
o The patients' response to questions about their health, o Symptoms spontaneously reported by the patient to be recorded in the CRF,
o Clinically relevant changes and abnormalities observed by the Investigator (e.g.,
local and systemic tolerability, clinically significant laboratory measurements confirmed by repeated measurement, vital signs, results of physical examinations);
If an AE worsens in intensity, it should be recorded as a new AE. If an AE gets milder in intensity, it continues as the first report until the patient is recovered.
trial title a phase 3
12.1.2. action taken and follow-up

AEs requiring intervention must be treated according to the standard care procedures to protect the health and well-being of the patient. Appropriate resuscitation equipment and medicines must be available to ensure the treatment of an emergency situation.  
Treatment due to an AE will be recorded as concomitant medication.
trial title a phase 3
12.1.3. follow-up of aes

The investigator will follow up on each AE until it is resolved, until the medical condition of the patient is stable, or until the AE is otherwise explained by the PI. All relevant follow-up information will be reported to the sponsor. The outcome of an AE will be classified as recovered, recovered with sequelae, not yet recovered, or death.  
  
  
Adverse events will be reported according to Section 19- "Management of Adverse events".
trial title a phase 3
12.2. telephone contact 24-32 hours

For patients treated via retrograde fashion only:
After each instillation in the treatment period, the patient will be given a questionnaire with the questions, and will be notified that the site will contact him/her the day after to collect the answers. Questions are:
How long after the treatment did you have your first urination? How long after the treatment was the urine clear (no purple color) for the first time?  
Twenty-four (24) to 32 hours post each instillation, the patient will be contacted (via telephone) and information for the questionnaire will be collected answers will be completed and form will be signed by the site. At this point, any spontaneously reported adverse events will also be recorded. If necessary, a patient may be summoned for an unscheduled visit to follow up on any post treatment adverse event that requires clinical evaluation or follow-up. See Appendix IV.
trial title a phase 3
12.3. vas questionnaire - pain

Following each of the instillations 1-6 the patients will be requested to mark the degree of pain they felt during the IP instillation (and not during catheter insertion), in a VAS questionnaire 0-10 (100mm scale). The study coordinator than will measure with cm ruler from left to right and document the degree of pain in the patients' file and CRF [Wewers ME, Lowe NK, 1990].
trial title a phase 3
12.4. tests for assessment of

A pregnancy urine test will be conducted in female participants of childbearing potential in each of the study visit. If positive, a pregnancy blood test will be performed to verify. A female is considered of childbearing potential unless she is:
At least 12 months since the last menstrual bleeding; or Without a uterus and/or both ovaries; or Has been surgically sterile for at least 6 months prior to trial drug administration.
trial title a phase 3
12.4.2. clinical evaluation

At the specified visits, a full physical exam or urology-oriented physical exam will be performed. The patient's physical condition will be examined and documented. This includes examination of main body systems, with focus on the urinary system. Vital signs (including heart rate and blood pressure, temperature, and respiration rate) will be taken See **Appendix I** & **Appendix II**.
trial title a phase 3
12.4.3. laboratory assessments

All general blood and urine specimens will be analyzed by Local lab (**Appendix III** for the listing of tests). Blood samples for analysis of plasma level of Mitomycin (Pharmacokinetics) will be sent to the central PK lab (Appendix VII: Collection and Handling of Plasma Samples for MMC Pharmacokinetics).
trial title a phase 3
13. trial conduct and procedures

Pre-Screening stage- this stage in aiming to eliminate the screening of patients without the potential to meet the study criteria due to some complexity of their situation which can affect their compliance, and also to improve the adherence to the protocol procedures and timelines. This stage is very important due to the complexity of this protocol. The sites will be given a pre-screening questionnaire which they should fill-in in a timely manner and send it to the sponsor prior the consenting process.
trial title a phase 3
13.1. patient eligibility review and

Every patient must first sign the informed consent. In order to obtain screening number, the site will need to register the patient in the electronic CRF (eCRF).  
Soon after patient registration, the site will email to the site CRA and UroGen personnel and the de-identified source documents accompanied by completed submission form, **no later than 7 working days after the screening visit**. In addition, site will upload the Pyelography/CT/MRI images relevant for taking the eligibility decision to the secure . The documents and images must be patient de-identified (with no personal patient identifiers) prior to upload.  
Prior to the first instillation on Visit 1 (V1), patient eligibility to the trial must be confirmed by the sponsor. The sponsor will consult with the trial principle coordinating investigator (Dr. Seth Lerner) on a case by case basis and will notify the site investigator  
  
 via email about the patient's eligibility.  
Upon eligibility approval, the site will record the approval in the eCRF and will perform patient enrollment. Patient enrollment number will be given automatically by the CRF. Enrollment of patient into the trial must occur prior to the day of first instillation to allow enough time for kit dispensing via the EDC and preparation of the IP. Refer to section 23.2 for patient registration, and enrolment procedures.
trial title a phase 3
13.2. screening visit (v0) -4

Following the informed consent process and mutual signatures on the ICF, potential patients will undergo the following screening procedures:
**Review of eligibility criteria** and determination of the patient's eligibility based on patient file and medical history;
**Medical history** - Including specific information regarding previous recurrences of urothelial carcinoma in the bladder, urethra, ureter and in the UUT; including information about the Tumor stage, grade, morphology etc. (according to the documentation level in the CRF.);
The following documentation is required only for enrolled patients. **Default Planned**
UTUC Treatment **Documentation** had the patient not been enrolled in the trail;
**Smoking history** documentation (current smoker? Number of years, cigarettes per day, smoking stop date);
CTU - In the event that a CTU from the last 3 months is not available, or the one that is available does not reflect the current disease episode, or in the event that the investigator believes that an updated CTU in the screening will lead to a better tumor evaluation due to a patient's specific anatomy a new one should be obtained during the screening period; in the event that CTU is not applicable for any reason, an MRI should be performed instead.  
**Concomitant medication** - All ongoing medications/therapies, including prior therapies & procedures given for the previous urothelial carcinomas;
**General physical exam**, urology oriented physical exam, vital signs measurements
(**Appendix I & Appendix II**);
**Blood tests (Appendix III**);
Urinalysis and Urine Culture to rule out UTI
**Pregnancy serum test** (for women with childbearing potential **Appendix III**);  
  
 **Upper tract wash urine cytology** - The upper tract wash urine cytology can be collected using ureteroscope or ureteral catheter (wash), **before** any biopsy or topical treatment was done.  
**Biopsy for histopathology** - should be performed prior to recording tumor size and location.  
UUT urine cytology and biopsy need not be repeated if done within the past 2 months (or 3 months prior to the first instillation), provided the records can be made available for the trial and the slides can be reviewed by the trial central pathology service. In this case, patients should be scheduled for a Screening Visit, during which URS for lesions mapping (when it was not documented properly within 8 weeks to the screening), and documentation as well as pyelography and volumetric estimation will be performed as described above (if not done as part of the SOC before the screening). In the event that a patient has undergone surgical procedure in which the lesions were partially removed (i.e. de-bulking), the surgical procedure should be documented in the patient's medical history record; Diagnostic URS with C-ARM pyelography in order to demonstrate the pyelocalyceal system, by two views: 1. Superior view; 2. Oblique view in order to reveal hidden calyx / baseline UUT lesion assessment and videotape/photography record (if not done within past 2 months or if the documentation wasn't done according to the protocol requirements):
o Number, location (upper calyx, middle calyx, lower calyx, renal pelvis, UPJ), size by visual estimation (the longest diameter); the measurement shall be performed post biopsy.  
o Lesion appearance (visually described as papillary, solid, nodular, or sessile).  
Information must be recorded in the worksheet "UUT Lesion Documentation Form" provided by the Sponsor.  
o In case URS needs to be repeated at screening but the investigator does not wish to repeat the test due to medical considerations (e.g., general anesthesia), a CTU can be performed instead if this test can reflect the tumors status for the specific patient (e.g., tumors is bigger than 4mm)
Pyelography for assessment of the upper tract anatomy and volume measurement: The  
  
  
volumetric measurements of the "Pyelocalyceal System" (PS) should be performed under fluoroscopy and be documented. The "Contrast Agent admixture 20%" (CA) shall be injected to the PS, until the CA start to flow backwards below the UPJ. The estimated total volume to be injected may vary due to patient's PS anatomy. The volumetric measurements shall be repeated three times followed by mean calculation of the CA injected to the PS. MitoGel™ volume to be instilled to the PS shall be 100% of the measured PS or 15mL, whichever is lower. The volumetric measurement should be documented in the source data and the CRF;
If a single J in-dwelling ureteral catheter is to be used for instillation, catheterization can be done at any time during the screening period prior to treatment. In case that single J catheter remained in the pyelocalyceal system, reduce from the measurable volume 1 mL IP (dead volume) which is left in the catheter (e.g., measured volume is 11 mL the volume to be injected is 10mL). Following the instillation, the single J catheter should be flushed with 1.5mL of WFI in order to keep the catheter shaft open.  
The decision on whether to enroll patient into the trial will be based on the histopathology and cytopathology results obtained from the local institutional pathologist; however, all biopsies and urine cytology obtained at Screening/baseline (or earlier if within 2 months of screening) and at PDE will be reviewed again centrally. The results of the central reading will be used as a sensitivity analysis.  
The sponsor highly recommends to wait for the central review prior the beginning of any treatment administration to have a better confidence that the patient is having LG disease.  
Once all eligibility criteria have been confirmed, the patient will be registered into the trial by receiving an enrollment number. This should take place prior to treatment with sufficient lead-time to allow for preparation of the IP by the pharmacy; Patient should be prescribed with sodium bicarbonate in advance and should be given written instructions to consume 1.3 g of Sodium Bicarbonate the night before instillation, the morning of, and 30 min (total of 3.9 g) prior to the instillation, in case that patient is planned to be anesthetized, bicarbonate may not be taken 30 minutes prior to the treatment. If patient is enrolled, a reminder phone contact to the patient should be done the day before the instillation; Aiming to minimize the risk for Urinary Tract Infections (UTI), especially Acute  
  
  
Pyelonephritis, anti-microbial prophylaxis (e.g., Ciprofloxacin) should be prescribed according to the AUA Best Practice Policy Statement on Urologic Surgery Antimicrobial Prophylaxis (See Appendix VI: Recommended Antimicrobial Prophylaxis for Urologic Procedure);
Prophylactic anti-allergic treatment - Anti-histaminic agents to be taken the day before instillation, on the day of instillation and up to three days after the instillation; this treatment will be at the investigator's discretion.  
It is recommended to allow the patients using a relaxing pill such a diazepam 5-10 mg
(or any other relaxation pill) to reduce the anxiety before each of the instillations; Patient should be given patient guidance letter for UUT MMC-TC-3 Gel instillation. Patient should be provided with a patient card with treatment information and investigator details to be contacted in case of an emergency; Patient should be provided with a letter notifying his general physician about his participation in the study.
trial title a phase 3
13.3. treatment visits

The pharmacy should be notified ahead of time regarding the required preparation of MitoGel™. Prescription signed by the investigator must be provided ahead.