Conditions: Bladder Cancer
Keywords: Non-invasive bladder cancer Chemophase Intravesical administration Superficial Bladder Cancer
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 27
Healthy volunteers: no

Brief summary:
The purpose of this study is to explore a treatment that potentially enhances the delivery of chemotherapy to tumors in participants with superficial bladder cancer. The investigational medication to be studied is an enzyme called ChemophaseTM (recombinant human hyaluronidase, rHuPH20). Chemophase is being specifically developed for use with other anticancer drug to increase the local penetration of the anticancer drug for the treatment of superficial bladder cancer. In this study, Chemophase will be given in combination with mitomycin C directly into the bladder. Mitomycin C is an anti-tumor drug that is commonly used to treat superficial bladder cancer. It is envisioned that Chemophase with mitomycin C may potentially increase the local penetration of mitomycin C into remaining cancer cells following surgery to treat superficial bladder cancer.

Detailed description:
The primary objectives of this study are to:

1. determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of escalating doses of Chemophase in combination with mitomycin (mitomycin C, MMC) administered as weekly intravesical instillations for five weeks, and
2. establish the dose of Chemophase with MMC recommended for future studies.

The secondary objectives of this study are to:

1. assess the pharmacokinetics of intravesical administration of MMC alone and in combination with intravesical administration of Chemophase,
2. for those participants treated at the MTD, assess the safety and tolerability of intravesical administration of MMC with Chemophase over up to 7 additional maintenance treatments every 3 months following the initial six weekly instillations, and
3. observe participants for any preliminary evidence of anti-tumor activity of MMC and Chemophase when combined.

Study participants will receive six weekly study treatments administered intravesically (at Weeks 1 through 6) followed by post-treatment evaluations, at Weeks 8 and 12. The 12 participants treated at MTD will continue to receive combination therapy every three months until the end of Year 2 or until the time of documented tumor recurrence, whichever occurs first. For other participants, long-term follow-up after Week 12 will consist of disease monitoring of participants by telephone and will be performed every three months beginning three months after last study treatment for two years and then every six months thereafter, until bladder tumor recurrence.

Arms:
arm 1: Participants will receive 40 milligrams (mg) MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 20,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 2: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 60,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 3: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 200,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 4: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 400,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 5: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 800,000 U Chemophase intravesically once weekly from Weeks 2 through 6.

Interventions: intervention 1: Mitomycin C intervention 2: Chemophase
Intervention descriptions: intervention 1: intravesical administration intervention 2: intravesical administration

Protocol document:
Prot_000.pdf: 
Halozyme Therapeutics, Inc. 
Protocol HZ2-05-01 
CONFIDENTIAL 
Page 1 of 89 
Version 4.0  26 Feb 2009 
Clinical Trial Protocol 
Title: 
A Phase I-IIa, Multicenter, Open-Label, Multiple Dose, 
Safety, Tolerability and Pharmacokinetic Study of 
Recombinant Human Hyaluronidase (Chemophase) 
in Combination with Mitomycin in Patients with Non-
Muscular-Invasive Bladder Cancer 
Protocol Number: 
HZ2-05-01 
Version Number: 
4.0 
Version Date: 
26 February 2009 
Supersedes: 
Version 3.0, 30 April 2007 
Version 2.0, 17 March 2006 
Version 1.0, 29 August 2005 
Sponsor: 
Halozyme Therapeutics, Inc. (Halozyme) 
11588 Sorrento Valley Road, Suite 17 
San Diego, California  92121 
Tel:  
 
This document and the information it contains is the property of Halozyme Therapeutics, Inc. 
and is provided for the sole and exclusive use of Investigators of this clinical investigation. 
The information in this document may not be disclosed unless such disclosure is required by 
Federal or applicable State Law or Regulations or unless there is prior written consent from 
Halozyme Therapeutics, Inc. Subject to the foregoing, this information may be disclosed only 
to those persons involved in the clinical investigation who have a need to know, and who 
share the obligation not to further disseminate this information. 
NCT # NCT00318643


Halozyme Therapeutics, Inc. 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS.............................................................................................. 2 
Tables ..................................................................................................................... 5 
Figures .................................................................................................................... 5 
1. 
STUDY SYNOPSIS ............................................................................................. 6 
2. 
STUDY SCHEDULE OF EVENTS .................................................................... 12 
3. 
GLOSSARY AND ABBREVIATIONS .............................................................. 15 
4. 
BACKGROUND AND RATIONALE ................................................................ 16 
4.1. 
Introduction to Hyaluronidases, rHuPH20, and Chemophase ..................... 16 
4.2. 
Background on Non-Muscular-Invasive Bladder Carcinoma ......................... 17 
4.3. 
Rationale for Use of Chemophase in Bladder Cancer .................................... 19 
5. 
STUDY OBJECTIVES ....................................................................................... 23 
5.1. 
Primary Objectives ...................................................................................... 23 
5.2. 
Secondary Objectives .................................................................................. 23 
6. 
STUDY DESIGN ............................................................................................... 24 
6.1. 
Overview of Study Design ........................................................................... 24 
6.2. 
Number of Patients...................................................................................... 25 
6.3. 
Patient Recruitment ..................................................................................... 25 
6.4. 
Treatment Summary .................................................................................... 26 
6.5. 
Study Duration ............................................................................................ 27 
7. 
STUDY POPULATION ..................................................................................... 27 
7.1. 
Inclusion Criteria......................................................................................... 27 
7.2. 
Exclusion Criteria ....................................................................................... 28 
7.3. 
Prohibitions and Restrictions during the Study ............................................. 29 
7.4. 
Contraindications, Warnings and Precautions with Regard to MMC 
Administration ............................................................................................ 29 
8. 
STUDY METHODS AND PROCEDURES ........................................................ 30 
8.1. 
Designated Laboratories:  Central, Local, PK, and Biomarker Labs............... 30 
8.2. 
Procedures Prior to Screening (Day -28 to Day -1) ....................................... 31 
8.3. 
Screening Procedures (Day -28 to Day -1).................................................... 31 
8.4. 
Patient Registration and Replacement of Patients ......................................... 33 
8.5. 
Patient Randomization Procedures and Blinding........................................... 34 
8.6. 
Treatment Procedures on Day 1/Week 1....................................................... 34 
8.7. 
Treatment Procedures Week 2 through Week 6 ............................................ 35 
8.8. 
Dose-Limiting Toxicity (DLT) .................................................................... 36 
8.9. 
Escalation to Next Dose Cohort, Stopping Rules, and Determination of MTD 37 
8.10. 
Premature Termination of Treatment/Withdrawal of Patients .................... 39 
8.11. 
Post-Treatment Procedures at Week 8 ...................................................... 39 
8.12. 
Post-Treatment Procedures at Week 12 .................................................... 40 
8.13. 
Long-Term Maintenance Therapy and Follow-Up (Following Week 12) ... 41 
9. 
STUDY MEDICATIONS AND ADMINISTRATION......................................... 42 


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9.1. 
Mitomycin (Mitomycin C, MMC)................................................................ 42 
9.1.1. 
Supply of MMC................................................................................... 42 
9.1.2. 
Storage and Stability of MMC .............................................................. 43 
9.1.3. 
Procedures for Proper Handling and Disposal of MMC ......................... 43 
9.1.4. 
Preparation of MMC for Intravesical Instillation ................................... 43 
9.2. 
Chemophase (rHuPH20).............................................................................. 44 
9.2.1. 
Formulation and Supply of Chemophase............................................... 44 
9.2.2. 
Storage and Stability of Chemophase.................................................... 44 
9.2.3. 
Preparation of Chemophase for Intravesical Instillation ......................... 44 
9.3. 
Dosing Schedule and Procedure for Intravesical Instillation of MMC with and 
without Chemophase ................................................................................... 46 
10. 
ADVERSE EVENTS AND SAFETY MONITORING ..................................... 48 
10.1. 
AE Definitions ........................................................................................ 48 
10.2. 
Pre-Treatment-Emergent Adverse Events ................................................. 50 
10.2. 
Laboratory Abnormalities as Adverse Events ........................................... 50 
10.3. 
Classification of Adverse Events by Severity............................................ 51 
10.4. 
Classification of Adverse Events by Relationship to Study Drug 
Administration ........................................................................................ 51 
10.5. 
Known Toxicity Profiles of MMC and Chemophase ................................. 53 
10.5.1. 
Known Toxicity Profile of MMC ......................................................... 53 
10.5.2. 
Known Toxicity Profile of Chemophase ............................................... 55 
10.6. 
Reporting of Adverse Events ................................................................... 56 
10.6.1. 
Reporting of Serious Adverse Events.................................................... 56 
10.6.2. 
Duration of Follow-Up of Adverse Events ............................................ 57 
10.6.3. 
Other Information on t he Reporting of Adverse Events ......................... 57 
10.6.4. 
Reporting of Safety Information to the Institutional Review Board ........ 58 
10.7. 
Pregnancy ............................................................................................... 58 
10.8. 
Concomitant Medications and Procedures ................................................ 58 
11. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................... 59 
11.1. 
Study Hypotheses .................................................................................... 59 
11.2. 
Patient Data Sets for Analysis .................................................................. 60 
11.3. 
Endpoints and Statistical Analyses ........................................................... 60 
11.4. 
Sample Size Considerations ..................................................................... 61 
11.5. 
PK Analyses and Neutralizing Antibodies to rHuPH20 ............................. 61 
12. 
REGULATORY/ADMINISTRATIVE PROCEDURES AND 
DOCUMENTATION...................................................................................... 61 
12.1. 
Ethics ...................................................................................................... 61 
12.2. 
Institutional Review Board and Approval ................................................. 62 
12.3. 
Informed Consent .................................................................................... 63 
12.4. 
Laboratory Accreditation ......................................................................... 64 
12.5. 
Drug Accountability ................................................................................ 64 
12.6. 
Protocol Compliance and Protocol Deviations .......................................... 65 
12.7. 
Protocol Amendments ............................................................................. 65 
12.8. 
Data Collection and Case Report Forms ................................................... 66 
12.9. 
Study Initiation, Monitoring and Closeout Visits and Reports ................... 66 


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12.10. 
Study Documentation and Retention of Records ....................................... 68 
12.11. 
Investigator’s Final Report....................................................................... 69 
12.12. 
Financial D isclosure ................................................................................ 69 
12.13 
Disclosure of Data and Publication........................................................... 69 
13. 
REFERENCES ............................................................................................... 70 
14. 
APPENDICES ................................................................................................ 71 
Appendix A. TNM Staging of Bladder Cancer ........................................................ 72 
Appendix B. Karnofsky Performance Status ........................................................... 74 
Appendix C. United Stages Package Insert for Mitomycin....................................... 75 
Appendix D. Canadian Package Insert for Mitomycin ............................................. 76 
Appendix E. United Kingdom Summary of Product Characteristics for Mitomycin .. 84 
 


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Tables 
 
Table 6.1-A. Dose Cohorts ......................................................................................... 24 
Table 9.2-A. Volume of Chemophase Withdrawn from Vial for Intravesical 
Administration ........................................................................................................... 45 
Table 9.3-A. Dosing Schedule for MMC and Chemophase .......................................... 47 
Table 10.5-A. Probability Estimates of Treatment Complications from Intravesical MMC
 .................................................................................................................................. 54 
 
 
Figures 
 
Figure 8.9-A. Flow Diagram of Dose Escalation Schema ............................................. 38 
 


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1. 
STUDY SYNOPSIS 
  
Protocol No. 
HZ2-05-01 
Study Title 
A Phase I-IIa, Multicenter, Open-Label, Multiple Dose, Safety, Tolerability 
and Pharmacokinetic Study of Recombinant Human Hyaluronidase 
(Chemophase) in Combination with Mitomycin in Patients with Non-
Muscular-Invasive Bladder Cancer 
Sponsor 
Halozyme Therapeutics, Inc. (Halozyme) 
11588 Sorrento Valley Road, Suite 17 
San Diego, CA  92121 
Office: 
 
Primary 
Objectives 
• 
Determine the maximum tolerated dose (MTD) and dose-limiting toxicities 
(DLTs) of escalating doses of Chemophase in combination with mitomycin 
(mitomycin C, MMC) administered as weekly intravesical ins tillations  for 
five weeks 
• 
Establish the dose of Chemophase with MMC recommended for future 
studies 
Secondary 
Objectives 
• 
Assess the pharmacokinetics of intravesical administration of MMC alone 
and in combination with intravesical administration of Chemophase 
• 
For those patients treated at the MTD, assess the safety and tolerability of 
intravesical administration of MMC with Chemophase over up to 7 
additional maintenance treatments every 3 months following the initial six 
weekly instillations. 
• 
Observe patients for any preliminary evidence of anti-tumor activity of 
MMC and Chemophase when combined 
Study Design 
Phase I-IIa, open-label, multicenter, dose-escalation, safety, tolerability and 
pharmacokinetics study. Long-term follow-up information will be collected to 
help make a preliminary assessment of possible anti-tumor activity. 
Study 
Medications 
• Chemophase (hyaluronidase, human recombinant; rHuPH20) 
• Mitomycin (Mitomycin C, MMC) 
Duration 
Study patients will receive six (6) weekly study treatments (at Weeks 1 
through 6) followed by post-treatment evaluations, at Weeks 8 and 12. The 12 
patients treated at MTD will continue to receive combination therapy every 
three months until the end of Year 2 or until the time of documented tumor 
recurrence, whichever occurs first. For other patients, long-term follow-up 
after Week 12 will consist of disease monitoring of patients by telephone and 
will be performed every three (3) months beginning three months after last 
study treatment for two years following day 1 or until bladder tumor 
recurrence, whichever occurs first.  
Patient 
Population 
Patients with initial pr esentation or recurrence of Stage Ta , T1 or Tis, any 
grade, bladder cancer after TURBT 


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Planned Total 
Sample Size 
Up to 36 evaluable patients will be enrolled. It is anticipated that no more than 
a total of 44 patients will need to be enrolled. An evaluable patient is one who 
receives all protocol-specified six weekly intravesical treatments with at least a 
90-minute retention and has had MMC plasma concentration determinations 
and safety assessments adequate for the determination of tolerability. Patients 
not meeting these criteria, including those withdrawn prematurely for reasons 
other than toxicity, will be replaced. Groups of either 3 or 6 patients will 
participate in each of the five individual dose cohorts in the dose escalation 
phase of the study. Once the MTD has been established, 6 additional evaluable 
patients will be enrolled at the MTD dose level, yielding a total of 12 evaluable 
patients at MTD upon which to confirm safety and tolerability of the MTD 
regimen. 
Intravesical 
Administration, 
Dose-Escalation 
Scheme, and 
Stopping Rules 
 
Cohort 
Week 1 Dosing 
Weekly Dosing Week 2 through Week 6 
1 
MMC 40 mg/20 mL 
  20,000 U Chemophase with MMC 40 mg/20 mL 
2 
MMC 40 mg/20 mL 
  60,000 U Chemophase with MMC 40 mg/20 mL 
3 
MMC 40 mg/20 mL 
200,000 U Chemophase with MMC 40 mg/20 mL 
4 
MMC 40 mg/20 mL 
400,000 U Chemophase with MMC 40 mg/20 mL 
5 
MMC 40 mg/20 mL 
800,000 U Chemophase with MMC 40 mg/20 mL 
 
A dose-limiting toxicity (DLT) is defined as either (a) plasma MMC 
concentration ≥ 100 ng/mL, (b) National Cancer Institute (NCI) Common 
Terminology Criteria (CTC) (Version 3 or current version) AE Grade 3 or 
higher toxicity, or (c) new, treatment-emergent diagnosis of bladder fibrosis.  
 
Each intravesical administration will remain in the bladder for two hours after 
instillation. In each cohort, at Week 1 patients will receive MMC 40 mg alone 
(without Chemophase) in 20 mL of sterile water. If no DLT is observed prior 
to Week 2, this first treatment will be followed by five weekly intravesical 
instillations (at Weeks 2 through 6) of Chemophase at the dose specified by the 
assigned cohort followed by MMC 40 mg in 20 mL of sterile water. 
 
All 3 patients within a given cohort may begin treatment simultaneously. The 
next higher dose cohort can be immediately opened for patient enrollment if, at 
the time all 3 patients in a given cohort have completed the fourth (4th) 
instillation of MMC (i.e., third instillation of MMC plus Chemophase), there 
is: 
• 
no NCI CTC adverse event Grade 2 or higher toxicity,  
• 
no MMC plasma concentration ≥ 100 ng/mL, and  
• 
no new, treatment-emergent, diagnosis of bladder fibrosis. 
Note that an NCI CTC adverse event Grade 2 toxicity will delay opening the 
next higher dose cohort to enrollment until safety data are reviewed from all 
six
Because this study is being conducted at more than one study center, the 
enrollment of patients, assignment to cohorts, and opening of each sequential 
cohort will be controlled centrally for all study centers by Halozyme. Each 
time a new patient is consented for the study, the study center must 
 weekly instillations for all 3 patients in that cohort. 
 




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• Absolute neutrophils count (ANC) ≥ 2,500 cells/mm3,  
• Platelet count ≥ 150,000/mm3, and  
• Hemoglobin ≥ 10.0 g/dL. 
10. Urinalysis showing no clinically significant abnormalities except those 
attributable to bladder cancer. 
11. For men and women of child-producing potential, agreement to use an 
effective contraceptive method during the treatment period of the study. 
12. Signed, written IRB-approved informed consent. 
Exclusion 
Criteria 
1. History or previous diagnosis of bladder fibrosis. 
2. Total bladder capacity estimated at cystoscopy to be < 150 mL. 
3. Urinary incontinence of a severity that would compromise the ability of 
the patient to retain the study drug intravesical instillation for two hours. 
4. Severe irritative voiding symptoms such as urgency, frequency, or 
nocturia. 
5. Known other malignant disease except squamous or basal cell skin cancer 
unless the malignancy has been in complete remission off therapy for at 
least 5 years. 
6. Major surgery, other than TURBT and diagnostic surgery, within 28 days 
prior to Day 1/Week 1. 
7. Active, uncontrolled bacterial, viral, or fungal infections, including 
urinary tract infection. 
8. Treatment with radiation therapy, surgery, chemotherapy, or 
investigational therapy within one (1) month prior to Day 1/Week 1 on 
study (two [2] months for nitroureas or MMC), unless given as standard 
treatment for bladder cancer and provided that patient is free of all 
treatment-related toxicities as of Day 1/Week 1. 
9. Known infection with HIV. 
10. Known active infection with hepatitis B or hepatitis C. 
11. Serious disease (e.g., hydronephrosis, liver failure, or other conditions) 
that could compromise protocol objectives in the opinion of the 
Investigator and/or the Sponsor (Halozyme). 
12. History of a hypersensitivity or idiosyncratic reaction to, or other 
contraindication to, mitomycin. 
13. Known allergy to bee or vespid venom. 
14. Known coagulation disorder or bleeding tendency.  
15. Treatment with heparin or anticipation of heparin treatment during the 
treatment period in this study.  
16. Unwillingness or inability to comply with procedures required in this 
protocol. 


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Therapy 
Prohibited 
During Study 
The following therapies are prohibited from the time of enrollment through 
Week 12 of the study: 
• treatment with heparin, 
• any intravesical therapy except for MMC and Chemophase, and 
• any potentially myelosuppressive therapy.  
For the MTD patients who are receiving continued study drug treatments after 
Week 12, the following therapies are prohibited for the duration for study drug 
treatment: 
• any intravesical therapy except for MMC and Chemophase, and 
• any potentially myelosuppressive therapy.  
Pre-Study, 
Standard of 
Care, 
Procedures  
• 
Transurethral resection of bladder tumors (TURBT), with cystoscopy and 
estimate of bladder capacity 
•    Intravesical standard of care therapy, if indicated 
•    Histopathology report 
Safety and 
Efficacy 
Assessments 
•    Signed informed consent 
• 
Karnofsky performance status 
•    Complete medical history  
•    Detailed urologic history 
• 
Physical examination 
•    Vital signs 
• Concomitant medication assessment 
• 
Pregnancy test (women of child-bearing potential) 
• 
CBC w ith differential 
• 
Clinical c hemistries 
•    Urinalysis and urine dipstick evaluation 
• 
Urine biomarkers (NMP22®BladderChek® Test and UroVysionTM) 
• 
Electrocardiogram, 12-lead 
•    Adverse event collection/toxicity assessment 
•    Blood collection for assay of levels of MMC and rHuPH20, and 
neutralizing antibodies to rHuPH20 
• Cystoscopy, with estimate of bladder capacity, urine cytology 
• Long-term follow-up disease monitoring 
 


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Data Analysis 
This is a Phase I-IIa study of Chemophase in humans, and is not powered for 
formal statistical comparisons. The sample size of 3 to 6 patients per dose 
cohort is standard for the determination of safety and tolerability in many 
initial c linical trials for oncology indications. Once the MTD has been 
established, 6 additional evaluable patients will be enrolled at the MTD dose 
level, yielding a total of 12 evaluable patients at MTD upon which to confirm 
safety and tolerability of the MTD regimen. It is believed that 12 patients will 
provide an adequate sample size to establish the tolerability of this dose 
regimen for subsequent clinical trials and possibly provide a preliminary 
estimate of anti-tumor activity. 
 
The primary endpoint in this study is the rate of toxicities observed with the 
combination of Chemophase and MMC. The primary statistical analysis will 
consist of point estimates and the 95% confidence intervals constructed around 
the point estimates. All safety data will be examined, such as adverse event s 
(including overall incidence by treatment group), physical examination 
findings and vital signs, laboratory data, plasma MMC concentration, and 
ECGs. Descriptive statistics will be used to summarize all safety variables. The 
MTD will be determined based on DLTs. 
 
Based on the long-term follow-up monitoring, the data will be assessed for the 
median time to tumor recurrence, and the one-year, two-year, etc. rate of 
recurrence. Recurrences will be characterized with regard to the number of 
tumors, TNM stage, and grading. Information on tumor progression will be 
summarized. The data collected on the urine biomarker, comparing baseline to 
Week 8 values, will be summarized.  
PK 
Assessments 
Blood samples for assay of rHuPH20 (Weeks 2 & 6:  predose and 1, 2, and 3 
hrs postdose), MMC (Weeks 1, 2, 5 & 6:  predose and 1, 2, and 3 hrs postdose) 
and neutralizing antibodies to rHuPH20 (Weeks 1 & 6; will only analyze 
Week 1 if Week 6 assay is positive).  




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1. Required prior to any protocol-specified activities and before consenting patient for screening. 
2. TURBT, along with cystoscopy and estimate of bladder capacity performed within Day -42 to Day -1 (i.e., TURBT must be done no more than 
42 days prior to Day 1) 
3. Bladder capacity will be estimated at the time of cystoscopy. For the baseline study prior to Day 1, the cystoscopy performed at the time of 
TURBT is acceptable. There must be a urine cytology for Screening collected more than 5 days after the TURBT and within two weeks prior to 
the date of enrollment in this study. 
4. In women of child-bearing potential. 
5. CBC, chemistries and urinalysis must be performed within 7 days prior to Day 1, Week 1. 
6. CBC at these Week 1 through Week 6 visits must be performed and results known prior to each study drug administration 
7. Clinical chemistries consist of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, glucose, albumin, total protein, 
uric acid, phosphorus, AST, ALT, alkaline phosphatase, GGT, total bilirubin, and creatine kinase. 
8. Results of urine dipstick showing no evidence of urinary tract infection must be known prior to each study drug administration. 
9. Urine biomarkers consisting of the NMP22® BladderChek® Test performed in clinic on a urine specimen obtained between midnight and noon, 
and collected more than 5 days after cystoscopy/TURBT, and UroVysionTM sample collected in clinic and sent to central vendor for analysis. 
10.12-Lead ECG up to 42 days prior to Day 1; preoperative ECG obtained for TURBT is acceptable. 
11.Blood samples sent to vendor lab for immediate processing; assays for rHuPH20 (Wks 2 & 6:  predose and 1, 2, and 3 hrs postdose), MMC 
(Wks 1, 2, 5 & 6:  predose and 1, 2, and 3 hrs postdose) and neutralizing antibodies (Wks 1 & 6; will only analyze Wk 1 if Wk 6 assay is 
positive). 
12.Includes information collected by telephone survey (or at c linic visit) on any cystoscopy, urine cytology, bladder biopsy, tumor recurrence, and 
treatment administered for bladder cancer. 
Note:  Weekly visits are expected to occur at 7-day intervals, +/- 3 days, counting from Day 1, Week 1. 
Note:  For the purpose of this study, tumor recurrence is defined as a biopsy that histologically confirms the recurrence of bladder carcinoma. 




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3. 
GLOSSARY AND ABBREVIATIONS 
 
Abbreviations 
Term 
AE 
Adverse event 
AJCC 
American Joint Committee on Cancer 
ALT 
Alanine transaminase (SGPT) 
ANC 
Absolute neutrophil count 
API 
Active pharmaceutical ingredient 
AST 
Aspartate transaminase (SGOT) 
AUA 
American Urological Association 
BCG 
Bacillus Calmette-Guérin 
BUN 
Blood urea nitrogen 
CAP 
College of American Pathologists 
CAS Registry 
Chemical Abstracts Service Registry 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CRF 
Case report form 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FISH 
Florescence in situ hybridization 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyltransferase 
GPI 
Glycosyl-phosphatidylinositol 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IC50 
Inhibition Concentration 50% 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary of Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MMC 
Mitomycin C, Mitomycin 
MTD 
Maximum tolerated dose 
NAB 
Neutralizing antibody 
NCI 
National Cancer Institute 
NMP 
Nuclear matrix protein 
PHI 
Protected Health Information 
PK 
Pharmacokinetic 
RBC 
Red blood cells 
rHuPH20 
Recombinant human hyaluronidase 
SAE 
Serious adverse event 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvate transaminase (ALT) 
 


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SOC 
System Organ Class 
SPC 
Summary of Product Characteristics 
T24 
T24 human bladder cancer cell line 
TNM 
Tumor Node Metastasis 
TURBT 
Transurethral resection of bladder tumor 
ULN 
Upper limit of the normal range 
USAN 
United States Adoptive Name 
WBC 
White blood cells 
U.S. 
United States 
 
4. 
BACKGROUND AND RATIONALE 
 
4.1. 
Introduction to Hyaluronidases, rHuPH20, and Chemophase 
 
Mammalian hyaluronidase preparations differing in source, species, and manufacturing 
process have been the subject of multiple investigations and regulatory approvals in 
Europe, the United States, and Asia. The extent of human administration of these 
products in the U.S. has been estimated to be in the tens of millions of patients. 
Additionally, patients have been treated with other regulatory-approved preparations of 
hyaluronidase in Europe and Asia. Collectively, this usage spans more than 50 years of 
clinical history in humans.  
 
The U.S. Food and Drug Administration (FDA) contracted a review of the efficacy and 
safety of several hyaluronidase drug products through a program known as the Drug 
Efficacy Study Implementation (DESI). The studies were conducted by the National 
Academy of Sciences and the National Research Council. The DESI review findings 
published in the Federal Register (September 23, 1970; 35(185):14800-1) established that 
hyaluronidase injection was “effective” for the following indications: 
 
For use as an adjunct to increase the absorption and dispersion of other 
injected drugs; for hypodermoclysis; as an adjunct in subcutaneous 
urography; for improving the resorption of radiopaque agents.  
 
The DESI review also concluded that hyaluronidase was “probably effective” for 
the following indications: 
 
As an aid in retrobulbar and cone injection infiltrative anesthesia in 
ocular surgery; as an adjunct in reducing painful swelling by resorption 
of locally accumulated fluid; for hastening the onset of action and 
diffuseability of local anesthetics; in minimizing tumefaction during 
surgery; and for reducing postoperative edema and ecchymosis.  
 
The hyaluronidase drugs included in the DESI reviews included injectable hyaluronidase 
preparation derived from bovine testes. Replacing animal-derived slaughterhouse 
products with recombinant human biotechnology-developed materials potentially 
alleviates risks associated with animal pathogens, transmissible spongiform 
encephalopathies, and allergy and immunogenicity to foreign proteins.  


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Chemophase is a formulation that contains a highly purified human hyaluronidase, 
rHuPH20, which is a glycoprotein enzyme generated by recombinant DNA technology. 
PH20 is a neutral pH-active hyaluronidase enzyme that degrades hyaluronan under 
physiologic conditions, but is normally locked on the plasma membrane through a 
glycosyl-phosphatidylinositol (GPI) moiety anchor. Therefore, Halozyme developed a 
recombinant soluble GPI-anchor deletion mutant form of the human PH20 hyaluronidase 
(rHuPH20) that, in non-human primates, does not elicit gross or histologic toxicity, 
neutralizing antibodies, or inflammatory responses at the site of injection across a three-
log therapeutic dose range.  
 
rHuPH20is a 447-amino acid single chain polypeptide with N-linked and O-linked glycan 
structures. rHuPH20is synthesized in Chinese hamster ovary (CHO) cells that have been 
transfected with a plasmid containing the DNA sequence encoding the GPI-anchor 
deleted human PH20 hyaluronidase. The protein is purified through a series of 
chromatographic steps that results in a purified protein with high specific activity. 
rHuPH20 is up to 100-times more pure than slaughterhouse-derived hyaluronidases based 
on specific activity. rHuPH20 degrades hyaluronan by hydrolysis of the β-1,4 linkage 
between the C1 position of N-acetyl glucosamine and the C4 position of glucuronic acid.  
 
4.2. 
Background on Non-Muscular-Invasive Bladder Carcinoma 
 
Non-muscular-invasive transitional bladder carcinomas are those tumors that have not 
infiltrated beyond the lamina propria, and consist of American Joint Committee on 
Cancer (AJCC) TNM classifications Ta (non-invasive papillary tumor confined to the 
urothelium), T1 (tumor penetrating the below the basement membrane and infiltrating the 
lamina propria subepithelial connective tissue), and Tis (Cis, carcinoma in situ, “flat 
tumor”) (see Appendix A). The histology of bladder carcinoma is often characterized as 
Grade 1 ( low, or well differentiated), Grade 2 (intermediate, or moderately 
differentiated), and Grade 3 (high, or poorly differentiated).  
 
Non-muscular-invasive bladder carcinoma has a high rate of tumor recurrence within the 
bladder, which requires repetition of surgery and medical therapy. The rate of recurrence 
of superficial (non-muscular-invasive) bladder cancer is reported to range from 40% to 
85% [1]. The FDA’s Oncology Drugs Advisory Committee concluded in 1988 that as a 
general rule, over 50% of recurring patients will have recurrence within the first year [2]. 
The American Urologic Association (AUA) Bladder Cancer Guidelines Panel concluded 
in 1999 that intravesical treatment-related reductions in the probability of recurrence 
were detected within the first year of observation in most studies and the observed 
reductions were carried forward into subsequent years [3]. With tumor recurrence comes 
an increased risk of tumor progression and the possibility of medical/surgical treatment 
complications and anesthesia complications and their effect on t he patient’s quality of 
life.  
 
Most non-muscular-invasive bladder cancers are initially treated with transurethral 
surgical resection of the bladder tumor (TURBT), and less commonly with fulguration 


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and/or laser therapy. Following resection, adjuvant intravesical chemotherapy or 
immunotherapy is commonly used to prevent recurrences and eradicate residual disease. 
The most commonly administered intravesical therapies are bacillus Calmette-Guérin 
(BCG) and mitomycin (Mitomycin C, MMC). Other intravesical agents include thiotepa, 
doxorubicin, epirubicin, valrubicin, and interferon.  
 
Both intravesical BCG and intravesical MMC following TURBT have been shown in 
randomized clinical trials to statistically reduce the rate of tumor recurrence when 
compared to TURBT alone [3]. For patients with established bladder cancer of any grade, 
Stage Ta or T1, with or without Tis, who have not had prior intravesical therapy, the 
AUA includes a “Guideline” of “Intravesical instillation of either BCG or mitomycin is 
recommended for treatment of CIS and for treatment after endoscopic removal of T1 
tumors and high-grade Ta tumors” [3]. Additionally, the AUA includes an “Option” of 
“Adjuvant intravesical chemotherapy or immunotherapy is an option for treatment after 
endoscopic removal of low-grade Ta bladder cancers.”  Thus, both BCG and MMC have 
a role in the intravesical therapy of patients. However, there remains a substantial rate to 
tumor recurrence after intravesical therapy, and therefore an unmet medical need for 
therapy that is safe and more effective in preventing tumor recurrences and also tumor 
progression. 
 
BCG is widely used for intravesical immunotherapy, and has become first-line treatment 
for Stage Tis. The most serious side effect of BCG is sepsis, and the most common side 
effects are cystitis and hematuria. BCG may cause irritative voiding symptoms in about 
two-thirds of patients, and flu-like symptoms/systemic side effects in about one quarter of 
patients [3]. 
 
MMC is a purple antibiotic isolated from the broth of Streptomyces caespitosus and was 
initially investigated as an antibiotic. Later found to selectively inhibit the synthesis of 
DNA as an alkylating agent, MMC was studied as an anti-tumor agent. The AUA 
Bladder Cancer Guidelines Panel found that based on randomized clinical trials, 
intravesical MMC conferred about a 15% reduction in tumor recurrence compared to 
TURBT alone [3]. Despite the clinical trial data supporting the safety and effectiveness of 
MMC for bladder carcinoma, MMC has not been approved by the United States FDA for 
intravesical therapy of bladder cancer. The approved product label in the U.S. (see 
Appendix C) states that “Mitomycin for Injection is not recommended as single-agent, 
primary therapy. It has been shown to be useful in the therapy of disseminated 
adenocarcinoma of the stomach or pancreas in proven combinations with other approved 
chemotherapeutic agents and as palliative treatment when other modalities have failed.”  
When used to treat bladder carcinoma in the U.S., MMC is typically administered by 
intravesical instillation at doses of 20 to 40 mg at a concentration of 1-2 mg/ml in a f inal 
volume of 20 to 40 ml for a residence time of 1 to 2 hours.  
 
MMC is approved for use in Canada (see Appendix D) and the United Kingdom 
(see Appendix E) as a single agent “as topical therapy for superficial (no invasion 
beyond the lamina propria) transitional cell carcinoma of the urinary bladder. Efficacy 
has been demonstrated both in patients who have had no prior intravesical chemotherapy 


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and in those who have failed such therapy with thiotepa and other neoplastic agents.”  
The approved dose is 20 to 40 mg in 30 to 60 mL of sterile water given intravesically 
once weekly for up t o eight weeks. Patients are advised to abstain from liquids for 12 
hours prior to therapy. The patient is catheterized, the bladder is drained, and MMC is 
instilled. The solution should be retained for two hours, during which time the patient 
may rotate positions every 15 minutes to promote maximum area of contact in the 
bladder. The approved dose in the U.K. for treatment of tumors is 20 to 40 mg dissolved 
in 20 t o 40 [mL, sic] of diluent weekly or three times a week for a total of 20 doses. 
Mitomycin is also approved in the U.K. for prevention of recurrent superficial bladder 
tumors, with various doses having been used, including 20 mg in 20 mL of diluent every 
two weeks and 40 mg in 40 mL of diluent monthly or three monthly. 
 
Myelosuppression is the major dose-limiting toxicity after intravenous MMC 
administration, and may be cumulative, occurring any time within eight weeks of onset of 
therapy, often with a late onset at 3 to 4 weeks, with recovery by 8 to 10 weeks. With a 
moderately high molecular weight of 329 daltons, MMC is not well absorbed through the 
bladder urothelium and therefore the risk of myelosuppression is very low. 
Myelosuppression has not been noted with intravesical administration [4]. In 55 patients 
treated with doses of 20 t o 40 mg of MMC by intravesical instillation, serial plasma 
samples collected during and 30 minutes after therapy contained no detectable MMC at 
an assay limit of 10 t o 100 ng/mL [5]. Based on data from intravenous administration, a 
serum MMC concentration of 400 ng/mL has been cited as predictive of 
myelosuppression [6]. Dalton et al. studied the pharmacokinetics of MMC in 10 patients 
after TURBT given six weekly instillations of 20 mg MMC in 40 mL water and found 
that at the first cycle (Treatment 1), maximal plasma concentrations of MMC during and 
up to four hours after instillation averaged 43 ng/mL (range 2.1 to 180.5 ng/mL) [7]. The 
concentrations measured at the subsequent Treatments 2, 4, and 6 were at least four-fold 
lower than those in Treatment 1 and in most cases were below the detection limit of 
0.5 ng/mL. Thus, plasma levels were well below the 400 ng/mL level known to be 
predictive of myelosuppression, and MMC absorption in subsequent treatments was less 
than during the first treatment.  
 
Intravesical MMC may cause irritative voiding symptoms (e.g., dysuria, 
frequency/nocturia) in about 35% to 42% of patients, hematuria in about 16%, and skin 
rash in about 13% as the most common side effects [3]. Bladder fibrosis with a reduction 
in bladder capacity is an uncommon but known complication of generally long-term 
intravesical MMC therapy, the incidence of which appears to correlate directly with the 
cumulative MMC dose and correlate inversely with the time interval between a second 
tumor resection and the first MMC instillation [8].  
 
4.3. 
Rationale for Use of Chemophase in Bladder Cancer 
 
Chemophase (recombinant human hyaluronidase, rHuPH20) is being developed as a 
novel chemoadjuvant to enhance the delivery of chemotherapy to tumors in patients with 
various solid tumor malignancies (e.g., bladder, breast, colon, lung, and prostate) that 
accumulate hyaluronan (also known as hyaluronic acid). Clinical trials of animal-derived, 


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bovine hyaluronidase PH20 in hundreds of patients have shown promise in enhancing 
chemotherapy regimens using adjunctive hyaluronidase in previously chemo-refractory 
patients. However, the animal-derived hyaluronidases have been impaired by 
immunologic limitations upon repeat administration.  
 
Chemophase (recombinant human hyaluronidase) Solution for Intravesical Instillation is 
being specifically developed for use as an adjuvant with MMC in non-muscular-invasive 
bladder carcinoma following TURBT. It is envisioned that the Chemophase product 
would be administered with MMC as an adjuvant to increase the local penetration of 
MMC into residual malignant disease following TURBT. By reducing tumor recurrence 
rates, Chemophase adjuvant therapy with MMC could provide clinical benefit for patients 
by limiting repeated surgical resections and possible complications from medical and 
surgical treatment and anesthesia. Furthermore, reduced recurrence rates may 
conceivably limit the progression of disease such that the need for cystectomy or 
systemic chemotherapy may be delayed or eliminated. 
 
Nonclinical pharmacology studies have shown that rHuPH20 enhances the dispersion of 
co-administered molecules up to 200 nm in diameter in a dose-dependent fashion, 
decreasing in relation to the increasing size of co-administered molecules, and rHuPH20 
increases hydraulic conductivity more than ten-fold. Application of rHuPH20 to T24 
human bladder tumor cells in vitro effectively removes pericellular hyaluronan and 
allows direct contact with tumor cell membranes, an effect confirmed to be due to 
degradation of hyaluronan, which rapidly regenerated upon removal of rHuPH20 from 
the culture media. Incubation with rHuPH20 dramatically increased the doxorubicin 
penetration into T24 bladder cancer multicellular tumor spheroid cores. rHuPH20 
induced a dose-dependent, up t o 2.5-fold change in the IC50 for MMC in T24 bladder 
cancer cell monolayers, and a 7.8-fold change in IC50 for spheroids, thereby increasing 
the sensitization of bladder tumor aggregates to MMC by increasing the penetration into 
the inner cellular layers. 
 
Application of rHuPH20 to human osteosarcoma orthotopic xenograft models resulted in 
a significant reduction in tumor interstitial fluid pressure within one hour of 
administration. As increased interstitial fluid pressure is a key factor limiting bulk fluid 
flow in solid tumors, it is reasonable to conclude that rHuPH20 warrants testing as an 
adjunct to chemotherapy agents to increase the therapeutic index of those agents. 
 
Three nonclinical toxicology studies have been conducted to assess the toxicity of 
co-administration of rHuPH20 with MMC. A GLP study in 60 rats of the acute 
intravenous administration of MMC and rHuPH20 found transient slight decreases in the 
weight in female animals receiving rHuPH20, but no overt toxicity following the 
administration of rHuPH20 alone or in combination with MMC at any dose level. A GLP 
study in 60 rats of the local tolerance of repeated exposure to intravesical MMC and 
rHuPH20 found that six weekly intravesical instillations of rHuPH20 alone at 6,000 units 
and MMC 0.4 mg (2 mg/mL) combined with rHuPH20 at dose levels of 0, 60, 600, and 
6,000 units were well tolerated and no toxicity was observed. A GLP study in 48 New 
Zealand white rabbits of the tolerance of a single intravesical instillation of MMC 


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(8 mg/animal) and rHuPH20 (4,000, 40,000 and 160,000 units/animal) found the study 
drug treatment well-tolerated without evidence of test article-related toxicity. In addition, 
a GLP study in s ix rhesus monkeys of the local tolerance of repeated exposure to 
intravesical rHuPH20 alone (without MMC) found no toxicity.  
 
As an adjuvant to intravesically administered MMC, animal-derived, bovine 
hyaluronidase has been previously studied in clinical trials in at least 43 patients with 
bladder carcinoma. The rationale for the adjuvant use of PH20 in this setting is that the 
pharmacologic activity of hyaluronidase as a spreading agent could increase the 
penetration of MMC into residual hya luronan-rich bladder tumors, thereby increasing the 
effectiveness of MMC in killing residual malignant cells and reducing the risk of tumor 
recurrence.  
 
In 1986, Maier and Baumgartner published a series of 20 patients undergoing TURBT or 
multiple transurethral biopsies receiving a single dose of 20 mg intravesical MMC in 
20 mL distilled water, 10 of whom received intravesical bovine hyaluronidase 200,000 
units added to the dissolved MMC [9]. Serum levels of MMC were assayed at 30 and 
60 minutes after instillation and found to range from < 1 t o 31.5 ng/mL. The systemic 
absorption of MMC was not affected by hyaluronidase. The mean MMC concentrations 
at 30 minutes were 14.2 ± 8.4 ng/mL for MMC alone and 13.4 ± 6.5 ng/mL for MMC 
with hyaluronidase. The respective mean concentrations at 60 minutes were 
10.9 ± 7.1 ng/mL and 10.0 ± 6.4 ng/ mL. The highest serum level overall, 31.5 ng/mL, 
was measured in a patient not given hyaluronidase. Thus, MMC concentrations in this 
study remained below one tenth of 400 ng/mL, the critical systemic level that is believed 
to be predictive of myelosuppression [6]. This study concluded that hyaluronidase at a 
dose of 200,000 units does not enhance the systemic absorption of MMC given as a 
perioperative intravesical instillation.  
 
In 1989, Maier and Baumgartner published a larger, double-blind, randomized trial of 56 
patients who had undergone TURBT and were randomized equally to multiple doses of 
either intravesical MMC 20 mg in 20 mL or the same dose of MMC plus 200,000 units of 
bovine hyaluronidase [10]. Twenty patients were Stage Ta, 27 were T1, and nine were 
T2. Twenty-nine patients were Grade 1, 22 were Grade 2, and five were Grade 3. Thirty-
one patients were treated for primary tumors and 25 for recurrences. The treatment 
groups were comparable statistically. Intravesical instillations were started approximately 
one week after TURBT and given every two weeks for the first six months, followed by 
every four weeks until the end of two years (total of about 30 instillations per patient). 
Cystoscopy with lavage cytology follow-up was scheduled every three months for the 
first two years, and then biannually thereafter.  
 
Of the 28 patients treated with MMC alone (who received a total of 788 instillations), 
five (17.8%) had side effects, including four with cystitis and one with skin rash. Of the 
28 patients treated with MMC and hyaluronidase (who received a total of 750 
instillations), four (14.2%) had side effects, including three with cystitis and one with 
skin rash. There was no significant alteration in white blood count during therapy.  
 


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A total of 32.1% (9/28) of MMC monotherapy patients had recurrent tumors over a 
median observation period of 21.1 months, compared to 7.1% (2/28) of MMC plus 
hyaluronidase patients over a median observation of 20.2 months (p < 0.05). The nine 
tumor recurrences in the MMC monotherapy group were detected at a mean of 11 months 
(range 6 to 24 months) compared to a mean of 13 months (6 and 20 months) for the two 
recurrences for MMC plus hyaluronidase. The nine MMC monotherapy recurrences were 
the same stage and grade as the primary tumor for four patients, downstaged for three, 
and upstaged for two. Both recurrences in the MMC plus hyaluronidase group were 
downstaged. This study, which consisted of a large number of exposures (about 30 per 
patient) over a relatively long duration (two years), concluded a significant additive 
benefit of hyaluronidase when given with MMC for the prevention of recurrent bladder 
tumors without an increase in adverse effects. 
 
In 1992, Hobarth, Maier and Marberger published long-term follow-up of 43 patients 
undergoing TURBT of Ta-T1 bladder tumors treated with intravesical bovine 
hyaluronidase plus MMC [11]. Twenty-four patients were Stage T1 and 19 were Stage 
Ta. Twenty-eight patients were Grade 1, 14 were Grade 2, and one was Grade 3. Thirty-
seven patients had primary tumors and six had recurrent tumors. Beginning 
approximately one week after TURBT, these patients received 200,000 units of 
hyaluronidase along with 20 mg of MMC intravesically every two weeks for six months, 
then every four weeks until the end of two years. The tumor recurrence rate was 25% 
(11/43) over a mean follow-up of 48.5 months (range 42 to 66 months). These data 
compared favorably to a retrospective study of 63 comparable patients who demonstrated 
a tumor recurrence rate of 52.5% during and after two years of intravesical MMC 
monotherapy. Side effect of the combination therapy were observed in a total of 14% 
(6/43) of patients, and consisted of bacterial cystitis (6.9%), chemocystitis (4.6%), and 
skin allergy (2.3%). No patients were withdrawn due to side effects. This study 
concluded that the considerable reduction in tumor recurrence rate observed with 
hyaluronidase plus MMC compared to that seen after MMC monotherapy and the 
absence of any evidence of an increase in local side effects justify the application of 
hyaluronidase in this c linical setting. The authors postulated that, like other tumor cells, 
malignant transitional urothelial cells might be surrounded by a halo of hyaluronan, and 
destruction of this protective halo by hyaluronidase would explain the local enhancement 
of the anti-tumor effect of MMC. 
 
A Phase I safety, tolerability, and PK single-administration clinical trial (HZ2-05-02) of a 
low dose (20,000 units) of Chemophase with 40 mg MMC administered intravesically in 
a targeted sample size of five evaluable patients who had undergone transurethral 
resection of bladder tumor (TURBT) for transitional cell bladder cancer Stage Ta , T1 or 
Tis (any grade), were free of known bladder cancer recurrence, and were being monitored 
for recurrence of superficial transitional cell bladder cancer was initiated in August 2005 
and completed enrollment on 2 March 2006. All five patients completed the study. There 
were no deaths, serious AEs, AEs judged to be possibly or more related to either study 
drug, moderate or severe AEs, premature withdrawals, or dose-limiting toxicities. The 
only three AEs reported in the study were, by MedDRA Preferred Terms, Influenza, 
Urinary tract infection, and Acne. All plasma samples for MMC were below the lower 


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limit of quantitation (10 ng/mL) and all plasma samples of PH20 were below the lower 
limit of quantitation (10 U/mL). 
 
In summary, the previous human experience with bovine hyaluronidase administered as 
an adjunct to intravesical MMC collectively in at least 43 patients, based on two clinical 
trials and a larger sample size follow-up publication, demonstrated no increase in toxicity 
and no increase in systemic absorption of MMC, but did show a statistically significant 
and clinically meaningful benefit in the prevention of tumor recurrences. The bovine 
hyaluronidase studies are important in establishing the anticipated safety and efficacy of 
the investigation of Chemophase as an adjunct in the treatment of bladder cancer. The 
nonclinical data for rHuPH20 in various tumor models including the T24 human bladder 
cancer cell line and the tolerability of co-administered rHuPH20 with mitomycin in two 
animal species (rats and rabbits) provide additional support for the study of Chemophase 
as an adjunct to the treatment of bladder carcinoma. Taken together, the nonclinical 
findings for rHuPH20 and the human clinical trial data for bovine hyaluronidase support 
the rationale for the anticipated safety and the potential efficacy of Chemophase 
administered intravesically along with MMC for non-muscular-invasive bladder 
carcinoma.  
 
5. 
STUDY OBJECTIVES 
 
5.1. 
Primary Objectives 
 
• Determine the maximum tolerated dose (MTD) and dose-limiting toxicities 
(DLTs) of escalating doses of Chemophase in combination with mitomycin 
(Mitomycin C, MMC) administered as weekly intravesical instillations for five 
weeks. 
 
• Establish the dose of Chemophase with MMC recommended for future studies. 
 
5.2. 
Secondary Objectives 
 
• Assess the pharmacokinetics of intravesical administration of MMC alone and in 
combination with intravesical administration of Chemophase. 
 
• For those patients treated at the MTD, assess the safety and tolerability of 
intravesical administration of MMC with Chemophase over up to 7 additional 
maintenance treatments every 3 months following the initial six weekly 
instillations. 
 
• Observe patients for any preliminary evidence of anti-tumor activity of MMC and 
Chemophase when combined. 
 


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6. 
STUDY DESIGN 
 
6.1. 
Overview of Study Design 
 
This is a Phase I-IIa multiple dose study of intravesical treatment with the combination of 
Chemophase and MMC. All patients will receive six weekly intravesical instillations of 
chemotherapy. The 12 patients treated at MTD will continue to receive combination 
therapy every three months until the end of Year 2 from Day 1 or until the time of 
documented tumor recurrence, whichever occurs first. For the purpose of this study, 
tumor recurrence is defined as a biopsy that histologically confirms the recurrence of 
bladder carcinoma. 
 
All patients will be assigned to a single dose cohort, and the escalating dose cohorts will 
be enrolled sequentially after the safety and tolerability of the immediately preceding 
cohort has been ascertained. 
 
On Day 1 of Week 1, all patients in all cohorts (Cohorts 1 through 5) will receive MMC 
40 mg/20 mL monotherapy via intravesical administration. In Weeks 2 through 6, 
patients will receive weekly intravesical administrations of a combination of MMC and 
Chemophase, in cohorts with escalating doses of Chemophase while the MMC dose 
remains constant at 40 mg/20 mL (see Table 6.1-A).  
 
Table 6.1-A. Dose Cohorts 
Cohort 
Week 1 Dosing 
Weekly Dosing Week 2 through Week 6 
1 
MMC 40 mg/20 mL 
  20,000 U Chemophase followed by MMC 40 mg/20 mL 
2 
MMC 40 mg/20 mL 
  60,000 U Chemophase followed by MMC 40 mg/20 mL 
3 
MMC 40 mg/20 mL 
200,000 U Chemophase followed by MMC 40 mg/20 mL 
4 
MMC 40 mg/20 mL 
400,000 U Chemophase followed by MMC 40 mg/20 mL 
5 
MMC 40 mg/20 mL 
800,000 U Chemophase followed by MMC 40 mg/20 mL 
 
Post-treatment evaluations will be performed at Weeks 8 and 12. The 12 patients treated 
at MTD will continue to receive combination therapy every three months until the end of 
Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs 
first. For all patients, long-term follow-up after Week 12 w ill consist of disease 
monitoring of patients by telephone (or at clinic visits for those patients still being treated 
at MTD) and will be performed every three months beginning three months after the last 
study treatment for two years and then every six months thereafter until the time of 
bladder tumor recurrence.  
 


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6.2. 
Number of Patients 
 
Up to 36 evaluable patients will be enrolled in this study. It is anticipated that no more 
than a total of 44 patients will need to be enrolled to achieve this number of evaluable 
patients. Groups of either 3 or 6 patients will participate in each of the f ive individual 
dose cohorts in the dose escalation phase of the study. Once the MTD has been 
established (see Section 8.9), 6 additional evaluable patients will be enrolled at the MTD 
dose level, yielding a total of 12 evaluable patients at MTD upon which to confirm safety 
and tolerability of the MTD regimen. 
 
An evaluable patient is one who: 
 
• has received all protocol-specified six weekly intravesical treatments with at least 
a 90-minute retention, and 
• has had MMC plasma concentration determinations and safety assessments 
adequate for the determination of safety and tolerability.  
 
Each patient not meeting all these criteria for evaluability, including patients withdrawn 
prematurely for reasons other than toxicity, will be replaced by t he enrollment of an 
additional patient.  
 
6.3. 
Patient Recruitment 
 
Patients will be recruited by each Investigator at each study center from their private 
practice, their institution or through referrals. Prior to consenting/enrolling patients, the 
Investigator will obtain Institutional Review Board (IRB) review and approval of the 
clinical investigation, including this protocol accompanied by t he Investigator’s Brochure 
(IB), the informed consent form, and any material provided to patients and any other 
advertising for study patients. 
 
Prior to patient screening and enrollment in this study, all patients must have had 
transurethral resection of bladder tumor(s) (TURBT) according to standard of care within 
42 days prior to Day 1/ Week 1, followed by intravesical standard of care under the 
judgment of the patient’s physician and subsequent histopathology report following 
TURBT, which will be used to determine if the prospective patient meets the bladder 
carcinoma staging and grading eligibility criteria for this study. 
 
A Screening Log must be maintained at each site documenting all patients screened for 
participation in this study and noting reasons for non-enrollment and/or ineligibility. 
 


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6.4. 
Treatment Summary 
 
This study will involve one (1) intravesical dose of MMC followed by five (5) 
subsequent weekly intravesical dose administrations of a combination of a fixed dose of 
MMC preceded by t he dose of Chemophase defined by the assigned dose cohort. The 12 
patients treated at MTD will continue to receive combination therapy every three months 
until the end of Year 2 from Day 1 or until the time of documented tumor recurrence, 
whichever occurs first. 
 
In each cohort, at Week 1 patients will receive MMC 40 mg alone (without Chemophase) 
in 20 mL of sterile water. If no dose-limiting toxicity (DLT, see Section 8.8) is observed 
during the course of this and subsequent study drug treatments, this first treatment will be 
followed by five weekly intravesical instillations (at Weeks 2 through 6) of Chemophase 
at the dose specified by the assigned cohort followed by MMC 40 mg in 20 mL of sterile 
water. 
 
All 3 patients within a given cohort may begin treatment simultaneously. The next higher 
dose cohort can be immediately opened for patient enrollment if, at the time all 3 patients 
in a given cohort have completed the fourth (4th) instillation of MMC ( i.e., third 
instillation of MMC plus Chemophase), there is: 
 
• no NCI CTC adverse event Grade 2 or higher toxicity,  
• no MMC plasma concentration ≥ 100 ng/ mL, and  
• no new, treatment-emergent, diagnosis of bladder fibrosis. 
 
Note that an NCI CTC adverse event Grade 2 toxicity will delay opening the next higher 
dose cohort to enrollment until safety data are reviewed from all six weekly instillations 
for all 3 patients in that cohort. 
 
Because this study is being conducted at more than one study center, the enrollment of 
patients, assignment to cohorts, and opening of each sequential cohort will be controlled 
centrally for all study centers by Halozyme. Each time a new patient is consented for the 
study, the study center must immediately fax the updated Screening Log to Halozyme or 
its designee. In turn, Halozyme or its designee will keep all centers immediately apprised 
of the number of patients enrolled and patients in screening, so that new patients are not 
consented if there is no possibility of enrollment because there is no room for additional 
patients in the ongoing cohort.  
 
At the time a patient has fulfilled all eligibility criteria, the study center must fax a 
completed Enrollment/Registration Form to Halozyme or its designee, in response to 
which Halozyme or its designee will provide authorization to dose and confirmation of 
the dose cohort to which the new patient will be assigned (see Section 8.4). 
 


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6.5. 
Study Duration 
 
Study patients will receive six (6) weekly study treatments (at Weeks 1 through 6) 
followed by post-treatment evaluations, at Weeks 8 and 12. The 12 patients treated at 
MTD will continue to receive combination therapy every three months until the end of 
Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs 
first. For all patients, long-term follow-up after Week 12 w ill consist of disease 
monitoring of patients by telephone (or at clinic visits for MTD patients continuing on 
study drug treatment) and will be performed every three (3) months beginning three 
months after last study treatment to the end of two years and 29 days following Day 1 or 
until bladder tumor recurrence, whichever occurs first. 
 
7. 
STUDY POPULATION 
 
7.1. 
Inclusion Criteria 
 
Patients must satisfy all of the following inclusion criteria in order to be enrolled in the 
study. 
 
1. Patients with initial
• Bilirubin ≤ 1.5 times upper limit of normal, and  
 presentation or recurrence of Stage Ta , T1 or Tis, any grade, 
bladder cancer after TURBT. 
 
2. TURBT within 42 days prior to Day 1/Week 1. 
 
3. Karnofsky Performance Status ≥ 80% (see Appendix B).  
 
4. Life expectancy at least 3 years. 
 
5. Age ≥ 18 years. 
 
6. A negative pregnancy test (if female of child-bearing potential). 
 
7. Acceptable liver function within 7 days defined as: 
• AST (SGOT), ALT (SGPT), and Alkaline phosphatase ≤ 2.5 times upper limit 
of normal. 
 
8. Acceptable renal function within 7 days defined as: 
• Serum creatinine ≤ 1.5 times upper limit of normal, OR 
• Calculated creatinine clearance ≥ 40 mL/min/1.73 m2. 
 
9. Acceptable hematologic status within 7 days defined as: 
• Absolute neutrophils count (ANC) ≥ 2,500 cells/mm3,  
• Platelet count ≥ 150,000/mm3, and  
• Hemoglobin ≥ 10.0 g/dL. 
 


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10. Urinalysis showing no clinically significant abnormalities except those 
attributable to bladder cancer. 
 
11. For men and women of child-producing potential, agreement to use an effective 
contraceptive method during the treatment period of the study. 
 
12. Signed, written IRB-approved informed consent. 
 
7.2. 
Exclusion Criteria 
 
Patients satisfying any one or more of the following exclusion criteria must not be 
enrolled in this study. 
 
1. History or previous diagnosis of bladder fibrosis. 
 
2. Total bladder capacity estimated at cystoscopy to be < 150 mL. 
 
3. Urinary incontinence of a severity that would compromise the ability of the 
patient to retain the study drug intravesical instillation for two hours. 
 
4. Severe irritative voiding symptoms such as urgency, frequency, or nocturia. 
 
5. Known other malignant disease except squamous or basal cell skin cancer unless 
the malignancy has been in complete remission off therapy for at least 5 years. 
 
6. Major surgery, other than TURBT and diagnostic surgery, within 28 days prior to 
Day 1/Week 1. 
 
7. Active, uncontrolled bacterial, viral, or fungal infections, including urinary tract 
infection. 
 
8. Treatment with radiation therapy, surgery, chemotherapy, or investigational 
therapy within one (1) month prior to Day 1/Week 1 on study (two [2] months for 
nitroureas or MMC), unless given as standard treatment for bladder cancer and 
provided that patient is free of all treatment-related toxicities as of Day 1/Week 1. 
 
9. Known infection with HIV. 
 
10. Known active infection with hepatitis B or hepatitis C. 
 
11. Serious disease (e.g., hydronephrosis, liver failure, or other conditions) that could 
compromise protocol objectives in the opinion of the Investigator and/or the 
Sponsor (Halozyme). 
 
12. History of a hypersensitivity or idiosyncratic reaction to, or other contraindication 
to, mitomycin. 


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13. Known allergy to bee or vespid venom. 
 
14. Known coagulation disorder or bleeding tendency.  
 
15. Treatment with heparin or anticipation of heparin treatment during the treatment 
period in this study.  
 
16. Unwillingness or inability to comply with procedures required in this protocol. 
 
7.3. 
Prohibitions and Restrictions during the Study 
 
The following therapies are prohibited from the time of enrollment through Week 12 of 
the study: 
 
• treatment with heparin, 
• any intravesical therapy except for MMC and Chemophase, and 
• any potentially myelosuppressive therapy.  
 
For the MTD patients who are receiving continued study drug treatments after Week 12, 
the following therapies are prohibited for the duration for study drug treatment: 
 
• any intravesical therapy except for MMC and Chemophase, and 
• any potentially myelosuppressive therapy.  
 
7.4. 
Contraindications, Warnings and Precautions with Regard to MMC 
Administration 
 
The administration of MMC in this protocol is guided in part by the approved product 
labeling for MMC. MMC is not approved by the United States FDA for intravesical 
administration but is approved for other indications. For the convenience of the 
Investigator, a representative U.S. package insert for MMC is provided in Appendix C 
and a representative Canadian package insert and United Kingdom SPC, which do allow 
for intravesical administration, may be found in Appendices D and E, respectively. 
These package inserts and SPC are current as of the date of this protocol version. It is the 
responsibility of the Investigator to refer to the product label that is current as of the time 
of treatment and management decisions. 
 
A boxed warning in the U.S. package insert notes that MMC should be administered 
under the supervision of a qualified physician experienced in the use of cancer 
chemotherapeutic agents. Appropriate management of therapy and complications is 
possible only when adequate diagnostic and treatment facilities are readily available. This 
boxed warning further provides information about bone marrow suppression contributing 
to overwhelming infections in an already immunocompromised patient, and about 
hemolytic uremic syndrome. 
 


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According to the U.S. package insert, MMC is contraindicated in patients who have 
demonstrated a hypersensitive or idiosyncratic reaction to MMC in the past. MMC is a lso 
contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in 
bleeding tendency due to other causes. The Canadian package insert includes the same 
contraindications, and adds leukopenia. 
 
Warnings in the U.S. package insert include the need for careful and frequent observation 
of patients during and after MMC therapy. The U.S. package insert, specific to 
intravenous administration of MMC, further warns about a high incidence of 
myelosuppression, the need for regular monitoring of hematologic laboratory parameters, 
and advising patients of this potential toxicity. Patients receiving MMC should be 
observed for evidence of renal toxicity, and MMC should not be given to patients with a 
serum creatinine greater than 1.7 mg/mL. The U.S. package insert further states that 
bladder fibrosis/contraction has been reported with intravesical administration (not an 
FDA-approved route of administration), which in rare cases has required cystectomy. 
 
The Canadian package insert adds warnings that MMC is a potent drug and should be 
used only by physicians experienced with cancer chemotherapeutic drugs. MMC should 
not be administered to any patient with a white blood cell count below 4,000/mm3 or a 
platelet count less than 150,000/mm3 or to patients with serious infections.  
 
The safety of MMC in pregnant women has not been established, and teratological 
changes have been noted in animal studies of MMC. It is not known if MMC is found in 
human breast milk, and it is recommended that women receiving MMC not breastfeed. 
 
The Investigator is referred to the full package insert(s) as the definitive, comprehensive, 
and most up-to-date guide to the administration of MMC. 
 
8. 
STUDY METHODS AND PROCEDURES 
 
8.1. 
Designated Laboratories:  Central, Local, PK, and Biomarker Labs 
 
A combination of a central laboratories and laboratories local to each study center will be 
used in this study. The central laboratories will receive and analyze all samples that are 
not tied to the need for an immediate evaluation of potential myelosuppression of treated 
patients. 
It is preferable that only one local laboratory be specified and used at each individual 
study center. The local laboratory will receive and analyze blood drawn for a complete 
blood count (CBC) and differential on a “stat” basis on Week 1/Day 1, Week 2/Day 8, 
Week 3/Day 15, Week 4/Day 22, Week 5/Day 29, and Week 6/Day 36. For consistency, 
At each dosing visit, intravesical dosing with study medication(s) must not 
be done until CBC and differential results are known, and the ANC is confirmed to 
be ≥ 1,500/mm3 and the platelet count confirmed to be ≥ 75,000/mm3. In addition, at 
each dosing visit and before any dose of study medication, a urine dipstick must be 
performed at the study center and the results known to not show evidence of 
urinary tract infection. 
 


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all protocol-specified CBCs will be performed at the local laboratory, including the CBCs 
at Screening, Week 8 and Week 12.  
 
Samples obtained for pharmacokinetic assays of MMC and rHuPH20and for assessment 
of antibodies to rHuPH20 will be sent to a separate central laboratory for analysis. 
 
For the urine biomarkers, the NMP22® BladderChek® Test will be performed in clinic 
and the UroVysion test will be obtained in the clinic and sent to a central vendor lab for 
analysis. 
 
8.2. 
Procedures Prior to Screening (Day -28 to Day -1) 
 
TURBT(s) must be done on a ll patients no more than 42 days prior to Day 1/Week 1. 
Post-operatively, patients are expected to receive standard of care as determined by their 
physician, which may or may not include intravesical therapy with MMC. The surgical 
operative notes and the histopathology report (or content of information therein) from the 
TURBT must be available to the Investigator prior to performing any screening 
procedures and prior to having any patient sign the informed consent document. 
Cystoscopy within 42 days prior to Day 1/Week 1 (generally performed at the time of 
TURBT) accompanied by an estimation of bladder capacity will be used to qualify 
patients for this study. There must be a urine cytology during Screening collected more 
than 5 days after the TURBT and within two weeks prior to the date of enrollment in this 
study. 
 
As noted in Section 2.0, the Schedule of Events for this study, activities taking place 
prior to consenting the patient (e.g., TURBT with cystoscopy and urine cytology, post-
operative standard of care, and histopathology reading and report) are not protocol-
specified activities, but are prerequisites before a patient can be consented for this study.  
 
8.3. 
Screening Procedures (Day -28 to Day -1) 
 
As shown in Section 2.0, Schedule of Events, the following activities are to be completed 
during this period. 
 
• Verification from source documents (medical record, TURBT notes, cystoscopy 
notes, histopathology report) that patient meets the disease-defining criteria in 
Section 7.1, for (1) patient with initial presentation or recurrence of Stage Ta, T1 
or Tis, any grade, bladder cancer after TURBT. The specific TNM stage will be 
recorded. 
 
• Assess for exclusion criteria (see Section 7.2), including but not limited to 
incontinence, irritative voiding symptoms, history of bladder fibrosis, known 
other malignant disease, other recent surgery and therapies, active infection, 
concurrent serious disease, known coagulation disorder, use of or anticipated use 
of heparin, and willingness and ability to comply with protocol procedures. 
 


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• Informed Consent:  The Investigator or one of the study staff must explain the 
study protocol to prospective study patients and have them read and ask questions 
regarding the informed consent form (ICF). This discussion must include, among 
other topics, the need for an effective contraception method during the treatment 
phase if this study. If the patient agrees to participate, they must sign and date the 
informed consent form and have it witnessed. Each patient must receive a copy of 
the signed informed consent. 
 
• Karnofsky performance status ≥ 80% (see Appendix B). 
 
• Complete medical history. 
 
• Detailed urologic history. This will include a complete description of the number, 
estimated size and gross appearance of tumors removed at TURBT; and the area 
and depth of involvement of the bladder mucosa after TURBT; the anatomic 
location of the tumor(s); estimated bladder capacity; histopathology; tumor stage 
and grade; prior history of bladder cancer; etc. 
 
• Complete physical exam. 
 
• Vital signs (blood pressure, heart rate, respiratory rate, oral temperature, height, 
and weight). 
 
• Concomitant medications. Concomitant medications taken during the time period 
beginning 28 days prior to initial dosing, on Day 1/Week 1, through the Week 12 
assessment (and, for MTD patients continuing on study drug treatment, through 
the last study drug instillation) will be collected (see Section 10.8). 
 
• Pregnancy test (if patient is female and of child-bearing potential). 
 
• CBC with differential within 7 da ys of Day 1/Week 1.  
 
• Clinical chemistries within 7 days of Day 1/Week 1. Clinical chemistries consist 
of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
calcium, glucose, albumin, total protein, uric acid, phosphorus, AST, ALT, 
alkaline phosphatase, GGT, total bilirubin, and creatine kinase. 
 
• Urinalysis within 7 days of Day 1/Week 1.  
 
• Electrocardiogram. A 12-lead ECG w ithin 42 days of Day 1/Week 1 must be 
available. An ECG performed within this timeframe in preparation for the 
TURBT is acceptable. 
 
• Tests for HIV and hepatitis if there is suspicion or unclear history of infection 
with HIV or active infection with hepatitis B or hepatitis C. Patient with known 


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history of infection with HIV or active infection with hepatitis B or hepatitis C are 
not eligible for enrollment.  
 
8.4. 
Patient Registration and Replacement of Patients 
 
Because this study is being conducted at more than one study center, the enrollment of 
patients, assignment to cohorts, and opening of each sequential cohort will be controlled 
centrally for all study centers by Halozyme. Each time a new patient is consented for the 
study, the study center must immediately fax the updated Screening Log to Halozyme or 
its designee. In turn, Halozyme or its designee will keep all centers immediately apprised 
of the number of patients enrolled and patients in screening, so that new patients are not 
consented if there is no possibility of enrollment because there is no room for additional 
patients in the ongoing cohort.  
 
At the time a patient has fulfilled all eligibility criteria (see Sections 7.1 and 7.2) and if 
there is room for a patient to be enrolled in the study, the study center must fax an 
updated Enrollment/Registration Form to Halozyme or its designee. Halozyme or its 
designee will review the information, confirm eligibility, and assign a patient 
identification number. Patient identification numbers will be set aside for use at each 
study center. Halozyme or its designee will fax a Registration Form to the clinical study 
center, providing authorization to dose and confirmation of the dose cohort to which the 
new patient will be assigned. The study center must not begin dosing any new patient 
without this prior Registration Form authorization from Halozyme or its designee
• has received all protocol-specified six weekly intravesical treatments, and 
. 
 
A copy of the Screening Log and Enrollment/Registration Forms will be kept on file at 
Halozyme or its designee and at the study center in the Investigator Files. 
 
If the next patient is to be enrolled as the first patient in a new, higher dose cohort, the 
procedures discussed in Section 8.9 must be followed. 
 
Patients not meeting all evaluability criteria will be replaced. An evaluable patient is one 
who: 
 
• has had MMC plasma concentration determinations and safety assessments 
adequate for the determination of safety and tolerability.  
 
Each patient not meeting all these criteria for evaluability, including patients withdrawn 
prematurely for reasons other than toxicity, will be replaced by t he enrollment of an 
additional patient. In the event that a patient withdraws from the study prematurely, every 
effort will be made to document the reason for termination and obtain follow-up safety 
data.  
 


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8.5. 
Patient Randomization Procedures and Blinding 
 
No randomization or blinding will be involved, as this is an open-label non-randomized 
study. See Section 7.4 for patient registration procedures. 
 
8.6. 
Treatment Procedures on Day 1/Week 1 
 
As shown in Section 2.0, Schedule of Events, the following activities are to be completed 
on this day. 
 
• Verification of all inclusion and exclusion criteria (see Sections 7.1 and 7.2) 
 
• Karnofsky performance status (see Appendix B). 
 
• Interim medical history (this history is for the interim period of time since the 
medical history previously performed, between Days -28 and Day -1). 
 
• Targeted physical exam (this physical exam is targeted at observations on a 
review of systems and follow-up of any findings on the previous physical exam). 
 
• Vital signs (blood pressure, pulse, oral temperature, and weight). 
 
• Concomitant medications.  
 
• Predose CBC with differential. The local lab will receive and analyze blood 
drawn for a CBC and differential on a “stat” basis. 
 
Intravesical dosing with 
study medication(s) on an individual patient basis on a given treatment day 
must not be done until CBC and differential results are known and the ANC 
is confirmed to be ≥ 1,500/mm3 and the platelet count is ≥ 75,000/mm3. 
• Predose clinical chemistries. These blood samples will be drawn at the same time 
as the CBC and differential. Samples will be sent to the central lab for analysis.  
 
• Predose urinalysis. A urine sample will be obtained from each patient prior to 
intravesical dosing with study medication and sent to the central lab for analysis. 
 
• Predose urine dipstick analysis. In addition to the full urinalysis at Day 1, a urine 
dipstick analysis is performed on t he day of dosing, and the results must be 
known with no evidence of urinary tract infection prior to study drug dosing
 
. 
• Urine biomarkers for bladder carcinoma. The NMP22® BladderChek® Test will 
be performed in clinic on a urine specimen obtained between midnight and noon, 
and collected more than five days after cystoscopy/TURBT. The UroVysion 
test will be obtained in the clinic and sent to a central vendor lab for analysis.  
 


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• Intravesical instillation of MMC (see Sections 9.1 and 9.3). All blood and urine 
samples must be obtained and results for CBC with differential and urine dipstick 
analysis must be known prior to intravesical dosing of MMC
 
. 
• Blood collection for pharmacokinetics (PK) for MMC and for antibodies. Blood 
samples will be drawn, sent to the appropriate laboratory, and assays performed 
immediately for MMC PK at the following timepoints:  predose, and 1 hour, 2 
hours and 3 hours after intravesical instillation of MMC. Blood will be collected 
predose for assessment of neutralizing antibodies, but will be analyzed only if the 
Week 6/Day 36 assay for antibodies is positive. 
 
• Adverse events/toxicity assessment. Assessment for AEs will commence after the 
initial exposure to MMC at this visit, and continue during the study (see 
Sections 10.1 through 10.6).  
 
8.7. 
Treatment Procedures Week 2 through Week 6 
 
As shown in Section 2.0, Schedule of Events, the following activities are to be completed 
on the clinic visit days at each of these weekly visits. 
 
• Karnofsky performance status (see Appendix B). 
 
• Interim medical history (this history is for the interim period of time since the 
previous medical history). 
 
• Targeted physical exam (this physical exam is targeted at observations on a 
review of systems and follow-up of any findings on the previous physical exam). 
 
• Vital signs (blood pressure, pulse, oral temperature, and weight). 
 
• Concomitant medications. 
 
• Predose CBC with differential. The local lab will receive and analyze blood 
drawn for a CBC and differential on a “stat” basis. 
 
Intravesical dosing with 
study medication(s) on an individual patient basis on a given treatment day 
must not be done until CBC and differential results are known and the ANC 
is confirmed to be ≥ 1,500/mm3 and the platelet count is ≥ 75,000/mm3. 
• Predose clinical chemistries. These blood samples will be drawn at the same time 
as the CBC and differential. Samples will be sent to the central lab for analysis. 
 
• Predose urine dipstick analysis. A urine dipstick analysis is performed on t he day 
of dosing, and the results must be known with no evidence of urinary tract 
infection prior to study drug dosing
 
. 


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• Intravesical instillation of MMC with the appropriate dose of Chemophase (see 
Sections 9.1 through 9.3). All blood and urine samples must be obtained and 
results for CBC with differential and urine dipstick analysis must be known prior 
to intravesical dosing of Chemophase and MMC
 
. 
• Blood collection for pharmacokinetics (PK) for MMC and rHuPH20 and for 
antibodies. Blood samples will be drawn, sent to vendor laboratory, and assays 
performed immediately for MMC and rHuPH20 PK on the following schedule:   
 
 Week 2/Day 8
 
:  Both MMC and rHuPH20 at predose, and 1, 2 and 3 hours 
postdose after intravesical instillation of MMC.  
 Week 5/Day29
 
:  MMC only at predose, and 1, 2 and 3 hours postdose 
after intravesical instillation of MMC. 
 Week 6/Day 36
 
:  Both MMC and rHuPH20 at predose, and 1, 2 and 3 
hours postdose after intravesical instillation of MMC. 
 Week 6/Day 36
 
:  B lood collected for neutralizing antibodies at 3 hours 
postdose after intravesical instillation of MMC. 
 T
 
he plasma concentration of MMC must be known to be < 100 ng/mL for 
a given patient prior to the next intravesical dosing of study medications 
(see Section 8.8). 
• Adverse events/toxicity assessment (see Sections 10.1 through 10.6).  
 
8.8. 
Dose-Limiting Toxicity (DLT) 
 
A dose-limiting toxicity (DLT) is defined as any of the following: 
 
• plasma MMC concentration ≥ 100 ng/mL,  
 
• National Cancer Institute (NCI) Common Terminology Criteria (CTC) (Version 3 
or current version) adverse event Grade 3 or higher toxicity (see 
http://ctep.cancer.gov/reporting/ctc.html) [12], or  
 
• new, treatment-emergent diagnosis of bladder fibrosis.  
 


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8.9. 
Escalation to Next Dose Cohort, Stopping Rules, and Determination of MTD 
 
In each cohort, at Week 1, patients will receive MMC 40 mg in 20 mL of sterile water 
alone (without Chemophase). If no dose-limiting toxicities (DLTs) are observed (see 
Section 8.8) during this and subsequent study drug treatments, this will be followed by 
five weekly instillations (Week 2 t hrough Week 6) of the specified dose of Chemophase 
followed by MMC 40 mg in 20 mL as long as no DLTs are observed with the previous 
instillations.  
 
A flow diagram of the dose escalation schema and stopping rules is provided in 
Figure 8.9-A. If at any time during the study, 1 of the 3 patients in a given cohort 
experiences a DLT, an additional 3 patients will be enrolled in that same cohort before 
consideration of enrolling the next higher dose cohort.  
 
If 2 or more out of 3 patients, or 2 or more out of 6 patients, in a given cohort experience 
a DLT, that dose will be declared not tolerated and 3 additional patients will be enrolled 
in the next lower dose cohort.  
 
If 0 or 1 patient at the highest cohort studied to date experiences a DLT, 3 additional 
patients will be enrolled at that same dose.  
 
If the dose in a given cohort is found to be not tolerated after dosing has begun in the next 
higher dose cohort, all patients in that next higher dose cohort will be immediately dose 
reduced to the highest dose cohort that has not been determined to be intolerable.  
 
The maximum tolerated dose (MTD) is defined as the dose level at which ≤ 2 of 6 
patients experience a DLT.  
 




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8.10. Premature Termination of Treatment/Withdrawal of Patients 
 
The Investigator must guard the patient’s welfare and should discontinue study drug 
treatment at any time that this action appears to be in the patient’s best interest. Patients 
may discontinue study drug treatment and may withdraw or be removed from the study at 
any time. Possible reasons for such actions may include, but are not limited to, the 
following: 
 
• Dose-limiting toxicity, as defined in Section 8.8. 
• Clinical need for concomitant or ancillary therapy that is not permitted during the 
study (e.g., intravesical therapy other than study medications) (see Section 7.3). 
• Unrelated intercurrent illness that in the judgment of the Investigator will 
significantly affect assessments of clinical status. 
• Pregnancy (see Section 10.7). 
• General or specific changes in the patient’s condition that in the judgment of the 
Investigator render the patient unacceptable for further study drug treatment. 
• Patient’s request to withdraw. 
• Unwillingness or inability to comply with study requirements. 
 
It is the right and duty of the Investigator to interrupt the treatment of any study patient 
whose health or well-being may be threatened by continuation in this study. Such patients 
should have study drug treatment discontinued, rather than be continued under a modified 
treatment regimen that is not within the specifications of this protocol.  
 
Once a study patient has received MMC or Chemophase under this protocol, the patient 
must be followed for safety as required in the protocol (see Section 10). In the event that 
a study patient withdraws from the study prematurely, every effort will be made to 
document the reason for premature termination and obtain follow-up safety data. The 
specific reason for and date of the premature discontinuation will be documented in the 
CRFs. The date of the last dose of study medications will also be documented.  
 
Should the enrollment rate lag or significant numbers of clearly non-eligible and/or non-
evaluable patients be entered in the study, Halozyme may elect to terminate the study. 
Halozyme also has the right to terminate the study at any time for non-adherence to 
protocol, unavailability of the Investigator or his or her study staff for Halozyme or its 
designated monitoring personnel, or for administrative reasons, at any time. 
 
8.11. Post-Treatment Procedures at Week 8 
 
As shown in Section 2.0, Schedule of Events, the following activities are to be completed 
on the Week 8 clinic visit day. 
 
• Karnofsky performance status (see Appendix B). 
 
• Complete physical exam 
 


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• Vital signs (blood pressure, pulse, oral temperature, and weight). 
 
• Concomitant medications. 
 
• Pregnancy test if female patient of child-bearing potential. 
 
• CBC with differential. 
 
• Clinical chemistries. 
 
• Urinalysis. 
 
• 12-Lead electrocardiogram. 
 
• Urine biomarkers for bladder carcinoma. The NMP22® BladderChek® Test will 
be performed in clinic on a urine specimen obtained between midnight and noon, 
and collected more than five days after cystoscopy/TURBT. The UroVysion 
test will be obtained in the clinic and sent to a central vendor lab for analysis. 
 
• Adverse events/toxicity assessment (see Sections 10.1 through 10.6).  
 
8.12. Post-Treatment Procedures at Week 12 
 
As shown in Section 2.0, Schedule of Events, the following activities are to be completed 
at the Week 12 clinic visit day. 
 
• Karnofsky performance status (see Appendix B). 
 
• Interim medical history (this history is for the interim period of time since the 
previous medical history). 
 
• Targeted physical exam (this physical exam is targeted at observations on a 
review of systems and follow-up of any findings on the previous physical exam). 
 
• Vital signs (blood pressure, pulse, oral temperature, and weight). 
 
• Concomitant medications. 
 
• Cystoscopy with bladder tumor assessment, accompanied by urine cytology and 
estimate of bladder capacity. 
 
• CBC with differential. 
 
• Clinical chemistries. 
 


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• Adverse events/toxicity assessment (see Sections 10.1 through 10.6).  
 
8.13. Long-Term Maintenance Therapy and Follow-Up (Following Week 12) 
 
Long-term follow-up for disease monitoring for all patients will start 3 months after the 
last of the weekly study drug treatments for every study patient and be performed every 
three (3) months for two (2) years after Day 1 or until the time of first bladder tumor 
recurrence if earlier (see Section 2.0, Schedule of Events). For the purpose of this study, 
tumor recurrence is defined as a biopsy that histologically confirms the recurrence of 
bladder carcinoma. It is expected that patients will be receiving standard of care 
according to the judgment of the Investigator and/or the patient’s other physician(s).  
 
For all patients NOT treated at the MTD
The 12 patients treated at MTD will continue to receive combination therapy at the same 
dose as during their six weekly treatments every three months until the end of Year 2 or 
until the time of documented tumor recurrence, whichever occurs first. Thus, they are 
intended to receive up to seven maintenance treatments in addition to the six initial 
weekly treatments. The maintenance treatments are intended to immediately follow the 
standard of care clinic evaluations and cystoscopies for monitoring of tumor recurrence. 
As shown in Section 2.0, Schedule of Events, the following activities are to be completed 
every three months after the Week 12 clinic visit to the end of 2 years from Day 1 for 
those patients still being treated at MTD. 
 
, there are no protocol-required activities during 
this 2years term except for first recurrence status and survival.  
 
• Interim medical history (this history is for the interim period of time since the 
previous medical history). 
 
• Targeted physical exam (this physical exam is targeted at observations on a 
review of systems and follow-up of any findings on the previous physical exam). 
 
• Vital signs (blood pressure, pulse, oral temperature, and weight). 
 
• Concomitant medications. 
 
• Cystoscopy (standard of care for monitoring of tumor recurrence), with urine 
cytology and estimate of bladder capacity. 
 
• Predose CBC with differential. The local lab will receive and analyze blood 
drawn for a CBC and differential on a “stat” basis. 
 
Intravesical dosing with 
study medication(s) on an individual patient basis on a given treatment day 
must not be done until CBC and differential results are known and the ANC 
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• Predose urine dipstick analysis. A urine dipstick analysis is performed on t he day 
of dosing, and the results must be known with no evidence of urinary tract 
infection prior to study drug dosing
 
. 
• After completion of cystoscopy and if no clinical contraindication, intravesical 
instillation of MMC with the defined MTD dose of Chemophase. Hematology and 
urine samples must be obtained and results for CBC with differential and urine 
dipstick analysis must be known prior to intravesical dosing of Chemophase and 
MMC
 
. 
• Adverse events/toxicity assessment (see Sections 10.1 through 10.6).  
 
Also as shown in Section 2.0, Schedule of Events, the following activities are to be 
completed 6 weeks before the every-three-month v isits after the Week 12 clinic visit for 
those patients still being treated at MTD
• Urine biomarkers for bladder carcinoma. The NMP22® BladderChek® Test will 
be performed in clinic on a urine specimen obtained between midnight and noon, 
and collected more than five days after cystoscopy/TURBT. The UroVysion test 
will be obtained in the clinic and sent to a central vendor lab for analysis. If either 
biomarker results are suggestive of tumor recurrence, it is anticipated that the 
patient will be brought back for a clinic evaluation as soon as possible, and 
undergo cystoscopic evaluation, if indicated. 
. 
 
 
9. 
STUDY MEDICATIONS AND ADMINISTRATION 
 
9.1. 
Mitomycin (Mitomycin C, MMC) 
 
9.1.1. 
Supply of MMC 
 
Commercially available MMC will be obtained through Halozyme and provided to the 
Investigator for this study. For the convenience of the Investigator, a representative U.S. 
package insert for MMC is provided in Appendix C, and a representative Canadian 
package insert and United Kingdom SPC for MMC are provided in Appendices D 
and E, respectively, current as of the date of this protocol version. It is the responsibility 
of the Investigator to refer to the appropriate product label that is current as of the time of 
treatment and management decisions. 
 
As noted in the U.S. package insert, MMC for injection is a sterile dry mixture of 
mitomycin and mannitol, which, when reconstituted in sterile water, provides a solution. 
MMC is supplied in individually-boxed vials of 5 mg, 20 mg, and 40 mg strengths. For 
this clinical trial, MMC will be supplied in 40 mg vials. Each 40 mg vial of MMC 
contains mannitol 80 mg. Each vial will be labeled with the study protocol number and 
the statement “Caution:  New Drug – Limited by Federal Law to Investigational Use.”  
The label will designate a space for the study center to enter the patient identification 


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number and initials. MMC vials will be supplied to each study center as bulk drug 
supply, and will not be labeled in advance to a specific patient identification number. 
 
9.1.2. 
Storage and Stability of MMC 
 
As noted in a representative U.S. package insert (see Appendix C), unreconstituted 
MMC should be stored at a controlled room temperature of 15ºC to 30ºC (59ºF to 86ºF), 
and is stable for the lot life indicated on t he package. Excessive heat (over 40ºC) should 
be avoided. All MMC supplies must be kept in a secure area with access limited to 
authorized clinical investigation personnel. 
 
When reconstituted for injection with sterile water to a concentration of 0.5 mg per mL, 
MMC is stable for 14 da ys refrigerated or 7 days at room temperature. Reconstituted 
solution should be protected from light. 
 
9.1.3. 
Procedures for Proper Handling and Disposal of MMC 
 
As noted in a representative U.S. package insert (see Appendix C), procedures for proper 
handling and disposal of anticancer drugs should be considered. Several guidelines on 
this subject have been published (see References 1-7 in Appendix C). There is no 
general agreement that all of the procedures recommended in the guidelines are necessary 
or appropriate. 
 
Anyone exposed to MMC should be cautioned to avoid contact with the skin. Study 
patients should be instructed to wash hands and genitals after voiding intravesically 
administered MMC. Towels or washcloths used by study patients should be thoroughly 
washed after use. 
 
Vials and any unused portions of vials must be handled in a manner consistent with the 
safe management of non-infectious biohazard material. For accidental spills, wear 
protective gloves and avoid physical contact during removal. Use normal clean-up 
procedures for liquid spillage and wash thoroughly with water.  
 
9.1.4. 
Preparation of MMC for Intravesical Instillation 
 
The reconstituted MMC for intravesical instillation will be aseptically prepared at the 
clinical study centers or designated pharmacies. For use in this clinical trial, 20 mL of 
sterile water will be added to one 40 mg vial of MMC, resulting in a concentration of 
2 mg/mL. The reconstituted MMC can be shaken to dissolve. If the MMC does not 
dissolve immediately, it can be allowed to stand at room temperature until a solution is 
obtained. For this clinical trial, MMC should be reconstituted no more than 24 hours 
before intravesical administration and stored a room temperature. The reconstituted 
MMC will not be admixed with the Chemophase solution for instillation (see 
Section 9.2.3), but rather will be instilled following instillation of the Chemophase 
solution and the sterile saline. The reconstituted MMC will then be delivered to the 
catheter for intravesical instillation (see Section 9.3).  


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All MMC vials supplied for this study, both used and unused, must be retained for drug 
accountability. The patient ID number and initials, and date of preparation, should be 
written in ink on the vial label. See Section 12.5 regarding drug accountability. 
 
9.2. 
Chemophase (rHuPH20) 
 
9.2.1. 
Formulation and Supply of Chemophase 
 
The rHuPH20 active pharmaceutical ingredient (API) in Chemophase is a frozen solution 
at 1 mg/mL, pH 6.8, in 10 mM Hepes and 130 mM sodium chloride. The rHuPH20 drug 
substance will be supplied by Halozyme in 1.0 mL and 5.0 mL Type I glass vials w ith a 
Type I bromobutyl rubber serum stopper, bot h with a concentration of approximately 
100,000 U/mL (see Section 9.2.3). Each vial will be labeled with the study protocol 
number and the statement “Caution:  New Drug – Limited by Federal Law to 
Investigational Use.”  The labels will designate a space for the study center to enter in ink 
the date the vial was first opened. Chemophase vials will be supplied to each study center 
as bulk drug supply, and will not be labeled in advance to a specific patient identification 
number. 
 
The Chemical Abstracts Index Name for rHuPH20 is 36-482-Hyaluronoglucosaminidase 
PH20 (human). The CAS Registry Number is [757971-58-7]. The USAN name is 
hyaluronidase (human recombinant). 
 
9.2.2. 
Storage and Stability of Chemophase 
 
Chemophase must be stored frozen. The recommended storage condition for the 
Chemophase API solution is -20 ± 5º C. All Chemophase supplies must be kept in a 
secure area with access limited to authorized clinical investigation personnel.  
 
Vials of Chemophase must be thawed (see Section 9.2.3) prior to removal of 
Chemophase for dosing, but any remaining material in the vial will be immediately re-
frozen at -20 ± 5º C. A given vial may be thawed, fluid withdrawn, and then frozen up to 
a total of five times, or over a maximum elapsed time of 12 months (or longer, as may be 
amended from time to time by the Sponsor based on additional stability data), whichever 
occurs first, after which the vial may not be used for any further dosing. 
9.2.3. 
Preparation of Chemophase for Intravesical Instillation 
The vial labels 
will designate a space for the study center to record in ink the “date opened.” 
 
 
The solution of Chemophase for intravesical instillation will be aseptically prepared at 
the clinical study centers or designated pharmacies. For this clinical trial, Chemophase 
should be prepared no more than 24 hours before intravesical administration. In 
preparation for patient dosing, the Chemophase vial should be removed the freezer and 
allowed to thaw either in the refrigerator for at least several hours (typically overnight) or 
at room temperature for at least one hour but not more than 24 hours. Chemophase should 


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be protected from bright light and heat. Thaw only enough vials to prepare the required 
dose.  
 
After the vial is completely thawed, the volume of solution appropriate for the dose of 
Chemophase to which the patient is assigned will be drawn into a syringe. The size and 
graduation markings of the syringe that is used should be appropriate for measuring 
volumes to the nearest 0.1 mL. The specific activity of Chemophase is anticipated to 
range from 100,000 to 120,000 units/mL. The volume of Chemophase to be instilled is 
based on an average of 110,000 units/mL (see Table 9.2-A). As shown in Table 9.2-A, 
the total volume of Chemophase drawn from the vial also provides for up to 0.2 mL 
hold-up volume due to filtering through the syringe filter. 
 
After the solution is drawn from the vial, the syringe needle will be removed and 
exchanged for a 0.2 micron syringe filter. This syringe filter has a hold-up volume of 0.1 
to 0.2 mL, which must be taken into account when withdrawing the dose to be dispensed. 
Next, the plunger on t he syringe is depressed and a small volume (approximately 0.1 mL) 
of the solution passed through the filter and discarded until the remaining volume of the 
solution in the syringe matches the exact volume for intravesical administration (e.g., for 
Cohort 1, a total of 0.4 mL is drawn into the syringe, the syringe needle replaced with the 
syringe filter, and the volume in the syringe is reduced to exactly 0.2 mL by expelling 
solution through the filter). After discarding the excess volume to reduce the remaining 
volume to the exact amount for intravesical instillation, the solution will then be passed 
through this filter as it is delivered into the catheter for intravesical instillation (see 
Section 9.3).  
 
The Chemophase solution for intravesical instillation will not be admixed with the 
reconstituted MMC for instillation (see Section 9.1.4), but rather will be instilled prior to 
instillation of the reconstituted MMC and before the instillation of the amount of sterile 
saline needed to follow the Chemophase to add up t o total of 8 mL (see Section 9.3).  
 
Table 9.2-A. Volume of Chemophase Withdrawn 
from Vial for Intravesical Administration 
 
 
Cohort 
Units of 
Chemophase for 
Instillation 
Volume of Chemophase 
Actual mL for 
Instillation 
Extra mL for 
Hold-up in Filter 
Total mL Drawn 
into Syringe 
1 
  20,000 
0.2 
0.2 
0.4 
2 
  60,000 
0.5 
0.2 
0.7 
3 
200,000 
1.8 
0.2 
2.0 
4 
400,000 
3.6 
0.2 
3.8 
5 
800,000 
7.3 
0.2 
7.5 
 
At the initial use of vial, the date that solution was first removed from the vial will be 
written in ink on the vial label and the vial immediately returned to the freezer. Each time 
the vial is thawed and solution removed, the date will be recorded. Note that the vials are 
not specific to an individual patient, and more than one patient can be dosed from the 
same vial. As noted in Section 9.2.2, a given vial may be thawed, fluid withdrawn, and 


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then frozen up to a total of five times, or over a maximum elapsed time of 10 months (or 
longer, as may be amended from time to time by the Sponsor based on additional stability 
data), which occurs first, after which the vial may not be used for any further dosing. 
 
The smallest number of vials necessary for a given intravesical instillation should be 
used. In general, the 1 mL-solution vials will be used for the lower doses (earlier cohorts) 
and the 5 mL-solution vials will be used for the higher doses (later cohorts). For example, 
for Cohorts 1 and 2, a 1 mL-solution vial w ill be used for the first, 0.2 or 0.6 mL volumes 
of instillation, respectively. The vial may be re-frozen and later thawed for continued use 
for subsequent dosing until the vial is empty. If there is insufficient volume in a given 
vial to complete a dose, the volume from that vial will be supplemented with volume 
from the next vial from the same lot number. Unless it is unavoidable in order to continue 
dosing of a patient without interruption, for any single instillation no patient should 
receive Chemophase study drug from more than one lot number
9.3. 
Dosing Schedule and Procedure for Intravesical Instillation of MMC with 
and without Chemophase 
. It is preferable to limit 
the number of lot numbers to which any given patient is exposed over the duration of that 
patient’s total exposure to Chemophase. For Cohorts 3, 4, and 5, the 5 mL-solution vials 
will be used in the same manner as the 1 mL-solution vials. For planning an adequate 
supply of study drug, note that it is not possible to extract the full 1.0 mL from a 1 mL-
solution vial, or the full 5.0 mL from a 5 mL-solution vial. Note also that allowances 
should be made for the 0.1 to 0.2 mL hold-up volume lost due to the syringe filter (see 
Table 9.2-A).  
 
All Chemophase vials supplied for this study, both used and unused, must be retained for 
drug accountability. See Section 12.5 regarding drug accountability. 
 
 
The only dose of MMC used in this study is 40 mg in 20 mL of Sterile Water. As shown 
in Table 9.3-A, the initial intravesical instillation (Day 1, Week 1) for each patient in 
each cohort is MMC alone (without Chemophase). For Weeks 2 through 6, the patient 
will receive five additional, weekly, intravesical instillations, which will consist of both 
Chemophase and MMC, administered sequentially in the manner described below. The 
12 patients treated at MTD will continue to receive combination therapy every three 
months until the end of Year 2 from Day 1 or until the time of documented tumor 
recurrence, whichever occurs first. 
 


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Table 9.3-A. Dosing Schedule for MMC and Chemophase 
 
Cohort 
Week 1 
(MMC Dose) 
Volume for Instillation Week 2 through Week 6 
(1) Chemophase Dose 
(2) Sterile Saline 
(3) MMC Dose 
1 
40 mg/20 mL 
  20,000 units in 0.2 mL 
7.8 mL 
40 mg/20 mL 
2 
40 mg/20 mL 
  60,000 units in 0.5 mL 
7.5 mL 
40 mg/20 mL 
3 
40 mg/20 mL 
200,000 units in 1.8 mL 
6.2 mL 
40 mg/20 mL 
4 
40 mg/20 mL 
400,000 units in 3.6 mL 
4.4 mL 
40 mg/20 mL 
5 
40 mg/20 mL 
800,000 units in 7.3 mL 
0.7 mL 
40 mg/20 mL 
1. First step of intravesical administration. 
2. Second step of intravesical administration. 
3. Third step of intravesical administration. 
 
All study patients should refrain from drinking fluids for at least eight (8) hours before 
intravesical therapy, and also during intravesical therapy, except for sips of water needed 
to take medications, unless there is a medical contraindication to this eight-hour 
dehydration. Just prior to intravesical instillation, the patient should void completely to 
empty the bladder. Using sterile technique, a catheter will be inserted in the bladder and 
the bladder will be carefully emptied of any residual urine using the catheter. The volume 
of any residual urine will be recorded. If necessary to fully drain the bladder, the lower 
abdomen will be gently compressed and the patient may be rolled from side to side.  
 
After the bladder is fully drained of urine and the volume of urine measured, sequential 
instillation of study drugs will begin. The intravesical instillation of study drug is a three-
step procedure in this study, as outlined below. The three sequential steps of instillation 
are presented in tabular format above, in Table 9.3-A. The intermediate step, instillation 
of sterile saline, has been incorporated in this clinical trial for the sole reason of having 
the overall volume of fluid administered held constant in all patients across all cohorts. 
The syringes with the Chemophase and saline and the reconstituted MMC should be 
prepared in advance of the actual catheterization, in order to allow for no interruption in 
the stepwise instillation. 
 
• First, the volume of prepared Chemophase solution (see Section 9.2.3) will be 
passed through the syringe filter and introduced into the sterile barrel of a syringe 
of at least 25 mL connected to the urinary catheter and allowed to enter the 
bladder by gravity flow.  
 
• Second, immediately following the Chemophase, the volume of sterile saline 
solution specified in Table 9.3-A will be introduced into the sterile barrel of the 
syringe connected to the urinary catheter and allowed to enter the bladder by 
gravity flow. 
 
• Third, immediately following the sterile saline, the prepared reconstituted 20 mL 
volume of MMC (see Section 9.1.3) will be shaken to mix the contents, the 
stopper removed from the vial, and the volume immediately poured from the vial 
into the sterile barrel of the syringe connected to the urinary catheter and allowed 
to enter the bladder by gravity flow. In order to assure that all the solutions have 
passed through the catheter and into the bladder, a small volume of air may be 


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gently pushed by s yringe into the catheter. The catheter is then withdrawn from 
the bladder. 
 
This procedure should ensure that all patients in all cohorts have received a total of 
28 mL of intravesical volume at each dosing cycle.  
 
Aseptic, appropriate technique must be used during administration of intravesical 
Chemophase, sterile saline, and MMC to avoid introducing contaminants into the urinary 
tract or unduly traumatizing the urinary mucosa.  
 
After the intravesical instillation is completed, study patients will be instructed to lie on 
their abdomen for at least 15 minutes, after which the patient is intended to be 
ambulatory. Patients should retain the solution in their bladder, if possible, for a total of 
two (2) hours. If the solution cannot be retained in the bladder for the entire two hours, 
this will be noted on t he CRF along with the total bladder retention time and the reasons 
cited for a less than two-hour retention.  
 
During the intravesical procedure and afterwards, patients should be observed and 
questioned about adverse events. Two hours after intravesical instillation, patients w ill be 
instructed to empty the bladder into a urine collection container. The volume of urine 
voided will be measured and recorded in the CRF. A 5 mL aliquot of this urine will be 
frozen at -20°C and retained for possible future analysis.  
 
Patients should be instructed to carefully clean their hands and genitalia after voiding the 
intravesically administered MMC. Patients may then leave the clinic if no adverse events 
are reported or observed that require them to remain for observation or treatment. 
 
10. ADVERSE EVENTS AND SAFETY MONITORING 
 
The safety parameters collected and monitored during this study include adverse events 
(AEs), laboratory determinations, physical examination and vital signs, 12-lead ECG, 
plasma concentration of MMC, and findings noted on cystoscopy. 
 
All AEs that occur during the study should be treated appropriately to protect and ensure 
the patient’s well-being. If such treatment constitutes a deviation from this protocol, 
Halozyme must be notified and the Investigator should comply with applicable 
Institutional Review Board (IRB)/Ethics Committee (EC) reporting requirements. If the 
patient is withdrawn from the study as a result of this deviation, the reason will be 
appropriately documented. 
 
10.1. AE Definitions 
 
The following definitions of terms are guided by the International Conference on 
Harmonization and the U.S. Code of Federal Regulations [21 CFR 312.32, effective 6 
April 1998] and are included herein. The terms "serious adverse event" and "adverse 
event," inserted in parentheses, are commonly used terminology. 


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An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product which does not necessarily 
have a causal relationship with this treatment. 
 
Serious adverse drug experience
• Is 
 (serious adverse event, SAE) is any adverse drug 
experience (AE) occurring at any dose that results in any of the following outcomes:   
 
fatal or immediately life-threatening
 
 (life-threatening is defined as a medical 
event during which the patient is at immediate risk of death from the reaction as it 
occurred; it does not include an event that, had it occurred in a more serious form, 
might have caused death); 
• Requires hospitalization, or prolongs existing hospitalization
 
. Any in-patient 
hospital admission, regardless of duration of hospital stay, will be considered as 
in-patient hos pitalization. Hospitalizations for procedures scheduled prior to 
enrollment into the study and emergency room visits do not constitute a serious 
AE. 
• Results in persistent or significant disability/incapacity
 
; 
• Results in a congenital anomaly or birth defect
 
; or 
• Is any other Important Medical Event. 
 
Important Medical Events that may not 
result in death, be life-threatening, or require hospitalization may be considered 
SAEs when, based upon appropriate medical judgment, they may jeopardize the 
patient or require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias, or convulsions that do not result in hospitalization of the patient, 
or the development of drug dependency or drug abuse. 
Life-threatening is any adverse drug experience (adverse event) that places the patient or 
subject, in the view of the Investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, 
might have caused death. 
 
Associated with the use of the drug means that there is a reasonable possibility that the 
experience (adverse event) may have been caused by the drug. 
 
Unexpected adverse drug experience means any adverse drug experience (adverse event), 
the specificity or severity of which is not consistent with the current Investigator 
Brochure (IB). 
 


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10.2. Pre-Treatment-Emergent Adverse Events 
 
Halozyme considers adverse events (AEs) that occur between the time the patient signs 
the informed consent document for the study and the time when that patient is first 
exposed to study drug (MMC or Chemophase in this study) as “pre-treatment-emergent” 
events. All known pre-treatment-emergent AEs that are serious (see Section 10.1) should 
be reported to Halozyme. The reason for collection of serious pre-treatment-emergent 
AEs is to allow for an assessment of whether or not the SAE was causally associated with 
any protocol-related activities. Halozyme will not collect information on pre-treatment-
emergent AEs that do not meet at least one accepted criterion for a serious classification 
under the most rigid and comprehensive of the applicable regulatory agency criteria for 
this study. Events occurring after first administration of study drug will be considered 
treatment-emergent AEs and will be captured on the AE CRF.  
 
10.2. Laboratory Abnormalities as Adverse Events 
 
It is anticipated that many laboratory abnormalities observed during the course of a study 
will be encompassed under a reported adverse event (AE) describing a clinical syndrome 
(e.g., elevated BUN and creatinine in the setting of an AE of renal failure, or elevated 
SGOT/SGPT in the setting of an AE of hepatitis). In these cases (e.g., an AE of renal 
failure), the laboratory abnormality itself (e.g., elevated creatinine) does not need to be 
recorded as an AE. 
 
In the absence of a reported AE identifying a clinical syndrome that encompasses the 
observed laboratory abnormality, that isolated laboratory abnormality itself should be 
reported as an AE if it is judged by the Investigator to be clinically significant for that 
patient. 
 
For the purposes of this study, criteria defining a "clinically significant" laboratory 
abnormality are: 
 
a) Laboratory abnormality leads to a dose-limiting toxicity (e.g., judged to be 
associated with study drug administration and resulting in study drug dose reduction, 
suspension or discontinuation), or 
 
b) Laboratory abnormality results in any therapeutic intervention (i.e., concomitant 
medication or therapy), or 
 
c) Other laboratory abnormality judged by the Investigator to be of other particular 
clinical relevance. 
 


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10.3. Classification of Adverse Events by Severity 
 
The Investigator must categorize the severity of each AE according to the following 
guidelines. The level of severity is guided by the National Cancer Institute (NCI) 
Common Terminology Criteria (CTC) for adverse events, which will be provided to each 
study center and is available on line at http://ctep.cancer.gov/reporting/ctc.html [12]. 
 
Mild: 
Grade 1 NCI Common Terminology Criteria AE; or  
 
if not found in the Common Terminology tables, an AE that is asymptomatic or barely 
noticeable to the patient; not interfering with patient’s daily activity performance or 
functioning; generally not requiring alteration or cessation of study drug administration; 
and/or ordinarily not needing therapeutic intervention. 
 
Moderate: 
Grade 2 NCI Common Terminology Criteria AE; or  
 
if not found in the Common Terminology tables, an AE of sufficient severity as to 
possibly make the patient moderately uncomfortable; possibly influencing the patient’s 
daily activity performance or functioning; generally not impairing the patient’s ability to 
continue in the study; and/or possibly needing therapeutic intervention. 
 
Severe: 
Grade 3 or 4 NCI Common Terminology Criteria AE; or  
 
if not found in the Common Terminology tables, an AE generally causing severe 
discomfort; significantly influencing the patient’s daily activity performance or 
functioning; generally requiring alteration or cessation of study drug administration; life-
threatening; resulting in significant disability or incapacity; and/or generally requiring 
therapeutic intervention. 
 
10.4. Classification of Adverse Events by Relationship to Study Drug 
Administration 
 
The relationship of each AE to the study drug administration will be assessed by the 
Investigator after careful consideration, and according to the following guidelines. 
Because there are two study drugs in this clinical trial (i.e., MMC and Chemophase), the 
Investigator will be expected to make his/her best assessment of the relationship of each 
event to each of the two study drugs. See Section 10.5 for information regarding the 
known toxicity profiles of MMC and Chemophase, which should guide the assessment of 
causality to each study drug.  
 


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No, Not Re lated: 
This category is applicable to those AEs that are clearly due to extraneous causes 
(concurrent drugs, environment, etc.) and do not meet the criteria for drug relationship 
listed under UNLIKELY; POSSIBLY; PROBABLY; AND YES, RELATED. 
 
Unlikely Related: 
This category applies to those AEs that are judged to be unlikely to be related to the study 
drug administration. An AE may be considered to be PROBABLY NOT RELATED 
when it meets at least two (2) of the following criteria: 
 
a) It does not follow a reasonable temporal sequence from administration of the 
study drug. 
 
b) It could readily have been produced by the patient’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the patient. 
 
c) It does not follow a known or expected response pattern to the study drug. 
 
d) It does not reappear or worsen when the study drug is re-administered. 
 
Possibly Related: 
This category applies to those AEs that are judged to be perhaps related to the study drug 
administration. An AE may be considered POSSIBLY RELATED when it meets at least 
one (1) of the following criteria: 
 
a) It follows a reasonable temporal sequence from administration of the study drug. 
 
b) It could not readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
patient. 
 
c) It follows a known or expected response pattern to the study drug. 
 
Probably Related: 
This category applies to those AEs that are felt with a high degree of certainty to be 
related to the study drug administration. An AE may be considered PROBABLY 
RELATED if it meets at least two
c) It disappears or decreases on cessation or reduction in study drug dose. There are 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
 (2) of the following criteria: 
 
a) It follows a reasonable temporal sequence from administration of the study drug. 
 
b) It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
 


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drug relatedness clearly exists (e.g., bone marrow depression, fixed drug 
eruptions, tardive dyskinesia, etc.). 
 
d) It follows a known or expected response pattern to the study drug. 
 
Yes, Related: 
This category applies to those AEs that are incontrovertibly related to study drug 
administration. An AE may be assigned to this category if it meets at least the first three
10.5. Known Toxicity Profiles of MMC and Chemophase 
 
(3) of the following criteria: 
 
a) It follows a reasonable temporal sequence from administration of the study drug. 
 
b) It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient. 
 
c) It disappears or decreases on cessation or reduction in study drug dose. There are 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug relatedness clearly exists (e.g., bone marrow depression, fixed drug 
eruptions, tardive dyskinesia, etc.). 
 
d) It follows a known or expected response pattern to the study drug. 
 
e) It reappears or worsens when the study drug is re-administered. 
 
 
As noted in Section 10.4, the Investigator is expected to make his/her best assessment of 
the causal relationship of each adverse event to each
10.5.1. 
Known Toxicity Profile of MMC 
 of the two study drugs (i.e., MMC 
and Chemophase) in this clinical trial. The information summarized below is intended to 
be only a guide to this assessment. The Investigator should base the assessment on all 
available information.  
 
 
The American Urologic Association (AUA) Bladder Cancer Guidelines Panel 1999 
Report on the Management of Non-Muscular-Invasive Bladder Cancer provided a 
summary of probability estimates of treatment complications for MMC based on its 
review of the literature [3]. Complications were grouped by local bladder symptoms, 
systemic symptoms, and other, and have been excerpted below for Table 10.5-A.  
 
Of the 28 patients who had undergone TURBT and treated with MMC alone (who 
received a total of 788 intravesical instillations) in a randomized clinical trial, five 
(17.8%) had side effects, including four with cystitis and one with skin rash [10]. 
(Note:  Of the 28 patients treated with MMC plus 200,000 units of bovine hyaluronidase 
[who received a total of 750 instillations], four [14.2%] had side effects, including three 


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with cystitis and one with skin rash. There was no significant alteration in white blood 
count during therapy.)   
 
In a separate publication, side effects of MMC plus 200,000 units of bovine 
hyaluronidase combination intravesical therapy were observed in a total of 14% (6/43) of 
patients, and consisted of bacterial cystitis (6.9%), chemocystitis (4.6%), and skin allergy 
(2.3%). No patients were withdrawn due to side effects [11].  
 
Bladder fibrosis with a reduction in bladder capacity is an uncommon but known 
complication of generally long-term intravesical MMC therapy, the incidence of which 
appears to correlate directly with the cumulative MMC dose and correlate inversely with 
the time interval between a second tumor resection and the first MMC instillation [8].  
 
Table 10.5-A. Probability Estimates of Treatment 
Complications from Intravesical MMC 
Treatment Complication 
Median Probability 
95% CI 
G/P* 
LOCAL BLADDER SYMTPOMS 
   Irritative Voiding Symptoms 
 
 
 
      Dysuria 
35% 
30-41% 
 4/456 
      Frequency/Nocturia 
42% 
26-59% 
 3/420 
      Irritative symptoms 
18% 
12-26% 
19/1596 
      Pain/Cramps 
10% 
6-14% 
1/220 
   Other Local Symptoms 
 
 
 
      Local side effects 
  5% 
3-9% 
2/296 
      Other side effects 
  2% 
0.3-4% 
1/148 
   Other 
 
 
 
      Bladder contracture 
  5% 
2-11% 
2/234 
      Bacterial c ystitis 
20% 
17-23% 
6/845 
      Hematuria 
16% 
7-28% 
7/800 
      Incontinence 
  1% 
0.4-4% 
1/220 
SYSTEMIC SYMPTOMS 
   Flu-Like 
 
 
 
      Arthralgia 
  9% 
0.1-47% 
2/278 
      Fever or Chills 
  3% 
1-7% 
5/686 
      Flu-like symptoms 
20% 
4-48% 
3/498 
   Infectious 
 
 
 
      Epid/Prost/Ureth infections 
  4% 
2-9% 
3/251 
      Hepatic changes 
     0.1% 
0-1% 
1/220 
      Pneumonia 
     0.2% 
0-2% 
1/148 
   Myelosuppression 
  2% 
0.3-7% 
2/102 
   Nausea/Vomiting 
  9% 
1-26% 
3/498 
   Skin Rash 
13% 
8-19% 
14/992 
   Systemic Side Effects 
  3% 
0.5-8% 
2/296 
OTHER 
   Treatment Incomplete 
  9% 
2-14% 
7/683 
   Treatment Interruption 
11% 
8-16% 
6/374 
* G = Number of Groups/Treatment arms extracted; P = Number of Patients in those groups. 
 


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10.5.2. 
Known Toxicity Profile of Chemophase 
 
Although there is an extensive body of knowledge establishing the clinical safety and 
tolerability of animal-derived hyaluronidases, there are no clinical data regarding the use 
of rHuPH20 administered intravesically. Except for the recently-initiated Phase I trial of 
a single administration of Chemophase and MMC, only one clinical trial has been 
conducted with rHuPH20 (except for trials of the ex vivo use of rHuPH20 to remove the 
cumulus matrix surrounding human oocytes for in vitro fertilization). This first exposure 
of rHuPH20 drug substance in humans was an investigation of the potential dermal 
sensitivity of an intradermal injection of Enhanze SC™ (rHuPH20 for injection) in 100 
normal healthy volunteers and showed no s ignal of allergy or immunogenicity. 
 
Animal-derived hyaluronidase preparations have been the subject of multiple 
investigations and regulatory approvals in Europe, the U.S. and Asia, and collectively 
encompass over 50 years of use in humans. The 11 October 2000 package insert for 
Wydase (bovine hyaluronidase) lists hypersensitivity to hyaluronidase as a 
Contraindication. Under Adverse Events, it is stated that allergic reactions (urticaria, 
angioedema) are rare, and anaphylactic-like reactions following retrobulbar block or 
intravenous injections have occurred. The U.S. FDA has indicated that recently marketed 
bovine-derived preparations have a reported level of immediate hypersensitivity of less 
than 0.1%.  
 
In 1998, Baumgartner et al. published a review of the literature of animal-derived 
hyaluronidases (Permease 7500 IU or Neopermease 200,000 IU) used additively to 
cytostastic agents in neoplastic diseases in 420 patients in a series of pilot studies [13]. 
Hyaluronidase was well-tolerated by multiple routes of administration, including 
intramuscular, intravenous, intraperitoneal, intrapleural, intrathecal, and intravesical 
routes of administration. Allergic reactions were noted in 4.2% (3/72) of patients treated 
intramuscularly, consisting of local inflammation and pain in two patients and nausea, 
vomiting, and circulation disturbance in a third. Allergic reactions were noted in 10% of 
patients treated intravenously (except for a 20% rate in astrocytoma patients), all of 
which were reversible and easily manageable.  
 
Because rHuPH20 is up to 100-fold more pure than animal-derived products based on 
activity and contains human amino acid sequences rather than bovine, it is expected that 
most or all of the allergic and immunogenic problems associated with the animal-derived 
impurities will be avoided.  
 
A Phase I safety, tolerability, and PK single-administration clinical trial (HZ2-05-02) of a 
low dose (20,000 units) of Chemophase with 40 mg MMC administered intravesically in 
a targeted sample size of five evaluable patients who had undergone transurethral 
resection of bladder tumor (TURBT) for transitional cell bladder cancer Stage Ta , T1 or 
Tis (any grade), were free of known bladder cancer recurrence, and were being monitored 
for recurrence of superficial transitional cell bladder cancer was initiated in August 2005 
and completed enrollment in March 2006. All five patients completed the study. There 
were no deaths, serious AEs, AEs judged to be possibly or more related to either study 


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drug, moderate or severe AEs, premature withdrawals, or dose-limiting toxicities. The 
only three AEs reported in the study were, by MedDRA Preferred Terms, Influenza, 
Urinary tract infection, and Acne. All plasma samples for MMC were below the lower 
limit of quantitation (10 ng/mL) and all plasma samples of PH20 were below the lower 
limit of quantitation (10 U/mL). 
 
10.6. Reporting of Adverse Events 
 
For the purpose of this study, all
10.6.1. 
Reporting of Serious Adve rse Events 
 AEs, regardless of seriousness, severity, expectedness, 
or relationship to the study drug (MMC or Chemophase in this study), will be collected if 
the date and time of onset of the AE was after the patient’s first exposure to either study 
drug and no later than 28 days after the last dose of study drug. There is no t ime 
limitation on the reporting of AEs that are treatment-emergent and assessed as reasonably 
associated with study drug (i.e., a drug-associated AE should be reported even if more 
than 28 days have passed since the last study drug treatment). 
 
Events that occur prior to first study drug administration will be considered pre-
treatment-emergent because the time of onset preceded the first exposure to study drug 
(see Section 10.2), and these observations will be captured on the patient’s Medical 
History CRF. Events occurring after first administration of study drug will be considered 
treatment-emergent AEs and will be captured on the AE CRF.  
 
Note that AEs that may be known, expected toxicities caused by MMC (see 
Section 10.5.1) and occurring during the study must be reported as AEs on the AE CRF. 
 
Patients will be questioned and/or examined by the Investigator and his/her designee for 
evidence of AEs. The questioning of study patients with regard to the possible occurrence 
of AEs will be generalized such as, “How have you been feeling since your last visit?”  
Information gathering for AEs should generally not begin with direct solicitation from 
patients regarding the presence or absence of specific AEs. 
 
All serious AEs (SAEs) occurring with any patient participating in this clinical trial must 
be reported to Halozyme as described in Section 10.6.1.  
 
 
CONTACT THE HALOZYME-DESIGNATED MEDICAL MONITOR 
IMMEDIATELY (WITHIN 24 HOURS) FOR ANY
• Reporter name and contact number, 
 SERIOUS ADVERSE EVENT. 
The minimum required information for an initial report of an SAE is:  
 
• Protocol number, 
• Site and patient identification information, and  
• The SAE term with a brief summary of the event including the causality 
assessment, if possible.  
 




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AE is judged to be related to the study drug administration. All such patients with AEs 
should be followed clinically and by the appropriate diagnostic evaluations. 
 
All AEs, regardless of severity, and whether or not ascribed to the study drug 
administration, will be recorded in the appropriate section of the CRF.  
 
10.6.4. 
Reporting of Safety Information to the Institutional Review Board 
 
It is the responsibility of the Investigator to inform the study center’s Institutional Review 
Board (IRB)/Ethics Committee (EC) of all SAEs and other safety information in 
accordance with applicable IRB’s/EC’s requirements. At the completion or early 
termination of the study, a final report should be made to the IRB/EC by the Investigator 
within the applicable IRB/EC time frames. 
 
10.7. Pregnancy 
 
A negative pregnancy test during screening for women of child- bearing potential and an 
agreement to use effective contraceptive methods during the treatment period of the study 
for men and women of child-bearing potential are be required for study eligibility. A 
pregnancy test will be repeated at Week 8 for women of child- bearing potential. 
 
Any pregnancy in a study patient must be immediately reported to the Investigator and in 
turn to Halozyme (see Section 10.6.1 for contact information). Pregnancy during the 
study period will be reported and followed until final resolution (i.e., delivery or early 
termination). Any birth defect or congenital anomaly will be reported to Halozyme 
immediately as an SAE. 
 
10.8. Concomitant Medications and Procedures 
 
Any medication taken during the study, other than study drug (i.e., MMC and 
Chemophase), is regarded as concomitant medication. A history of current medications 
will be obtained from each patient during screening and recorded in the CRF. Patients 
must be queried regarding both prescription and over-the-counter medications that they 
take. Concomitant medications taken during the time period beginning 28 days prior to 
initial dosing, on Day 1/Week 1, through the Week 12 assessment will be collected for all 
patients, and through the last study drug treatment visit for the MTD patients who are 
continuing on study drug treatment after Week 12. 
 
Concomitant medications will be updated at each subsequent visit according to the 
Schedule of Events (see Section 2), including any medication taken to treat an AE. At 
each study visit, patients will be asked if there has been any change in the medications 
they have taken since their last study visit. Changes will be recorded on t he Concomitant 
Medications CRF. 
 


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Recording of concomitant medications will include the name of the drug, dosage, route, 
frequency, date of treatment, and the clinical indication for which the medication was 
taken.  
 
Patients may receive medical care during the study including but not limited to 
antibiotics, analgesics, antipyretics, etc., when clinically indicated. Whenever possible, 
the patient should avoid starting any new medications during the treatment period of this 
study (including over-the-counter medications) unless the Investigator deems such 
medication medically necessary. A list of medications prohibited during the study is 
provided in Section 7.3 of this protocol. 
 
11. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
11.1. Study Hypotheses 
 
This is a study to primarily assess the safety and tolerability of Chemophase administered 
intravesically with MMC. The primary objective is to determine the MTD and DLTs of 
escalating doses of Chemophase with MMC and establish the dose of Chemophase 
recommended for future studies. It is anticipated, based on previous human studies using 
intravesical bovine hyaluronidase along with MMC, that Chemophase will be well 
tolerated and will not appreciably increase the systemic absorption or toxicity of MMC.  
 
A secondary objective of this study is to observe patients for any preliminary evidence of 
anti-tumor activity of Chemophase and MMC when co-administered intravesically. 
Based on nonclinical data of rHuPH20 in various tumor cell models and on previous 
human studies using intravesical bovine hyaluronidase along with MMC, it is 
hypothesized that, compared to historical data of MMC monotherapy, Chemophase with 
MMC will reduce the risk of tumor recurrence. However, this early study of Chemophase 
in humans is neither designed nor powered to show statistical significance or otherwise 
confirm an anti-tumor effect of Chemophase.  
 
In 1995, a Southwest Oncology Group Study comparing BCG to MMC intravesical 
therapy (weekly for six weeks, then monthly for one year) found a median time to tumor 
recurrence or death from any cause of 22 months for the 186 patients treated with MMC 
20 mg in 20 mL water [14].  
 
In 2001, the International Mitomycin C Consortium published a randomized clinical trial 
of six weekly intravesical treatments showing the median time to recurrence for 119 
patients in an optimized treatment arm (MMC 40 mg, PK manipulations to decrease urine 
volume, and urine alkalinization) was 29.1 months (95% CI 14.0 to 44.2 months) 
compared to 111 patients on standard, non-optimized therapy (MMC 20 mg) who had a 
median time to recurrence of 11.8 months (95% CI 7.2 to 16.4 months) [15]. 
 
Urine biomarkers for bladder cancer obtained at baseline and Week 8 (and beyond 
Week 8 for the MTD patients who are continuing on study drug treatment) will be 
assessed. The NMP22® BladderChek® Test biomarker is performed in clinic on a urine 


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specimen obtained between midnight and noon, and collected more than five days after 
cystoscopy/TURBT. The UroVysion test biomarker will be obtained in the clinic and 
sent to a central vendor lab for analysis. 
 
11.2. Patient Data Sets for Analysis 
 
All patients randomized and receiving one or more doses of Chemophase will be 
included in the safety analysis data set. Any patient receiving MMC on study but not 
receiving Chemophase will be considered for safety, but assessed separately from 
patients receiving Chemophase. 
 
A modified “intent-to-treat” (ITT) analysis data set for anti-tumor effects includes all 
patients receiving one or more doses of Chemophase with MMC. Patients who enter the 
baseline screening period but are not treated with Chemophase plus MMC will not be 
included in this modified ITT analysis.  
 
A “per-protocol” analysis for anti-tumor effects will include all ITT patients who met the 
following criteria:   
 
• Satisfied the disease-defining Inclusion Criteria #1 and #2 (see Section 7.1),  
• Received at least four protocol-specified doses of Chemophase with MMC over 
an interval not exceeding 8 weeks, 
• Retained at least four intravesical instillations for at least 90 minutes, and  
• Were monitored to the time of tumor recurrence, or at least 5 years, whichever 
occurs first. 
 
A listing of all screen failures, with the reasons for failure, will be recorded on the patient 
screening log. A patient listing of screen failures and a tabulation of the reasons for 
screen failure will be prepared. 
 
11.3. Endpoints and Statistical Analyses 
 
The primary endpoint in this study is the rate of toxicities observed with the combination 
of Chemophase and MMC. The primary statistical analysis w ill consist of point estimates 
and the 95% confidence intervals constructed around the point estimates. All safety data 
will be examined, such as AEs (including overall incidence by treatment group), physical 
examination findings and vital signs, laboratory data, plasma MMC concentration, and 
ECGs. Descriptive statistics will be used to summarize all safety variables. The MTD 
will be determined based on DLTs (see Sections 8.8 and 8.9). 
 
All AEs and toxicities will be recorded on the appropriate CRFs and reported according 
to severity and assessed relationship to the study medications. The NCI CTC grading of 
severity for AEs (CTCAE) Version 3 or higher [12] and the latest version of MedDRA 
will be used for reporting and medical coding of AEs. All AEs regardless of causality 
will be individually listed. The incidence of patients with AEs will be tabulated by 
MedDRA System Organ Class (SOC), Preferred Term, grade or severity, and also 


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summarized by study center. SAEs will also be listed and summarized separately. AEs 
will also be separated into localized bladder and systemic events.  
 
Based on the long-term follow-up monitoring, the data will be assessed for the median 
time to tumor recurrence and the two-year recurrence rate. 
For the purpose of this study, tumor recurrence is defined as a biopsy that histologically 
confirms the recurrence of bladder carcinoma. Recurrences will be characterized with 
regard to the number of tumors, TNM stage, and grading. Information on tumor 
progression will be summarized. The data collected on the urine biomarker, comparing 
baseline to post-baseline values, will be summarized.  
 
11.4. Sample Size Considerations 
 
This is a Phase I-IIa multiple dose study of Chemophase in humans, and is neither 
designed nor powered for formal statistical comparisons. The study does not include a 
MMC-only control arm or other parallel control group. The sample size of 3 to 6 patients 
per dose cohort is standard for the determination of safety and tolerability in many initial 
clinical trials for oncology indications. The protocol intends a sample size of 12 evaluable 
patients treated at the MTD level, and it is believed that 12 patients will provide an 
adequate sample size to establish the tolerability of this dose regimen for the anticipated 
subsequent clinical trials and possibly provide a preliminary estimate of anti-tumor 
activity. 
 
11.5. PK Analyses and Neutralizing Antibodies to rHuPH20 
 
A secondary endpoint of this study is to assess the pharmacokinetics (PK) of intravesical 
administration of MMC alone (at Week 1) and in combination with Chemophase 
(subsequent weeks). Samples will be collected and assayed according to the schedule in 
Section 8, and according to Footnote 7 in the Schedule of Events in Section 2. Although 
samples will be collected for neutralizing antibodies (NABs) at Week 1 and Week 6, the 
Week 1 samples will be assayed only if the Week 6 sample shows evidence of NABs.  
 
12. REGULATORY/ADMINISTRATIVE PROCEDURES AND 
DOCUMENTATION 
 
12.1. Ethics 
 
This study will be conducted under a U.S. Investigational New Drug (IND) Application. 
All applicable U.S. regulations governing human subject protection must be followed. All 
ethical and regulatory requirements necessary to comply with the principals of Good 
Clinical Practice (GCP) for the conduct and monitoring of clinical investigations must be 
followed.  
 
To ensure ethical conduct of this clinical study, Investigators will be expected to adhere 
to basic principles provided from generally recognized guidelines such the Belmont 
Report and the International Ethical Guidelines for Biomedical Research Involving 


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Human Subjects. The study has been designed to involve the participation of 
representative patients affected by the disease under investigation. Participants must have 
provided written informed consent to document their voluntary participation in this study. 
Updated safety information will be provided to the Investigators, Institutional Review 
Boards (IRBs)/Ethics Committees (ECs) and patients as necessary in order that they may 
consider relevant and emerging information that could affect their willingness to continue 
participation in this study. 
 
12.2. Institutional Review Board and Approval 
 
In accordance with 21 CFR Parts 50 and 56, the Investigator agrees to provide the 
appropriate Institutional Review Board (IRB)/Ethics Committee (EC) with all appropriate 
material, including a copy of the protocol, informed consent form (ICF), Investigator’s 
Brochure (IB), and any proposed advertisement for the study prior to the start of the 
study.  
 
The proposed informed consent form (ICF) and any proposed advertisement must also be 
agreed to by t he Sponsor (Halozyme). A copy of the IRB/EC approval letter of the 
protocol and the ICF must be supplied to Halozyme prior to consenting any patients for 
the study. A copy of the IRB/EC approval letter of any protocol amendments and any 
advertisements must be supplied to Halozyme prior to implementing these documents. 
The study may not begin screening or enrolling patients until the Investigator has 
obtained IRB/EC approval of the protocol and ICF and Halozyme has received a 
hardcopy documentation of each.  
 
The Investigator will supply to Halozyme a list of the names, professions, and affiliations 
of IRB/EC members to demonstrate compliance with membership requirements. If the 
Investigator or a subinvestigator is a routine voting member of the IRB/EC, Halozyme 
will be provided with a statement from the IRB/EC that the Investigator/subinvestigator 
did not and will not vote on the subject of this investigation.  
 
During the course of the study, the Investigator shall make timely and accurate reports to 
the IRB/EC on t he progress of the trial, at intervals not exceeding one year, as well as 
satisfying any other local IRB/EC regulations regarding reporting. Copies of all reports to 
and correspondence with and from the IRB/EC must be provided to Halozyme. 
Furthermore, at the completion or early termination of the study, a final report should be 
made to the IRB/EC by the Investigator within the applicable IRB/EC time frames. A 
copy of this report will be provided to Halozyme. 
 
Any significant changes or revisions in the study protocol or any changes that may alter 
patient risk must be approved by Halozyme (and may require FDA/other regulatory 
agency review and/or approval) and must be approved in writing by t he IRB/EC prior to 
implementation (see Section 12.7 for protocol amendments). The Investigator must also 
receive a written notice of approval from Halozyme prior to initiating the revised changes 
to the study protocol. A protocol change intended to eliminate an apparent immediate 
hazard may be implemented immediately, provided that Halozyme is immediately 


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notified and an amendment is subsequently provided by Halozyme and approved by t he 
IRB/EC. 
 
It is the Investigator's obligation to maintain an IRB/EC correspondence file, and to make 
this available for review by Halozyme or its designated representatives as part of the 
study monitoring process. 
 
12.3. Informed Consent 
 
A copy of the proposed informed consent form (ICF) document must be submitted to 
Halozyme for review and comment prior
Each patient (and/or legally authorized representative if the subject is a minor, mentally 
incompetent or physically incapacitated) found to be eligible for the study must have 
voluntarily provided written informed consent using the IRB/EC-approved ICF prior to 
screening procedures or enrollment in the study (i.e., before performing any protocol-
dictated procedures that are not part of normal patient care). A copy of the signed and 
 to submission to the reviewing IRB/EC. The 
ICF must be approved by t he IRB/EC and contain all elements required by all applicable 
federal, state, local, and institutional regulations or requirements prior to consenting a 
patient. Authorization to use or disclose Personal Health Information (PHI) in accordance 
with requirements of the Health Insurance Portability Act of 1996 (HIPAA) should be 
covered in the ICF or in a separate document to be signed by the patient.  
 
The proposed ICF must contain a full explanation of the purpose and nature of the study, 
a description of the procedures, the possible advantages, risks, alternate treatment 
options, and a statement of confidentiality of patient study records, a statement regarding 
voluntary compensation and availability of treatment in the case of injury, an explanation 
of whom to contact about the research, the patient’s rights, and notification that 
participation is voluntary and refusal will involve no penalty or loss of medical benefits. 
These requirements are in accordance with the U.S. Federal Regulations as detailed in the 
21CFR50.25 and the Declaration of Helsinki. The ICF should also indicate by signature 
that the patient, or where appropriate, legal guardian/representative, permits access to 
relevant medical records by t he Sponsor (Halozyme) and/or the Sponsor's duly appointed 
agent and by representatives of the U.S. Food and Drug Administration (FDA) or other 
applicable regulatory agency and permits their data to be used in publications. 
 
The Investigator will be responsible for obtaining written informed consent from 
potential patients prior to any study specific screening and entry into the study. The 
research study will be completely explained to each prospective study patient. The 
Investigator or designee must explain that the patient is free to refuse to enter the study, 
and free to withdraw from it at any time for any reason. If new safety information 
becomes available and results in significant changes in the risk/benefit assessment, the 
ICF should be reviewed and updated if necessary. Under this circumstance, all patients 
(including those already being treated) should be informed of the new information, given 
a copy of the revised ICF, and be allowed to re-evaluate their consent to continue in the 
study. 
 


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dated ICF document will be provided to the patient, and a copy will be maintained with 
the patient's CRFs, or in the study documentation. The original will be retained by the 
Investigator along with the CRFs. The ICF must be in a language that the patient can read 
and understand.  
 
12.4. Laboratory Accreditation 
 
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation. 
Reference values and/or normal ranges for the test results must be provided to Halozyme. 
Halozyme must be notified immediately in writing of any changes occurring in reference 
values during the course of the study. 
 
All local and central laboratories used in the study must have, at a minimum, the 
following. 
 
• College of American Pathologist (CAP) accreditation, and/or 
• Clinical Laboratory Improvement Amendments (CLIA) accreditation 
• Listing of laboratory normal reference values (for all protocol required tests) 
• Laboratory license 
• Curriculum vita of laboratory director may also be requested 
 
12.5. Drug Accountability 
 
Upon receipt of study drug(s), the Investigator, pharmacist or qualified designee is 
responsible for taking an inventory of the study drug(s). A record of this inventory must 
be kept and all usage of study drugs must be documented. All vials of study drug, both 
used and unused, must be retained as discussed in Sections 9.1 and 9.2.  
 
The investigational drug (both MMC and Chemophase) is to be administered/ prescribed 
only by t he Principal Investigator or appropriately qualified physician subinvestigators 
named on the Form FDA 1572. Under no c ircumstances will the Investigator(s) allow the 
investigational drug to be used other than as directed by t his protocol. Although 
appropriate personnel may be designated to administer/dispense drug and maintain drug 
accountability records, the Principal Investigator is ultimately responsible for all drug 
accountability. 
 
The Investigator or their designee must maintain accurate records accounting for the 
receipt of the investigational drug supplies and for the disposition of the drug. 
Documentation of the disposition of the drug should consist of a dosing record including 
the identification of the person to whom the drug is dosed, the quantity and the date of 
dosing, and any unused drug. This record is in addition to any drug accountability 
information recorded on the CRFs. At study end, unused drug will be reconciled with 
dosing records. All unused investigational drug shall be returned to Halozyme upon 
request unless otherwise instructed. A copy of the reconciled drug inventory record will 
be provided to Halozyme or its designee, and the original will be retained at the site.  


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12.6. Protocol Compliance and Protocol Deviations 
 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
patient, the protocol shall be conducted as specified. Any such change must be reported 
immediately to Halozyme and to the IRB/EC. 
 
From time to time, it is possible that Halozyme may prospectively authorize protocol 
deviations if the deviation is minor, and does not place patient at increased risk or the 
anticipated risk of potential benefit outweighs the anticipated risk of potential harm. All 
such protocol “waivers” must be provided in advance and in writing by Halozyme, and 
will be forwarded to the Investigator for filing with the patient’s study records. The 
Investigator must notify the IRB/EC of any and all protocol deviations according to the 
applicable IRB/EC policy. 
 
Written documentation of all protocol deviation must be kept in the study center file and 
provided to Halozyme. Examples of possible protocol deviations include, but are not 
limited to:  
 
• failure to obtain/maintain approval for research,  
• failure to obtain required informed consent,  
• failure to collect, report or file AE reports,  
• performance of an unapproved study procedure,  
• performance of research at an unapproved location, and  
• failure to file protocol modifications, and failure to adhere to an approved 
protocol.  
 
12.7. Protocol Amendments 
 
If the protocol is revised, protocol amendments will be prepared and must be approved by 
Halozyme. All protocol amendments must be submitted to the IRB/EC for review and 
approval pr ior to implementation. However, as discussed in Section 12.2, immediate 
implementation of a protocol amendment may be necessary if the nature of the 
amendment concerns the safety of patients and is required to be implemented on an 
urgent basis to protect the safety of patients. Any such immediate implementation of 
protocol amendments must be agreed to in advance and in writing by Halozyme. Hard 
copy documentation of IRB/EC approval must be forwarded to Halozyme. 
 
If an amendment significantly alters the study design, increases potential risk to the 
subject or otherwise affects statements in the informed consent form (ICF), the ICF must 
be revised accordingly and submitted to the IRB/EC for review and approval (see 
Section 12.3). The approved ICF must be used to obtain informed consent from new 
patients prior to enrollment and must be used to obtain informed consent from patients 
already enrolled if they are potentially affected by t he amendment and wish to continue 
participation. 
 


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12.8. Data Collection and Case Report Forms 
 
In accordance with 21 CFR 312.62, a case report form (CRF) must be completed for each 
patient enrolled in the study. CRFs are an integral part of the trial and subsequent reports. 
All data collected for each study patient will be recorded on CRFs provided or approved 
by Halozyme.  
 
CRFs need not be completed by the Investigator, but all entries in CRFs are the 
responsibility of the Investigator and entry of CRF data must be made under the 
supervision of the Investigator. CRF completion may be formally delegated to other 
study personnel. However, the Sponsor (Halozyme) must be informed in writing of the 
name of such persons and the scope of their authority. The Investigator is responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of all data reported in the 
CRFs and all required reports for each study patient. It is the obligation of the 
Investigator to review each page of the CRFs and to sign the designated and appropriate 
CRFs as the study's authority. The Investigator is also responsible for maintaining any 
source documentation related to the study, including, but not limited to, any operative 
reports, laboratory results, radiographic films, tracings, and computer discs, files or tapes.  
 
CRFs must be completed legibly, preferably with black ballpoint pen. A correction 
should be made by striking through the incorrect entry with a single line and entering the 
correct information adjacent to the incorrect entry. The correction must be initialed and 
dated by t he person making the correction. Erasure or the use of correction fluid or film is 
unacceptable. Entries to the CRFs should be made only in the spaces provided, and not in 
the margins. Information that cannot be accommodated by the spaces provided should be 
entered on the comments CRF page. 
 
For each study patient, the completed CRFs must be promptly reviewed, and required 
pages signed and dated by t he Investigator. The original copy of all CRFs will be 
reviewed and retrieved by the Study Monitor representing Halozyme. The Investigator 
must retain a copy of all CRFs. 
 
12.9. Study Initiation, Monitoring and Closeout Visits and Reports 
 
Representatives of Halozyme, in conjunction with Study Monitor(s) representing 
Halozyme, will perform a number of on-site visits to the study center. Prior to 
commencement of the study, representatives of Halozyme will visit the study center to 
assure adequacy of facilities to conduct the protocol, and to discuss with the Investigator 
the general obligations regarding studies with investigational new drugs. This visit w ill 
be documented in a report. If the study center has participated in a clinical trial in 
conjunction with Halozyme within one year, this Pre-Study Qualification visit may be 
waived. 
 
Upon satisfactory receipt of all necessary documentation (including, but not limited to, an 
allowed IND, the FDA Form 1572, an executed Clinical Trials Agreement, and IRB/EC 
approval of the protocol and informed consent form), Halozyme or its designee 


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monitor(s) will arrange for all study material to be delivered to the study center and for 
the scheduling of a mutually convenient appointment for a Study Initiation visit. Patient 
entry must not begin until this initiation visit by Halozyme or its designee personnel has 
been made. At this meeting, all personnel expected to be involved in the conduct of the 
study should undergo an orientation to include review of the study protocol, instruction 
for CRF completion, and overall responsibilities including those for drug accountability 
and study file maintenance. This visit will be documented in a report. 
 
Throughout the course of the study, the Halozyme or its designee monitor(s) will make 
frequent contacts with the Investigator. Study Monitors representing Halozyme will visit 
study centers periodically throughout the trial for Routine Monitoring visits. The Study 
Monitor will review CRFs to verify that they are accurate, complete and verifiable from 
source documents. They will also verify the rights and well-being of the study patients 
are protected and that the study conduct is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirements. As 
part of the data review it is expected that source documents (e.g., hospital records, office 
records) will be made available for review by Halozyme or its designee monitor(s). The 
study and its monitors may also be similarly evaluated by auditors representing 
Halozyme. For these purposes, the Investigator will make CRFs, source documents and 
study files available when requested. A report will be generated for each monitoring visit. 
 
At fulfillment of patient enrollment, each Investigator will be notified in writing by 
Halozyme. The study will be terminated and the study center closed when all completed 
original CRFs have been collected, all data discrepancies resolved, and drug 
accountability has been reconciled. A Closeout visit will be scheduled for study centers 
that enrolled at least one patient, during which Halozyme or its representative will review 
all informed consents, CRFs, drug accountability records, and other study-related 
documents. Halozyme or its representative will hold a final meeting with the Investigator 
and study staff to explain procedures for record retention, publication policy, site audit 
notification, and financial disclosure. A final letter to the site will record the events of 
this closeout visit. Study-closure activities will be documented in a report. It will be the 
responsibility of the Investigator to notify the IRB/EC that the study has been completed 
(see Section 12.11). 
 
The Sponsor (Halozyme) has the right to terminate the study for non-adherence to 
protocol, unavailability of the Investigator or his or her study staff for Halozyme or its 
designee monitoring personnel, or for administrative reasons, at any time. In that event, 
Halozyme will notify each Investigator in writing that the study is to be discontinued. 
The Investigator will comply with the Halozyme’s written instructions for study 
discontinuation, which will include the following:   
 
• Date discontinuation will occur, 
• Rationale for discontinuation, 
• Instructions on how discontinuation is to be performed, 
• Instructions for patients participating in the study, and 
• Instructions for retention of study documents. 


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In addition to monitoring by Halozyme or its designees, the study may be audited by 
representatives of the Food and Drug Administration (FDA), who will also be allowed 
access to study documents. The Investigator should immediately notify the Clinical 
Research Department at Halozyme of any proposed or scheduled audits with any 
regulatory authorities. 
 
12.10. Study Documentation and Retention of Records 
 
All records of this clinical study must be retained by the Investigator, including but not 
limited to, the following. 
 
• Protocol and all protocol amendments 
• All signed versions of the Statement of Investigator, Form FDA 1572 
• All drug accountability records 
• All IRB/EC approvals, correspondence and reports 
• Signed and dated informed consent forms for each patient 
• Completed CRFs for each patient 
• Copies of any other material distributed to patients 
• Any advertisements for this study 
• The Investigator’s final report to the IRB/EC 
• Source documents pertaining to the study, including, but not limited to, any 
operative reports, laboratory results, radiographic films, tracings, and computer 
discs, files or tapes 
 
The period of time these documents must be maintained is governed by U.S. law and, 
when applicable, non-U.S., regulations. Some countries require these documents to be 
maintained for 15 years or longer. All records are to be retained by the Investigator for a 
minimum of two (2) years after the FDA has approved the new drug application, or after 
the Sponsor (Halozyme) has notified the Investigator in writing that all investigations of 
the drug have been discontinued. However, because of international regulatory 
requirements, Halozyme may request retention for a longer period of time. Therefore, 
Halozyme or its designee will inform the Investigator when these documents may be 
destroyed. The Investigator must obtain written approval from the Halozyme prior to 
destruction of any records. 
 
The Investigator must advise Halozyme in writing if the records are to be moved to a 
location other than the Investigator’s archives. If the Investigator leaves the institution or 
study center, the records shall be transferred to an appropriate designee, at the study 
center, who assumes the responsibility for record retention. Notice of such transfer shall 
be documented in writing and provided to Halozyme. 
 
In the event of accidental loss or destruction of any study records, the Investigator will 
immediately notify Halozyme in writing. Halozyme or its designee must be notified in 
writing at least 30 days prior to the intended date of disposal of any study records related 
to this protocol. 


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12.11. Investigator’s Final Report 
 
Shortly after completion of the Investigator’s participation in the study, the Investigator 
will submit a written report to Halozyme. This report may be a copy of the Investigator’s 
end-of-study report to their IRB/EC, which will include, but not be limited to; 
notification that the study has concluded, the number of patients enrolled/ treated, and the 
number of adverse and serious AEs that occurred during the study. The report to the 
IRB/EC will be consistent with the applicable IRB/EC regulations and time frames. 
 
12.12. Financial Disclosure 
 
Each investigator is required to provide financial disclosure statements or certifications to 
Halozyme prior to study initiation. In accordance with 21 C FR 54, Investigators and all 
subinvestigators are required to disclose all financial interests in the Sponsor (Halozyme) 
in order to permit complete and accurate certification statements in an application for 
marketing authorization. This includes compensation affected by the outcome of a 
clinical study, significant equity interest in the Sponsor (Halozyme), and proprietary 
interest in the tested product. The investigators must promptly update this information if 
any relevant changes occur during the course of the investigation and over the period of 
one year following completion of the investigation (see 21 CFR 312.64(d)). 
 
12.13 Disclosure of Data and Publication 
 
All information obtained as a result of this study or during the conduct of this study will 
be regarded as confidential. All unpublished information relating to this drug or to the 
operations of the Sponsor (Halozyme), including clinical indications, formula, methods 
of manufacture, and any other related scientific data provided to or developed by the 
Investigator, is confidential and shall remain the sole property of the Sponsor 
(Halozyme). The Investigator agrees to use the information for the purpose of carrying 
out this study and for no other purpose, unless prior written permission from the Sponsor 
(Halozyme) is obtained. The Sponsor has full ownership of the CRFs and database 
resulting from this study. 
 
Disclosures (i.e., any release of information to any third party not noted herein) of any 
not previously known to be public information and/or results of the investigation for 
publication or by oral or poster presentation shall not be made earlier than 45 days after 
submission of the proposed material to the Sponsor (Halozyme) for inspection, unless the 
Sponsor consents to earlier disclosure. Any proposed publication must be submitted to 
the at least 40 days prior to intended submission for publication. Publication or 
presentation of any study information, whether presented orally or in writing, may not be 
undertaken either during or after the study without Sponsor’s (Halozyme’s) express 
written approval. The Sponsor (Halozyme) may, for any reason, withhold approval for 
publication or presentation. If the Investigator is to be listed as an author of a publication 
prepared by t he Sponsor (Halozyme), the Investigator will be given 40 days for review of 
the manuscript prior to publication. The Investigator expressly agrees that no publication 


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of interim, non-final, data will occur without the written authorization of the Sponsor 
(Halozyme). The Investigator will take appropriate cognizance of the Sponsor’s 
(Halozyme’s) suggestions before disclosure for publication or presentation consistent 
with protection of the Sponsor's right to its confidential data. 
 
The Investigator agrees that results from this study may be used by the Sponsor 
(Halozyme) for purposes of domestic and international new drug registration, for 
publication, and to inform medical and pharmaceutical professionals. Regulatory 
authorities will be notified of the Investigator’s name, address, qualifications, and extent 
of involvement. 
 
13. REFERENCES 
 
1. Torti FM, Lum LL. The biology and treatment of superficial bladder cancer. J Clin 
Oncol 1984;2;505-531. 
 
2. Draft FDA Requirements for Approval of Drugs to Treat Superficial Bladder Cancer, 
19 December 1988. Draft guidance document later withdrawn by FDA. 
 
3. Report on the management of non-muscular-invasive bladder cancer (Stages Ta, T1 
and Tis). Bladder cancer guidelines panel, American Urological Association, Inc. 
1999. 
 
4. BCCancer Drug Manual, 
http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Mitomycin.htm  
 
5. Novopharm product labeling for MMC, at www.rxmed.com 
 
6. Reich SD, C linical pharmacology of mitomycin C. In:  Carter S, Crooke ST, editors. 
Mitomycin C, current status and new developments. New York:  
Academic;1979;243-250. 
 
7. Dalton JT, Wientjes MG, Badalament RA, Drago JR, Au JL-S. Pharmacokinetics of 
intravesical mitomycin C in superficial bladder cancer patients. Cancer Research 
1991;51:5144-5152. 
 
8. Eijsten A, Knonagel H, Hotz E, Brutsch HP, Hauri D. Reduced bladder capacity in 
patients receiving intravesical chemoprophylaxis with mitomycin C. Br J Urol 
1990;66:386-388. 
 
9. Maier U, Baumgartner G. Mitomycin C plasma levels after intravesical instillation 
with and without hyaluronidase. J Urol 1986;135:845-846. 
 
10. Maier U, Baumgartner G. Metaphylactic effect of mitomycin C with and without 
hyaluronidase after transurethral resection of bladder cancer:  Randomized trial. J 
Urol 1989;141:529-530. 


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11. Höbarth K, Maier U, Marberger M. Topical chemotherapy of superficial bladder 
cancer with mitomycin C and adjuvant hyaluronidase. Eur Urol 1992;21:206-210. 
 
12. Common Terminology Criteria for Adverse Events (CTCAE), National Cancer 
Institute, National Institutes of Health, U.S. Department of Health and Human 
Services, http://ctep.cancer.gov/reporting/ctc.html. 
 
13. Baumgartner G, Gomar-Höss Ch, Sakr L, Ulsperger E, Wogritsch Ch. The impact of 
extracellular matrix on the chemoresistance of solid tumors – experimental and 
clinical result of hyaluronidase as additive to cytostatic chemotherapy. Cancer Letter 
1998;131:85-99. 
 
14. Au JL-S, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, et al. 
Methods to improve efficacy of intravesical mitomycin C:  Results of a randomized 
Phase III trial. J Nat Cancer Inst 2001;93(8):597-604. 
 
15. Lamm DL, Blumenstein BA, Crawford ED, Crissman JD, Lowe BA, Smith JA, et al. 
Randomized intergroup comparison of bacillus Calmette-Guerin immunotherapy and 
mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of 
the bladder. Urol Oncol 1995;1:119-126. 
 
14. APPENDICES 


Halozyme Therapeutics, Inc. 
 
Protocol HZ2-05-01 
Appendix A. TNM Staging of Bladder Cancer 
 
TNM DEFINITIONS 
 
Primary tumor (T) 
• 
TX: Primary tumor cannot be assessed  
• 
T0: No evidence of primary tumor  
• 
*Ta: Noninvasive papillary carcinoma  
• 
*Tis: Carcinoma in situ: “flat tumor”  
• 
*T1: Tumor invades subepithelial connective tissue 
• 
T2: Tumor invades muscle  
• 
pT2a: Tumor invades superficial muscle (inner half)  
• 
pT2b: Tumor invades deep muscle (outer half)  
• 
T3: Tumor invades perivesical tissue  
• 
pT3a: Microscopically  
• 
pT3b: Macroscopically (extravesical mass)  
• 
T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or 
abdominal wall  
• 
T4a: Tumor invades the prostate, uterus, vagina  
• 
T4b: Tumor invades the pelvic wall, abdominal wall  
(Note:  The suffix “m” should be added to the appropriate T category to indicate multiple lesions. The 
suffix “is” may be added to any T to indicate the presence of associated carcinoma in situ.) 
Regional lymph nodes (N) 
• 
NX: Regional lymph nodes cannot be assessed  
• 
N0: No regional lymph node metastasis  
• 
N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension  
• 
N2: Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in 
greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest 
dimension  
• 
N3: Metastasis in a lymph node, more than 5 cm in greatest dimension  
Distant metastasis (M) 
• 
MX: Distant metastasis cannot be assessed  
• 
M0: No distant metastasis  
• 
M1: Distant metastasis  
 
* Acceptable stage for enrollment in this study. 
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Halozyme Therapeutics, Inc. 
 
Protocol HZ2-05-01 
 
AJCC STAGE GROUPINGS 
 
Stage 0a 
• 
*Ta, N0, M0  
Stage 0is 
• 
*Tis, N0, M0  
Stage I 
• 
*T1, N0, M0  
Stage II 
• 
T2a, N0, M0  
• 
T2b, N0, M0  
Stage III 
• 
T3a, N0, M0  
• 
T3b, N0, M0  
• 
T4a, N0, M0  
Stage IV 
• 
T4b, N0, M0  
• 
Any T, N1, M0  
• 
Any T, N2, M0  
• 
Any T, N3, M0  
• 
Any T, any N, M1  
 
* Acceptable stage for enrollment in this study. 
 
 
Urinary bladder. In: American Joint Committee on Cancer.: AJCC Cancer Staging 
Manual. 6th ed. New York, NY: Springer, 2002:335-340. 
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Appendix C. United Stages Package Insert for Mitomycin 
 




INDICATIONS AND USAGE
Mitomycin for Injection is not recommended as single-agent, primary therapy. It has been shown to
be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven
combinations with other approved chemotherapeutic agents and as palliative treatment when other
modalities have failed. Mitomycin is not recommended to replace appropriate surgery and/or
radiotherapy.
CONTRAINDICATIONS
Mitomycin is contraindicated in patients who have demonstrated a hypersensitive or idiosyncratic
reaction to it in the past.
Mitomycin is contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase
in bleeding tendency due to other causes.
WARNINGS
Patients being treated with mitomycin must be observed carefully and frequently during and after
therapy.
The use of mitomycin results in a high incidence of bone marrow suppression, particularly
thrombocytopenia and leukopenia. Therefore, the following studies should be obtained repeatedly
during therapy and for at least 8 weeks following therapy: platelet count, white blood cell count,
differential, and hemoglobin. The occurrence of a platelet count below 100,000/mm3 or a WBC below
4,000/mm3 or a progressive decline in either is an indication to withhold further therapy until blood
counts have recovered above these levels.
Patients should be advised of the potential toxicity of this drug, particularly bone marrow suppression.
Deaths have been reported due to septicemia as a result of leukopenia due to the drug.
Patients receiving mitomycin should be observed for evidence of renal toxicity. Mitomycin should not
be given to patients with a serum creatinine greater than 1.7 mg percent.
Usage in Pregnancy: Safe use of mitomycin in pregnant women has not been established.
Teratological changes have been noted in animal studies. The effect of mitomycin on fertility is
unknown.
PRECAUTIONS
Acute shortness of breath and severe bronchospasm have been reported following the administration
of vinca alkaloids in patients who had previously or simultaneously received mitomycin. The onset of
this acute respiratory distress occurred within minutes to hours after the vinca alkaloid injection. The
total number of doses for each drug has varied considerably. Bronchodilators, steroids and/or oxygen
have produced symptomatic relief. 
A few cases of adult respiratory distress syndrome have been reported in patients receiving
mitomycin in combination with other chemotherapy and maintained at FIO2 concentrations greater
than 50% perioperatively. Therefore, caution should be exercised using only enough oxygen to
provide adequate arterial saturation since oxygen itself is toxic to the lungs. Careful attention should
be paid to fluid balance and overhydration should be avoided.
Bladder fibrosis/contraction has been reported with intravesical administration (not an approved route
of administration), which in rare cases has required cystectomy.
Nursing Mothers: It is not known if mitomycin is found in human milk. Because many drugs are
found in milk, it is recommended that women receiving mitomycin not breast feed because of the
potential for serious adverse reactions from mitomycin in nursing infants. 
Pediatric Use: Safety and effectiveness in pedriatric patients have not been established.
ADVERSE REACTIONS
Bone Marrow Toxicity: This was the most common and most serious toxicity, occurring in 605 of
937 patients (64.4%). Thrombocytopenia and/or leukopenia may occur anytime within 8 weeks after
onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within
10 weeks. About 25% of the leukopenic or thrombocytopenic episodes did not recover. Mitomycin
produces cumulative myelosuppression.
Integument and Mucous Membrane Toxicity: This has occurred in approximately 4% of patients
treated with mitomycin. Cellulitis at the injection site has been reported and is occasionally severe.
Stomatitis and alopecia also occur frequently. Rashes are rarely reported. The most important
dermatological problem with this drug, however, is the necrosis and consequent sloughing of tissue
which results if the drug is extravasated during injection. Extravasation may occur with or without an
accompanying stinging or burning sensation and even if there is adequate blood return when the
injection needle is aspirated. There have been reports of delayed erythema and/or ulceration
occurring either at or distant from the injection site, weeks to months after mitomycin, even when no
obvious evidence of extravasation was observed during administration. Skin grafting has been
required in some cases.
Renal Toxicity: 2% of 1,281 patients demonstrated a statistically significant rise in creatinine. There
appeared to be no correlation between total dose administered or duration of therapy and the degree
of renal impairment.
Pulmonary Toxicity: This has occurred infrequently but can be severe and may be life-threatening.
Dyspnea with a nonproductive cough and radiographic evidence of pulmonary infiltrates may be
indicative of mitomycin-induced pulmonary toxicity. If other etiologies are eliminated, mitomycin
therapy should be discontinued. Steroids have been employed as treatment of this toxicity, but the
therapeutic value has not been determined. A few cases of adult respiratory distress syndrome have
been reported in patients receiving mitomycin in combination with other chemotherapy and
maintained at FIO2 concentrations greater than 50% perioperatively.
Hemolytic Uremic Syndrome (HUS): This serious complication of chemotherapy, consisting
primarily of microangiopathic hemolytic anemia (hematocrit ≤25%), thrombocytopenia
(≤100,000/mm3), and irreversible renal failure (serum creatinine ≥1.6 mg/dL) has been reported in
patients receiving systemic mitomycin. Microangiopathic hemolysis with fragmented red blood cells
on peripheral blood smears has occurred in 98% of patients with the syndrome. Other less frequent
complications of the syndrome may include pulmonary edema (65%), neurologic abnormalities
(16%), and hypertension. Exacerbation of the symptoms associated with HUS has been reported in
some patients receiving blood product transfusions. A high mortality rate (52%) has been associated
with this syndrome.
The syndrome may occur at any time during systemic therapy with mitomycin as a single agent or in
combination with other cytotoxic drugs. Less frequently, HUS has also been reported in patients
receiving combinations of cytotoxic drugs not including mitomycin. Of 83 patients studied,
72 developed the syndrome at total doses exceeding 60 mg of mitomycin. Consequently, patients
receiving ≥60 mg of mitomycin should be monitored closely for unexplained anemia with fragmented
cells on peripheral blood smear, thrombocytopenia, and decreased renal function.
The incidence of the syndrome has not been defined.
Therapy for the syndrome is investigational.
Cardiac Toxicity: Congestive heart failure, often treated effectively with diuretics and cardiac
glycosides, has rarely been reported. Almost all patients who experienced this side effect had
received prior doxorubicin therapy.
Acute Side Effects Due to Mitomycin were fever, anorexia, nausea, and vomiting. They occurred in
about 14% of 1,281 patients.
Other: Headache, blurring of vision, confusion, drowsiness, syncope, fatigue, edema,
thrombophlebitis, hematemesis, diarrhea, and pain. These did not appear to be dose related and
were not unequivocally drug related. They may have been due to the primary or metastatic disease
processes. Malaise and asthenia have been reported as part of postmarketing surveillance. Bladder
fibrosis/contraction has been reported with intravesical administration (see PRECAUTIONS).
DOSAGE AND ADMINISTRATION
Mitomycin should be given intravenously only, using care to avoid extravasation of the compound. If
extravasation occurs, cellulitis, ulceration, and slough may result.
Each vial contains either mitomycin 5 mg and mannitol 10 mg, or mitomycin 20 mg and mannitol
40 mg, or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 mL
40 mL, or 80 mL, respectively. Shake to dissolve. If product does not dissolve immediately, allow to
stand at room temperature until solution is obtained.
After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy,
the following dosage schedule may be used at 6- to 8-week intervals:
20 mg/m2 intravenously as a single dose via a functioning intravenous catheter.
Because of cumulative myelosuppression, patients should be fully reevaluated after each course of
mitomycin, and the dose reduced if the patient has experienced any toxicities. Doses greater than
20 mg/m2 have not been shown to be more effective and are more toxic than lower doses.
The following schedule is suggested as a guide to dosage adjustment:
No repeat dosage should be given until leukocyte count has returned to 4000/mm3 and platelet count
to 100,000/mm3.
When mitomycin is used in combination with other myelosuppressive agents, the doses should be
adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug
should be stopped since chances of response are minimal.
Stability
1. Unreconstituted mitomycin stored at controlled room temperature is stable for the lot life indicated
on the package. Avoid excessive heat (over 40°C).
2. Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is
stable for 14 days refrigerated or 7 days at room temperature. Protect reconstituted solution
from light.
3. Diluted in various IV fluids at room temperature, to a concentration of 20 to 40 micrograms per mL:
Nadir After Prior Dose
Percentage of
Prior Dose
Leukocytes/mm3
Platelets/mm3
To be Given
>4000 
>100,000
100%
3000–3999
75,000–99,999
100%
2000–2999
25,000–74,999
70%
<2000
<25,000
50%
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Appendix D. Canadian Package Insert for Mitomycin 
 


Mitomycin
CCO Formulary
Revised 2004/2005
A
DRUG NAME:
MITOMYCIN
SYNONYM(S):
Mitomycin C, MMC
COMMON TRADE NAME(S):
Mutamycin®  (Bristol),  Mitomycin ( Mayne) (Novopharm)
B
MECHANISM OF ACTION AND PHARMACOKINETICS
Mitomycin is a purple antibiotic isolated from Streptomyces caespitosus.  Clinical trials were
begun in the United States in the late 1960's.  Mitomycin is activated in vivo to a bifunctional and
trifunctional alkylating agent.  Binding to DNA leads to cross-linking and inhibition of DNA
synthesis and function.  Mitomycin is cell cycle phase-nonspecific.
Oral Absorption
Erratic
Detectable levels in kidney, muscles, heart, lungs, intestine and
stomach, found in ascites
Cross blood brain barrier?
No
Vd
16-56 L/m2
Distribution
PPB
No information found
Prodrug activated in vivo, primary means of elimination is by hepatic
metabolism
Active metabolite(s)
Yes
Metabolism
Inactive metabolite(s)
Yes
Excreted in urine, detected in bile and feces, biliary level may
exceed plasma level
Urine
10% excreted unchanged in urine
t ½ α
8 minutes
t ½ β
48 minutes
Excretion
Cl
201-801 mL/min/m2
C
INDICATIONS AND STATUS
Topical
*
Bladder cancer (superficial)
Systemic
*
Gastric cancer (palliative)
*
Colorectal cancer (palliative)
*
Health Canada approved indication
Other uses include:
Breast cancer
Cervical cancer
Head and neck cancer
Pancreatic cancer
Biliary cancer
Page 79 of 89


Mitomycin
CCO Formulary
Revised 2004/2005
D
ADVERSE EFFECTS
ORGAN SITE
SIDE EFFECT
ONSET
Thromboembolism
E
Cardiac
Cardiac failure (rare, with prior
anthracyclines)
E
Headache
E
Ataxia
Blurred vision
Central nervous system
Acute encephalopathy (rare)
E
D
Alopecia
E
Blue bands in nails (rare)
E
Rash
I
Palmar erythema with desquamation
E
Dermatologic
Radiation recall reaction (rare)
I
Extravasation hazard
(refer to Appendix 2)
VESICANT
I
E
Nausea and vomiting
I
Diarrhea
  E
Stomatitis
E
Gastrointestinal
Anorexia
E
Hematologic
Myelosuppression
E
Hypersensitivity
Fever
I
Injection site
Chemical phlebitis
I
Interstitial pneumonitis, ARDS
E
Acute respiratory symptoms
especially with vinca’s
Pulmonary
Chronic fibrosis
D
Page 80 of 89


Mitomycin
CCO Formulary
Revised 2004/2005
D
ADVERSE EFFECTS
ORGAN SITE
SIDE EFFECT
ONSET
Cystitis / fibrosis (with intravesical
use, 25%)
I
Increased BUN
Renal/metabolic
Renal failure and hemolytic uremic
syndrome (10%)
D
Reproductive
Amenorrhea
E
Hypoglycaemia
Other
Fatigue
Dose-limiting side effects are underlined.
I = immediate (onset in hours to days); E = early (days to weeks);
D = delayed (weeks to months); L = late (months to years)
Myelosuppression is major dose limiting adverse effect, and may be cumulative.  Onset is late at 3-4 weeks,
with recovery by 8 – 10 weeks. Nausea and vomiting occur within 1-2 hours following administration.  Vomiting
usually subsides, but nausea may continue for 2-3 days.
The tissue necrosis that happens with extravasation may happen days to weeks after the treatment.  Patients
must be observed for delayed reactions and prior injection sites carefully inspected.  Soft tissue ulceration distal
to the injection site following uneventful injection in a peripheral vein has been reported.
Pulmonary toxicity consisting of dyspnea, non-productive cough has been reported with an incidence of 2.8-
12%.  Approximately 40% of patients who develop pulmonary toxicity will die of progressive pulmonary
dysfunction.  Threshold dose associated with pulmonary toxicity appears to be 50-60 mg/m 2.  Steroids may be of
some benefit. Acute respiratory distress syndrome may occur with high FIO 2 concentrations or with combination
chemotherapy.
A syndrome of renal failure and microangiopathic hemolytic anemia (hemolytic-uremic syndrome) has been
reported in 10% of patients.  This syndrome appears to have a threshold of 50-60 mg/m
2 and usually appears
after 6 months of therapy.  Patients should be monitored for development of renal failure or hemolysis.
The incidence of cardiotoxicity may be increased in patients receiving mitomycin in combination with
doxorubicin or in patients who have had prior exposure to doxorubicin.  No studies report cardiotoxicity in
patients only receiving mitomycin. Genitourinary irritation following intravesical (bladder) administration
includes dysuria, cystitis, nocturia, increased micturition and hematuria.  Myelosuppression has not been noted
with intravesical administration.
Mitomycin has the potential to enhance radiation injury to tissues.  While often called radiation recall reactions,
the timing of the radiation may be before, concurrent with or even after the administration of the mitomycin. 
Recurrent injury to a previously radiated site may occur weeks to months following radiation.
Page 81 of 89


Mitomycin
CCO Formulary
Revised 2004/2005
E
DOSING
Refer to protocol by which patient is being treated.   Numerous dosing schedules exist and depend on disease,
response and concomitant therapy.  Guidelines for dosing also include consideration of white blood cell count. 
Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation
therapy. Patients should not be retreated until haematological recovery has occurred.
Adults:
Intravenous:
q4-8w: 10-20 mg/m2
q6-8w: 2 mg/m2/day x 5 days, stop x 2 days, repeat x 1
Intravesical:
q1w: 20-40 mg in 30-60 ml SWI x 8 weeks
Dosage in myelosuppression:
modify according to protocol by which patient is being treated;
Lowest Value in Preceding Course
Leucocytes 
Platelets
% previous dose
> 3000
> 75,000
100
2-3.99 X 103
25-74.99 X 103
70
< 2000
< 25,000
50
Dosage in renal failure:
do not administer if creatinine > 150 µmol/L
Dosage in hepatic failure:
no adjustment required
F
ADMINISTRATION GUIDELINES (see Appendix 3a )
• 
Slow push through sidearm of free flowing IV (Normal Saline); Give 1.5mg/3mL per minute
• 
Doses may be mixed in 50mL minibag (Normal Saline); Infuse through sidearm of free flowing
IV over 10-30 minutes
G
SPECIAL PRECAUTIONS
Mitomycin is classified as dangerous goods under the Transportation of Dangerous Goods Act, and
must be declared as such for the purposes of transportation (substance is considered poisonous).
Mitomycin is contraindicated in patients with thrombocytopenia, leukopenia, coagulation disorder, or
an increased bleeding tendency due to other causes; with known hypersensitivity or an idiosyncratic
reaction to it, or any component of its formulations.
High FIO2 concentrations (anesthesia, oxygen therapy) should be avoided especially in patients with
pulmonary toxicity.
Mitomycin has been shown to be carcinogenic and teratogenic in animal studies and should not be
used in pregnancy.  Breast feeding is not recommended due to the potential secretion into breast
milk.
Page 82 of 89


Mitomycin
CCO Formulary
Revised 2004/2005
J
REFERENCES
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)
Compendium of Pharmaceuticals and Specialties.  2004. Mutamycin®.  Canadian Pharmacists
Association.
H
INTERACTIONS
AGENT
EFFECT
MECHANISM
MANAGEMENT
vinca alkaloids
(vincristine, vinblastine,
vindesine)
acute
bronchospasm
unknown
caution
I
RECOMMENDED CLINICAL MONITORING
Recommended Clinical Monitoring
Suggested Clinical Monitoring
• 
Clinical exam, including pulmonary,
neurological and local site toxicity
• 
Baseline & periodic renal function tests (if
failure suspected)
• 
Baseline and regular CBC
• 
Blood pressure at each visit
• 
Baseline  and regular liver function
tests
Page 83 of 89


Halozyme Therapeutics, Inc. 
 
Protocol HZ2-05-01 
CONFIDENTIAL 
Page 84 of 88 
Version 4.0  26 Feb 2009 
Appendix E. United Kingdom Summary of Product Characteristics for Mitomycin 
 
 
 
 




6. It has a possible role in combination with other cytotoxic drugs in colo-rectal 
cancer. 
7. It shows a degree of activity as a single agent or part of combination therapy 
in cancer of the head and neck. 
8. It shows a degree of activity as a single agent in cancer of the prostate. 
9. It has a possible role in skin cancer. 
10. It has a degree of activity in leukaemia and non-solid tumours. 
11. It has a possible role in sarcomas. 
12. It has been successfully used in combination with surgery, pre-operatively 
(oesophageal squamous cell carcinoma) and post-operatively (gastric cancer). 
13. It has shown to be effective when used in combination with radiotherapy. 
 
 4.2 Posology and method of administration  
 
For parenteral use. 
Intravenously, the dose should be given with great care in order to avoid 
extravasation. The usual dose is in the range of 4 – 10mg (0.06-0.15mg/kg) 
given at 1 – 6 weekly intervals depending on whether other drugs are given in 
combination and on bone marrow recovery. In a number of combination 
schedules, the dose is 10mg/m2 of body surface area, the course being repeated 
at intervals for as long as required. A course ranging from 40-80mg (0.58 –
1.2mg/kg) is often required for a satisfactory response when used alone or in 
combination. A higher dosage course may be given when used alone or as part of 
a particular combination schedule and total cumulative doses exceeding 2mg/kg 
have been given. 
For administration into specific tissues, Mitomycin-C Kyowa can be given by the 
intra-arterial route directly into the tumours. 
Because of cumulative myelosuppression, patients should be fully re-evaluated 
after each course and the dose reduced if the patient has experienced any toxic 
effects. Doses greater than 0.6mg/kg have not been shown to be more effective 
and are more toxic than lower doses. 
Treatment of superficial bladder tumours : In the treatment of superficial bladder 
tumours the usual dose is 20-40mg dissolved in 20-40 of diluent, instilled into the 
bladder through a urethral catheter, weekly or three times a week for a total of 
20 doses. The dose should be retained by the patient for a minimum of one hour. 
During this one-hour period the patient should be rotated every 15 minutes to 
ensure that the Mitomycin-C comes into contact with all areas of the bladder 
urthelium. 
When the bladder is emptied in the voiding process, care must be taken to ensure 
that no contamination occurs locally in the groin and genitalia areas. 
In the prevention of recurrent superficial bladder tumours, various doses have 
been used. These include 20mg in 20ml of diluent every two weeks and 40mg in 
40ml of diluent monthly or three monthly. The dose is instilled into the bladder 
through a urethral catheter. 
 
 
 4.3 Contraindications  
 
Patients who have demonstrated a hypersensitive or idiosyncratic reaction to 
Mitomycin-C Kyowa in the past. Thrombocytopenia, coagulation disorders and 
increased bleeding tendency. 
 
 
Page 86 of 89


 4.4 Special warnings and special precautions for use  
 
Mitomycin-C Kyowa should be administered under the supervision of a physician 
experienced in cytotoxic cancer chemotherapy. Local ulceration and cellulitis may 
be caused by tissue extravasation during intravenous injection and utmost care 
should be taken in administration. 
If extravasation occurs, it is recommended that the area is immediately infiltrated 
with sodium bicarbonate 8.4% solution, followed by an injection of 4mg 
dexamethasone. A systemic injection of 200mg of Vitamin B6 may be of some 
value in promoting the regrowth of tissues that have been damaged. 
Mitomycin-C Kyowa should not be allowed to come into contact with the skin. If it 
does, it should be washed several times with 8.4% sodium bicarbonate solution, 
followed by soap and water. Hand creams and emollients should not be used as 
they may assist the penetration of the drug into the epidermal tissue. 
In the event of contact with the eye, it should be rinsed several times with 8.4% 
sodium bicarbonate solution. It should then be observed for several days for 
evidence of corneal damage. If necessary, appropriate treatment should be 
instituted. 
 
 
 4.5 Interaction with other medicinal products and other forms 
of Interaction  
 Not Known. 
 
 
 4.6 Pregnancy and lactation  
 
Mitomycin-C Kyowa should not normally be administrated to patients who are 
pregnant or to mothers who are breast-feeding. Teratological changes have been 
noted in animal studies. 
 
 
 4.7 Effects on ability to drive and use machines  
 Generalised weakness and lethargy have been reported on rare occasions. If 
affected, patients should be advised not to drive or operate machinery. 
 
 
 4.8 Undesirable effects  
 
Thrombocytopenia and leucopenia resulting from myelosuppression, which is 
delayed and cumulative. Patients should be monitored closely during each course 
of treatment, paying particular attention to peripheral blood count including 
platelet count. No repeat dose should be given unless the leucocyte count is 
above 3.0 x 109/L or more and the platelet count is 90 x 109/L or more. The nadir 
is usually around four weeks after treatment and toxicity is usually cumulative, 
with increasing risk after each course of treatment. If disease progression 
continues after two courses of treatment, the drug should be stopped since the 
chances of response are minimal. Severe renal toxicity has occasionally been 
reported after treatment and renal function should be monitored before starting 
treatment and again after each course. Nausea and vomiting are sometimes 
experienced immediately after treatment, but these are usually mild and of short 
duration. Pulmonary toxicity and fever have been reported. Skin toxicity may 
occur in a small proportion of patients, with side effects such as alopecia 
(although this is less frequent and less severe than with certain other cytotoxic 
agents). Bleeding, rashes and mouth ulcers have been reported. General 
 
Page 87 of 89


weakness and lethargy have been reported on rare occasions. Other reported 
effects include anorexia, diarrhoea, stomatitis, interstitial pneumonitis, pulmonary 
fibrosis and microangiopathic haemolytic anaemia syndrome. 
 
 4.9 Overdose  
 
In the unlikely event of accidental overdosage then an increase in the more 
common side effects should be expected, such as fever, nausea, vomiting and 
myelosuppression. Appropriate supportive measures should be instituted. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
  
 
 
 5.1 Pharmacodynamic properties  
 
Mitomycin-C Kyowa is an antitumour antibiotic that is activated in the tissues to 
an alkylating agent which disrupts deoxyribonucleic acid (DNA) in cancer cells by 
forming a complex with DNA and also acts by inhibiting division of cancer cells by 
interfering with the biosynthesis of DNA. 
 
 
 5.2 Pharmacokinetic properties  
 
In vivo 
Mitomycin-C Kyowa is rapidly cleared from the serum after intravenous 
administration. The time required to reduce the serum concentration by 50% 
after a 30mg bolus injection is 17 minutes. After injection of 30mg, 20mg or 
10mg intravenously, the maximal serum concentrations were 2.4 mcg/ml, 1.7 
mcg/ml and 0.52mcg/ml respectively. Clearance is effected primarily by 
metabolism in the liver, but metabolism occurs in other tissues as well. The rate 
of clearance is inversely proportional to the maximal serum concentration 
because, it is thought, of saturation of the degradative pathways. Approximately 
10% of a dose of Mitomycin-C Kyowa is excreted unchanged in the urine. Since 
metabolic pathways are saturated at relatively low doses, the percentage dose 
excreted in the urine increases with increasing dose. In children, the excretion of 
intravenously administered Mitomycin-C Kyowa is similar to that in adults. 
 
 
 5.3 Preclinical safety data  
 There are no preclinical data of relevance to the prescriber which are additional to 
that already included elsewhere in the SPC. 
 
 
6. PHARMACEUTICAL PARTICULARS 
  
 
 
 6.1 List of excipients  
 Sodium Chloride Ph.Eur. 
 
 
 6.2 Incompatibilities  
Page 88 of 89


 Not known 
 
 
 6.3 Shelf life  
 
Four years from the date of manufacture. 
After reconstitution, the solution is stable for 24 hours when protected from light 
and stored in a cool place. Do not refrigerate. 
 
 
 
 6.4 Special precautions for storage  
 None. 
 
 
 6.5 Nature and contents of container  
 
Mitomycin-C Kyowa consists of a blue/purple crystalline powder, contained within 
a colourless, type I or III glass vial with a rubber stopper and an aluminium seal. 
The vials are packaged into cardboard cartons containing 1, 5 or 10 vials. 
 
 
 6.6 Instructions for use and handling  
 
The contents of the vial should be reconstituted with Water for Injections or saline 
solution, at least 5 ml for the 2 mg vial, at least 10 ml for the 10 mg vial, at least 
20 ml for the 20 mg vial, and at least 40 ml for the 40 mg vial. 
 
 
 
 Administrative Data  
  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Kyowa Hakko (UK) Ltd 
258 Bath Road 
Slough 
Berkshire 
SL1 4DX 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 PL12196/0001/0002/0003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 
 26th November 1992  
 
 
10. DATE OF REVISION OF THE TEXT 
 July 2003 
 
 
 
Page 89 of 89

SAP_001.pdf: 




 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
3
TABLE OF CONTENTS 
 
1. 
INTRODUCTION .................................................................................................................. 4 
2. 
OBJECTIVES ........................................................................................................................ 4 
3. 
STUDY OVERVIEW ............................................................................................................ 4 
4. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................... 5 
5. 
ANALYSIS SETS ................................................................................................................... 5 
6. 
PATIENT DISPOSITION ..................................................................................................... 6 
7. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................ 6 
8. 
STUDY DRUG ADMINISTRATION .................................................................................. 6 
9. 
PHARMACOKINETIC ANALYSES .................................................................................. 7 
10 OTHER ANTI CANCER ANALYSES ................................................................................ 7 
11. SAFETY ANALYSES ............................................................................................................ 7 
11.1 ADVERSE EVENTS .......................................................................................................... 7 
11.2 CLINICAL LABORATORY EVALUATION ......................................................................... 8 
11.3 OTHER SAFETY ANALYSES ............................................................................................ 8 
11.4 CONCOMITANT MEDICATIONS ....................................................................................... 9 
12 LONG-TERM FOLLOW-UP ............................................................................................... 9 
13. SAMPLE SIZE CALCULATION ........................................................................................ 9 
APPENDIX A: LIST OF TABLES, FIGURES AND LISTINGS ........................................... 10 
APPENDIX B:  TABLE LAYOUTS .......................................................................................... 14 
APPENDIX C: LISTING LAYOUTS ........................................................................................ 56 
APPENDIX D: INTERNATIONALLY AGREED ORDER FOR SOC ............................... 104 
 
 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users\
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
4
1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of 
data collected within the scope of Halozyme Therapeutics, Inc. Protocol Number HZ2-
05-01 [A Phase I-IIa, Open-Label, Multiple Dose, Safety, Tolerability and 
Pharmacokinetic Study of Recombinant Human Hyaluronidase (Chemophase™) in 
Combination with Mitomycin in Patients with Non-Muscular-Invasive Bladder Cancer].  
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed.  Any deviations from these guidelines must be substantiated by sound statistical 
reasoning. 
2. OBJECTIVES 
The primary objectives for this study are the following: 
 Determine the maximum tolerated dose (MTD) and dose-limiting toxicities 
(DLTs) of escalating doses of Chemophase in combination with mitomycin 
(Mitomycin, C, MMC) administered as weekly intravesical instillations for five 
weeks; 
 Establish the dose of Chemophase with MMC recommended for future studies. 
 
Secondary objectives for this study include: 
 Assess the pharmacokinetics of intravesical administration of MMC alone and in 
combination with intravesical administration of Chemophase; 
 For the patients treated at the MTD, assess the safety and tolerability of 
intravesical administration of MMC with Chemophase over up to 7 additional 
maintenance treatments every 3 months following the initial six weekly 
instillations; 
 Observe patients for any preliminary evidence of anti-tumor activity of MMC and 
Chemophase when combined. 
3. STUDY OVERVIEW 
This is a Phase I-IIa, open-label, multicenter, dose-escalation, safety, tolerability, and 
pharmacokinetic study of intravesical treatment with combination of Chemophase and 
MMC.  
 
Patient may be considered for enrollment in this study if they have initial presentation or 
recurrence of Stage Ta, T1 or Tis, any grade, bladder cancer after TURBT.   
 
Groups of up to 6 patients will participate in each of the five individual dose cohorts in 
the dose escalation phase of the study.  The amounts of Chemophase to be given for each 
of the five cohorts are as follows: 20,000 U, 60,000 U, 200,000 U, 400,000 U and 
800,000 U.  Once the maximum tolerated dose (MTD) has been established, 6 additional 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
5
evaluable patients will be enrolled at the MTD dose level.  This will provide a total of 12 
evaluable patients at MTD upon which to confirm safety and tolerability of the MTD 
regimen.  In total, up to 36 evaluable patients will be enrolled.  To reach this number, it is 
anticipated that no more than 44 patients will need to be enrolled. 
 
The MTD will be determined based on number of patients experiencing a dose-limiting 
toxicity (DLT) at a particular dose level.  A patient will be considered to have 
experienced a DLT if any of the following occur: 
 Plasma MMC Concentration >= 100 ng/mL; 
 Adverse Event (AE) with a Common Toxicity Criteria (CTC) grade greater than 
or equal to 3; 
 New, treatment-emergent diagnosis of bladder fibrosis. 
For further details on MTD determination, refer to the protocol. 
 
Study patients will receive six weekly study treatments followed by post-treatment 
evaluations, at Weeks 8 and 12.  In addition, the twelve patients receiving the MTD will 
continue to receive combination therapy every 3 months until the end of year 2 or until 
the time of documented tumor recurrence, whichever occurs first.  Long-term follow-up 
information for those in the  MTD cohort will be collected to help make a preliminary 
assessment of possible anti-tumor activity. 
4. GENERAL ANALYSIS CONSIDERATIONS 
Statistical analyses will be reported using summary tables, figures, and data listings.  No 
tests for statistical significance will be performed. All analyses and tabulations will be 
performed using SAS Version 8.2 on a PC platform.  Continuous variables will be 
summarized with means, standard deviations, medians, minimums, and maximums.  
Categorical variables will be summarized by counts and by percentage of patients in 
corresponding categories.  All raw data obtained from the case report forms as well as 
any derived data will be included in data listings. 
5. ANALYSIS SETS 
The following patient population sets will be used for analyses:   
 
 The Safety Set will include all patients who received one or more doses of 
Chemophase.  Any patient receiving MMC on study but not receiving 
Chemophase will be considered for safety, but assessed separately from patients 
receiving Chemophase for selected analysis; 
 
 The Intent-To-Treat (ITT) Set (for anti-tumor effects) will include all patients 
receiving one or more doses of Chemophase with MMC.  It is recognized that this 
definition is a modification of the rigid definition of ITT; 
 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
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\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
6
 The Per-Protocol Set will include all ITT patients who met the following criteria: 
o Satisfied disease-defining Inclusion Criteria #1 and #2; 
o Received at least 4 protocol-specified doses of Chemophase with MMC 
over an interval not exceeding 8 weeks; 
o Retained at least 4 intravesical instillations for at least 90 minutes; 
o Were monitored to the time of tumor recurrence, or at least 5 years, 
whichever occurs first. 
 
Anti-tumor analysis will be performed on the ITT and Per Protocol Sets.  In the event all 
patients in the ITT Set are also in the Per Protocol Set, analysis will only be carried out 
on the ITT Set. 
 
Baseline and safety analysis will be performed on the Safety Set.  Any patient who 
received MMC on study but not Chemophase will be considered for selected safety 
assessments; however, those patients will be assessed separately from patients receiving 
Chemophase. 
6. PATIENT DISPOSITION 
Patient disposition information will be summarized for all patients.  Summaries will 
include: the number of enrolled patients, the number of patients in each analysis set, the 
number of patients completing the study without premature withdrawal, and the reasons 
for not completing the study.   
7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic variables include: age, sex, ethnicity, and race.  Other baseline 
characteristics include: Karnofsky performance status, medical history, urologic history 
and bladder cancer history.  Patient history endpoints to be summarized include the years 
since initial bladder cancer diagnosis, total number of bladder cancer occurrences, 
estimated bladder capacity, total number of bladder tumor treatments, total number of 
bladder cancer surgeries, total number of previous cystoscopies with tumor detected and 
without tumor detected.  When applicable, demographic and baseline characteristics will 
be summarized.    
8. STUDY DRUG ADMINISTRATION 
For each visit during the study drug administration phase of the study other than Day 1, 
patients are expected to receive a pre-specified amount of Chemophase, MMC and sterile 
saline based on the cohort they are assigned to (on Day 1, patients will only receive 
MMC).  Counts and percentages of those patients who receive the pre-specified dose of 
study drug as well as those who do not will be displayed by cohort and visit.  Also 
summarized will be the instillation dwell time (end time of instillation minus post-
instillation void time). 
 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
7
For amount of study drug and sterile saline to be administered for each cohort at each 
visit, refer to Table 9.3-A of the protocol. 
 
9. PHARMACOKINETIC ANALYSES 
The plasma concentrations for MMC and plasma concentrations of rHuPH20 are part of 
the study design, but will not be summarized in tabular form as part of the analysis plan.  
Concentrations will be presented in listings. 
10 OTHER ANTI CANCER ANALYSES 
Plasma determinations for rHuPH20 neutralizing antibodies are part of this study design, 
but will not be summarized in tabular form as part of this analysis plan.  Plasma 
determinations for antibodies will be presented in listings.   
 
All patients completing the study will have a cystoscopy performed at the Week 12 visit.  
For those patients being treated at MTD, cystoscopies will be performed every three 
months through the end of Year 2 starting 3 months after the last study drug treatment, 
which is anticipated to be at Week 6.  Endpoints to be collected include the cystoscopy 
result and the estimated bladder capacity.  Summaries of these endpoints will be 
presented by cohort. 
 
Biomarker tests, consisting of NMP22 BladderChek tests and UroVysion tests, are to be 
conducted during Week 1 and Week 8 of the study.  For those patients treated at MTD, 
these biomarker tests are also to be performed every 3 months, occurring 6 weeks before 
each every-three-month clinic visit.  Results from these tests will be used to construct a 
shift table with possible results of positive, negative, no valid result and not done for the 
BladderChek test and negative, positive, equivocal, other and not done for the Urovysion 
test. 
11. SAFETY ANALYSES 
All patients who received Chemophase will be included in the safety analyses.  Patients 
who receive MMC, but not Chemophase, will be summarized separately for adverse 
events.  Analysis will consist of point estimates and the 95% confidence interval 
constructed around the point estimates for the overall incidence of adverse events. 
11.1 Adverse Events 
The adverse events considered are Treatment Emergent Adverse Events (TEAE) defined 
as those AEs that occurred after initial study drug dosing (first dose of MMC) and those 
existing AEs that worsened after initial study drug dosing. All listings and tabular 
summaries of AEs will be restricted to only TEAEs, except for a separate listing showing 
only those AEs that are pre-treatment-emergent, should any such AEs exist in the 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
8
database. Verbatim terms on case report forms will be mapped to preferred terms and 
system organ classes using the MedDRA dictionary (version 8.0, or a later version at the 
discretion of Synteract). If a patient has more than one adverse event mapped to the same 
preferred term, that adverse event will be reported only once in a given summary table 
using the highest severity and/or closest relationship to study medication.  Patient 
incidence of adverse events will be displayed by system organ class (SOC) and preferred 
term. Adverse events will also be summarized by severity and relationship to each study 
drug (Chemophase, MMC) independently.  Patient incidence of serious adverse events 
(including deaths) will also be displayed. Tabular summaries of AEs will list SOCs 
according to the internationally agreed order, and within each individual SOC the AEs 
will be listed in order of decreasing incidence. See Appendix D for the internationally 
agreed order for SOC. 
11.2 Clinical Laboratory Evaluation 
Descriptive statistics of clinical laboratory assessment changes will be presented for 
baseline and each post baseline time point.  In addition, shift tables will be presented to 
assess abnormal laboratory values over time.  In constructing shift tables, baseline results 
will be compared to the most abnormal post baseline result.  Laboratory parameters will 
be classified as low, normal, high and patient counts of shifts from baseline will be 
presented.  The designation of clinical significance will be displayed. 
 
Listings will be provided for laboratory analyte values. Values outside of the normal 
range will be flagged as either high or low and the designation of clinical significance 
will be displayed. 
11.3 Other Safety Analyses 
Complete physical examinations will occur at screening and Week 8.  In addition, 
targeted physical examinations will take place through the study drug administration 
phase of the study.  Shift tables will be created for each body system to show any 
abnormal result both pre- and post-study drug.  
 
Results for vital signs will be summarized by cohort for each visit.  In addition, change 
from baseline will be presented. 
 
Information for 12-Lead ECG will be collected at screening and Week 8.  A shift table of 
the results for the test will be displayed along with summary statistics of QT, QTc, Heart 
Rate, P-R Interval and QRS. 
 
The Karnofsky Performance Status will performed on each patient at each visit.  Results 
will be shown by visit and cohort. 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
9
11.4 Concomitant Medications 
Concomitant medications taken during the time period beginning 28 days prior to initial 
dosing, on Day 1/Week 1, through the Week 12 assessment (and, for MTD patients 
continuing on study drug treatment, through the last study drug instillation) will be 
collected in this study.  Concomitant medications will be linked to generic terms and 
ATC classes using the WHO dictionary, Version 4.3.  Concomitant medication use will 
be presented in listings. 
12 LONG-TERM FOLLOW-UP 
The twelve patients receiving the MTD will continue to receive combination therapy 
every 3 months until the end of Year 2 or until the time of documented tumor recurrence, 
whichever occurs first.  During this time of extended, long-term, treatment information 
collected on patients will include vital signs, targeted physical examinations, cystoscopy 
and urine cytology, urine dipsticks, hematology results, study drug administration, AE 
collection, concomitant medications and NMP22 BladderChek and UroVysion biomarker 
tests.  Results for endpoints collected will be summarized in similar manner as the regular 
dosing portion of the study, except results will be presented for only the MTD cohort. 
 
In addition, any patients reported to have tumor recurrences will be recorded.  The data 
will be assessed to make Kaplan Meier estimates of time to tumor recurrence at 6, 12, 18 
and 24 months as well as determine median time to tumor recurrence.  All other 
information on tumor recurrences including number of tumors, TNM stage and grading 
will be shown in listings. 
13. SAMPLE SIZE CALCULATION 
This is a Phase I-IIa multiple dose study of Chemophase, and is neither designed nor 
powered for formal statistical comparisons.   
 


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
10
 
APPENDIX A: LIST OF TABLES, FIGURES AND LISTINGS 
List of Tables 
 
Table 
Number 
 
Table Description
1 
Patient Disposition
2 
Demographic Characteristics 
3 
Abnormal Medical History at Baseline (Safety)
4 
Urologic History/ Bladder Cancer History
5 
Bladder Treatments/ Surgeries/ Procedures
6 
Study Drug Administration 
7 
Cystoscopy at Week 12
8.1 
NMP22 BladderChek Test
8.2 
UroVysion FISH Biomarker Test
9.1 
Adverse Events by System Organ Class
9.2 
Adverse Events by System Organ Class and Severity
9.3 
Adverse Events by System Organ Class and Relationship to Chemophase
9.4 
Adverse Events by System Organ Class and Relationship to MMC  
9.5 
Serious Adverse Events by System Organ Class 
10 
Clinical Laboratory Results
11 
Shift Tables of Clinical Laboratory Results
12 
Physical Examination
13 
Vital Signs 
14.1 
Shift Table of 12-Lead ECG
14.2 
12-Lead ECG 
15 
Karnofsky Performance Study
16 
Long-Term Follow-Up- Vital Signs
17 
Long-Term Follow-Up- Physical Examination
18 
Long-Term Follow-Up- Cystoscopy
19 
Long-Term Follow-Up- Hematology
20 
Long-Term Follow-Up- Study Drug Administration
21 
Long-Term Follow-Up- NMP22 BladderChek Biomarker Test 
22 
Long-Term Follow-Up- UroVysion Biomarker Test
23 
Long-Term Follow-Up- Time to Tumor Recurrence from First Study Drug 
Administration (months)


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
11
List of Figures 
 
Figure 
Number 
 
Figure Description
1.1 
Time to Tumor Recurrence from First Study Drug (ITT Set) 
1.2 
Time to Tumor Recurrence from First Study Drug (Per Protocol Set) (If needed)


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
12
List of Data Listings 
 
Listing 
Number 
 
Listing Description 
CRF Plate 
Number 
1 
Patient Disposition 
Derived
2 
Inclusion Criteria 
1, 2
3 
Exclusion Criteria 
3,4
4 
Criteria Waiver 
5
5 
Demographics 
6
6 
Medical History 
7
7 
Urologic History / Bladder Cancer History
8
8 
Previous Bladder Tumor Treatments
9
9 
Previous Bladder Surgeries/Cystoscopies with Tumors Detected 
10
10 
Previous Bladder Cystoscopies without Tumors
11
11 
Previous Bladder Fibrosis / Contracture
12
12 
Previous Cystometrogram
12
13 
Instillation of Chemophase and MMC 
25,26
14 
Blood Collection and Results for MMC, rHuPH20 and  Neutralizing 
Antibodies (NAB) to rHuPH20
27 
15 
Urine Cytology 
17
16 
Cystoscopy 
17
17 
Urine Dipstick 
23
18.1 
NMP22 BladderChek Biomarker Test
24
18.2 
UroVysion FISH Biomarker Test
31
19.1 
Adverse Events (Treatment-Emergent)
97
19.2 
Pre-Treatment-Emergent Adverse Events
97
20 
Serious Adverse Events
97
21 
Reference Range Lab Normals - Hematology
350
22 
Reference Range Lab Normals - Chemistry
351,352
23 
Reference Range Lab Normals - Urinalysis
353
24 
Hematology Results 
19
25 
Chemistry Results 
20,21
26 
Urinalysis Results 
22
27 
Physical Examination
14,15
28 
Vital Signs and Karnofsky Performance Status
13,16
29 
12-Lead ECG 
18
30 
Pregnancy 
18
31 
Concomitant Medications
95
32 
Procedures 
96
33 
Comments 
98
34 
Death Report 
101
35 
Tumor Recurrence 
30


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
13
36 
Long-Term Follow-Up
28,29
37 
Utility Database Panel for Dose-Limiting Toxicities (DLTs) 
Derived


 
Halozyme Therapeutics, Inc. 
 
Statistical Analysis Plan 
Protocol number: HZ2-05-01 
 
January 11, 2008 
C:\Users
\Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 
 
 
 
14
 
 
 
 
 
 
APPENDIX B:  TABLE LAYOUTS 
 


 
 
 
15
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 1 
Patient Disposition 
All Patients 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
 
 
Patients Enrolled [1] 
n
n
n 
n
n
n
 
 
Received MMC Only 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Safety Set [2] 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
ITT Set [3] 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Per Protocol Set [4] 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
 
 
Completed Study Without Premature Withdrawal 
 
 
 
 
 
 
Yes 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
No 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Reasons Patient Did Not Complete Study [5] 
 
 
 
 
 
 
Did not receive all expected instillations of study drug 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Protocol Violation 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Lost to Follow-up 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Adverse Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Non-compliance 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Patient Decision 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Investigator Decision 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
Percentage based on number of patients enrolled. 
[1] Assigned to a treatment cohort. 
[2] Received at least one dose of Chemophase. 
[3] Received at least one dose of Chemophase with MMC. 
[4] Satisfied Inclusion Criteria 1 and 2; received at least 4 doses of Chemophase with MMC over an interval that did not exceed 8 weeks;  retained at least 4 intravesical instillations for at least 90 
minutes.  Note: the criterion “monitored to the time of tumor recurrence, or at least 5 years, whichever occurs first” was not applied for the generation of this table. 
[5] Patient may have more than one reason for not completing study. 
 
path\t_program.sas 
date 
time   


 
 
 
16
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 2.1 
Demographic Characteristics 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
 
(N=)
(N=)
(N=) 
(N=)
(N=)
(N=)
 
 
Age (years) [1] 
 
n 
n
n
n 
n
n
n
Mean (SD) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
Min, Max 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
 
 
Sex 
 
Male 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Female 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
    Hispanic or Latino 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    Not Hispanic or Latino 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
White 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Black, of African Heritage 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Asian 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
American Indian or Alaska Native 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Native Hawaiian or Other Pacific Islander 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Multiple Races 
 
 
 
 
 
 
     Combination 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
     Combination 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
[1] Age is calculated from the date of informed consent. 
path\t_program.sas 
date 
time   
 
Programmer Note  Tables 2.2-2.3 will be for the ITT and Per Protocol Sets (if needed). 
 
 


 
 
 
17
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 3 
Abnormal Medical History at Baseline 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U
400,000 U
800,000 U
Total
Body System 
(N=)
(N=)
(N=)
(N=)
(N=)
(N=)
 
Respiratory 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Cardiovascular 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Gastrointestinal 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Hepatic 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Endocrine/Metabolic 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Central Nervous System 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Hematopoietic/Lymphatic 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Dermatological 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Musculoskeletal 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Genitourinary/Reproductive 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Psychiatric 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Alcohol/Drug Abuse 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Drug Allergy 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Non-Drug Allergy 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
HEENT 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 


 
 
 
18
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 4 
Urologic History/ Bladder Cancer History 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
 
(N=)
(N=)
(N=)
(N=)
(N=)
(N=)
 
Years Since Initial Diagnosis [1] 
n 
n
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
Total Number of Bladder Cancer Occurrences 
 
 
 
 
 
 
n 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Most Recent Estimated Bladder Capacity (mL) 
 
 
 
 
 
 
n 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
[1] Years Since Initial Diagnosis= (Informed Consent Date- Date of Initial Bladder Cancer Diagnosis + 1)/(365.25). 
path\t_program.sas 
date 
time   
 
Programmer Note: Years Since Initial Diagnosis is calculated as the difference in years between the Date of Initial Bladder Cancer Diagnosis (MHSTDT) and the Date of Informed Consent 
(IEDT). If only the year of Initial Bladder Cancer Diagnosis is reported then calculate the difference using only the years.  
 
  
  
 


 
 
 
19
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 5 
Bladder Treatments/ Surgeries/ Procedures 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
 
(N=)
(N=)
(N=) 
(N=)
(N=)
(N=)
 
 
Total Number of Previous Bladder Tumor Treatments [1]
 
n 
n
n
n 
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Total Number of Previous Bladder Surgeries 
 
 
 
 
 
 
n 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Total Number of Previous Cystoscopies With Tumors Detected 
 
 
 
 
 
 
n 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Total Number of Previous Cystoscopies Without Tumors Detected 
 
 
 
 
 
 
n 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
[1] Each “treatment” may include multiple cycles of the same treatment. 
path\t_program.sas 
date 
time   


 
 
 
20
 
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 6 
Study Drug Administration 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
Visit 
(N=)
(N=)
(N=) 
(N=)
(N=)
(N=)
 
 
Week 1, Day 1 
n
n
n 
n
n
n
Dose of MMC Instilled 
 
40 mg 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Volume of MMC Instilled 
 
 
 
 
 
 
20 mL 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Dwell Time (min) [1] 
 
 
 
 
 
 
N 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
[1] Dwell Time= (Time of post-instillation voiding- end time of instillation) . 
path\t_program.sas 
date 
time   
 
Programmer Note  Table will repeat for each day study drug is administered.


 
 
 
21
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 6 
Study Drug Administration 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
Visit 
(N=)
(N=)
(N=) 
(N=)
(N=)
(N=)
 
 
Week 2, Day 8 
n
n
n 
n
n
n
Volume of Chemophase Instilled 
 
Expected Volume 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Other 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
 
 
Units of Chemophase Instilled 
 
Expected Units 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Other 
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
 
 
Volume of Saline Instilled 
 
 
 
 
 
 
Expected Volume 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Dose of MMC Instilled 
 
 
 
 
 
 
40 mg 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Volume of MMC Instilled 
 
 
 
 
 
 
20 mL 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Total Volume Instilled 
 
 
 
 
 
 
28 mL 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Other 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
Dwell Time (min) [1] 
 
 
 
 
 
 
N 
n 
n 
n 
n 
n 
n 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
[1] Dwell Time= (Time of post-instillation voiding- end time of instillation) . 
path\t_program.sas 
date 
time   
 
Programmer Note  Table will repeat for each day study drug is administered. 
 
 
  
 


 
 
 
22
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 7 
Cystoscopy at Week 12 
ITT Set 
 
 
20,000 U
60,000 U
200,000 U
400,000 U
800,000 U
Total
 
(N=)
(N=)
(N=)
(N=)
(N=)
(N=)
 
Result 
n
n
n
n
n
n
Normal 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Abnormal, Not Clinically Significant 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Abnormal, Clinically Significant 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
Estimated Bladder Capacity Volume 
n 
n
n
n
n
n
n
Mean (SD) 
xx.x (xx xx)
xx.x (xx.xx)
xx x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx x
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
Absence of Tumor Recurrence Verified 
Yes 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
No 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Not Applicable 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
path\t_program.sas 
date 
time 
 
Programmer Note  Table using ITT Set will be renumbered to 7.1 if analysis for Per Protocol Set is needed.  Table number for Per Protocol Set will be 7.2. 
 


 
 
 
23
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 8.1 
NMP22 BladderChek Biomarker Test at Week 8 
ITT Set 
Part 1 of 2 
 
 
Baseline [1] 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=) 
400,000 U (N=)
800,000 U (N=)
Time Point 
Neg 
Pos 
Inv[2] 
ND[3]
Neg
Pos
Inv[2]
ND[3]
Neg
Pos
Inv[2] 
ND[3]
Neg
Pos
Inv[2]
ND[3]
Neg
Pos
Inv[2]
ND[3]
 
 
 
 
 
 
Week 8 
n 
 
 
n
n
 
 
n
n
Negative 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Positive 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
No Valid Result (Invalid) n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Not Done 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Inv= No Valid Result (Invalid) 
[3] ND= Not Done 
If more than one test results is collected, the last repeated test is used. 
path\t_program.sas 
date 
time 
 
Programmer Note  Table using ITT Set will be renumbered to 8.1.1 if analysis for Per Protocol Set is needed.  Table number for Per Protocol Set will be 8.1.2. 


 
 
 
24
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 8.1 
NMP22 BladderChek Biomarker Test at Week 8 
ITT Set 
Part 2 of 2 
 
Baseline [1]  
Total (N=) 
Time Point
Neg
Pos
Inv[2] 
ND[3]
 
 
Week 8
n
 
 
Negative
n (%)
n (%)
n (%) 
n (%)
Positive
n (%)
n (%)
n (%) 
n (%)
No Valid Result (Invalid)
n (%)
n (%)
n (%) 
n (%)
Not Done
n (%)
n (%)
n (%) 
n (%)
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Inv= No Valid Result (Invalid) 
[3] ND= Not Done 
If more than one test results is collected, the last repeated test is used. 
path\t_program.sas 
date 
time 
 
Programmer Note  Table using ITT Set will be renumbered to 8.1.1 if analysis for Per Protocol Set is needed.  Table number for Per Protocol Set will be 8.1.2. 


 
 
 
25
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 8.2 
UroVysion FISH Biomarker Test at Week 8 
ITT Set 
 
 
Baseline [1]  
 
__20,000 U (N=)__
__60,000 U (N=)__
__200,000 U (N=)__
__400,000 U (N=)__
Time Point 
Neg 
Pos 
Eq[2] 
Oth[3]
ND[4]
Neg
Pos
Eq[2]
Oth[3]
ND[4]
Neg 
Pos
Eq[2]
Oth[3]
ND[4]
Neg
Pos
Eq[2]
Oth[3]
ND[4]
 
 
 
 
 
 
Week 8 
n 
 
 
n
n 
 
n
Negative 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Positive 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Equivocal 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Other 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Not Done 
n (%) 
n (%) 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Eq= Equivocal 
[3] Oth= Other 
[4] ND= Not Done 
 
path\t_program.sas 
date 
time 
 
Programmer Note  Table using ITT Set will be renumbered to 8.2.1 if analysis for Per Protocol Set is needed.  Table number for Per Protocol Set will be 8.2.2. 


 
 
 
26
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 8.2 
UroVysion FISH Biomarker Test at Week 8 
ITT Set 
 
 
Baseline [1] 
 
800,000 U (N=)
Total (N=)
Time Point 
Neg
Pos
Eq[2]
Oth[3]
ND[4]
Neg 
Pos
Eq[2]
Oth[3]
ND[4]
 
 
 
Week 8 
n
n 
 
Negative 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
Positive 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
Equivocal 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
Other 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
Not Done 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Eq= Equivocal 
[3] Oth= Other 
[4] ND= Not Done 
 
path\t_program.sas 
date 
time 
 
Programmer Note  Table using ITT Set will be renumbered to 8.2.1 if analysis for Per Protocol Set is needed.  Table number for Per Protocol Set will be 8.2.2. 


 
 
 
27
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 9.1 
Treatment Emergent Adverse Events by System Organ Class [1] 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U
400,000 U
800,000 U
Total [2]
Received Only MMC
System Organ Class / Preferred Term 
(N=)
(N=)
(N=)
(N=) 
(N=)
(N=)
(N=)
 
 
Patients Experiencing at Least One Adverse 
Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    95% CI [3] 
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx x, xx x)
(xx.x, xx.x)
 
 
System Organ Class 1 
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Preferred Term 1 
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Preferred Term 2 
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
. 
 
. 
 
 
 
System Organ Class 2 
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Preferred Term 1 
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
Preferred Term 2 
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
. 
 
. 
 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once. 
[2] Total column does not consider patients that received only MMC. 
[3] 95% Confidence Interval based on a binomial distribution. 
path\t_program.sas 
date 
time 
 
 
 
 
 


 
 
 
28
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 9.2 
Treatment Emergent Adverse Events by System Organ Class and Severity [1] 
Safety Set 
Part 1 of 2 
 
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
System Organ Class / Preferred Term 
Mild 
Mod
Sev
Mild
Mod
Sev
Mild
Mod 
Sev
Mild
Mod
Sev
Mild
Mod
Sev 
 
 
 
Patients Experiencing at Least One Adverse 
Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
System Organ Class 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
. 
 
 
. 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
. 
 
 
. 
 
 
 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the highest severity. 
path\t_program.sas 
date 
time 


 
 
 
29
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 9.2 
Treatment Emergent Adverse Events by System Organ Class and Severity [1] 
Safety Set 
Part 2 of 2 
 
Total (N=)
System Organ Class / Preferred Term
Mild
Mod 
Sev
 
Patients Experiencing at Least One Adverse 
Event
n (%) 
n (%) 
n (%) 
 
System Organ Class 1
n (%)
n (%) 
n (%)
Preferred Term 1
n (%)
n (%) 
n (%)
Preferred Term 2
n (%)
n (%) 
n (%)
.
 
.
 
 
System Organ Class 2
n (%)
n (%) 
n (%)
Preferred Term 1
n (%)
n (%) 
n (%)
Preferred Term 2
n (%)
n (%) 
n (%)
.
 
.
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the highest severity. 
path\t_program.sas 
date 
time 
 


 
 
 
30
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 9.3 
Treatment Emergent Adverse Events by System Organ Class and Relationship to Chemophase [1] 
Safety Set 
 
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
System Organ Class / Preferred Term 
Related [2] 
Not Rel [3]
Related [2]
Not Rel [3]
Related [2]
Not Rel [3] 
Related [2]
Not Rel [3]
Related [2]
Not Rel [3]
Related [2]
Not Rel [3] 
 
 
Patients Experiencing at Least One Adverse 
Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
System Organ Class 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
. 
 
. 
 
 
 
System Organ Class 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
. 
 
. 
 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the closest relationship to Chemophase. 
[2] Includes all events reported as “Possibly”, “Probably”, or “Related” relationship to Chemophase. 
[3] Includes all events reported as “Unlikely”, or “Not Related” relationship to Chemophase. 
path\t_program.sas 
date 
time 
 
 


 
 
 
31
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 9.4 
Treatment Emergent Adverse Events by System Organ Class and Relationship to MMC [1] 
Safety Set 
 
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
System Organ Class / Preferred Term 
Related [2] 
Not Rel [3]
Related [2]
Not Rel [3]
Related [2]
Not Rel [3] 
Related [2]
Not Rel [3]
Related [2]
Not Rel [3]
Related [2]
Not Rel [3] 
 
 
Patients Experiencing at Least One Adverse 
Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
System Organ Class 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
. 
 
. 
 
 
 
System Organ Class 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 1 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
Preferred Term 2 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
. 
 
. 
 
 
 
 
[1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the closest relationship to MMC. 
[2] Includes all events reported as “Possibly”, “Probably”, or “Related” relationship to MMC. 
[3] Includes all events reported as “Unlikely”, or “Not Related” relationship to MMC. 
path\t_program.sas 
date 
time  


 
 
 
32
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 9.5 
Treatment Emergent Serious Adverse Events by System Organ Class [1] 
Safety Set 
 
 
20,000 U
60,000 U
200,000 U 
400,000 U
800,000 U
Total
System Organ Class / Preferred Term 
(N=)
(N=)
(N=)
(N=)
(N=)
(N=)
 
Patients Experiencing at Least One Adverse 
Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    95% CI 
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x) 
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
 
System Organ Class 1 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Preferred Term 1 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Preferred Term 2 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
. 
. 
 
System Organ Class 2 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Preferred Term 1 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Preferred Term 2 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
. 
. 
 
 
[1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once. 
 
path\t_program.sas 
date 
time  
 


 
 
 
33
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 10.1 
Clinical Laboratory Results : Hematology 
Safety Set 
WBC (unit) 
 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
 
Result 
Change [2] 
Result
Change [2]
Result
Change [2]
Result 
Change [2]
Result
Change [2]
Result
Change [2]
 
 
 
Baseline [1] 
 
 
n 
n 
 
n
n
n 
n
n
Mean (SD) 
xx.x (xx.xx) 
 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
 
xx.x
xx.x
xx.x 
xx.x
xx.x
Min, Max 
xx, xx 
 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
 
 
 
Above Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
Below Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
Week 2, Day 8 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
Above Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
Below Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 
 


 
 
 
34
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 10.2 
Clinical Laboratory Results : Chemistry 
Safety Set 
Sodium (unit) 
 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
 
Result 
Change [2] 
Result
Change [2]
Result
Change [2]
Result 
Change [2]
Result
Change [2]
Result
Change [2]
 
 
 
Baseline [1] 
 
 
n 
n 
 
n
n
n 
n
n
Mean (SD) 
xx.x (xx.xx) 
 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
 
xx.x
xx.x
xx.x 
xx.x
xx.x
Min, Max 
xx, xx 
 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
 
 
 
Above Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
Below Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
Week 2, Day 8 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
Above Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
Below Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 


 
 
 
35
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 10.3 
Clinical Laboratory Results : Urinalysis 
Safety Set 
Specific Gravity 
 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
 
Result 
Change [2] 
Result
Change [2]
Result
Change [2]
Result 
Change [2]
Result
Change [2]
Result
Change [2]
 
 
 
Baseline [1] 
 
 
n 
n 
 
n
n
n 
n
n
Mean (SD) 
xx.x (xx.xx) 
 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
 
xx.x
xx.x
xx.x 
xx.x
xx.x
Min, Max 
xx, xx 
 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
 
 
 
Above Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
Below Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
Week 2, Day 8 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
Above Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
Below Normal 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 
 
 


 
 
 
36
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 11.1 
Shift Tables of Clinical Laboratory Results : Hematology 
Safety Set 
Part 1 of 2 
 
 
Baseline [1] 
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Most Abnormal Post Baseline Result [2] 
High 
Normal
Low
High
Normal
Low
High
Normal 
Low
High
Normal
Low
High
Normal
Low
 
 
 
WBC (unit) 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
ANC (unit) 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
RBC (unit) 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
… 
 
 
… 
 
 
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 


 
 
 
37
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 11.1 
Shift Tables of Clinical Laboratory Results : Hematology 
Safety Set 
Part 2 of 2 
 
Baseline [1] 
Total (N=) 
Most Abnormal Post Baseline Result [2]
High
Normal 
Low
 
WBC (unit)
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
ANC (unit)
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
RBC (unit)
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
…
 
…
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 
 


 
 
 
38
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 11.2 
Shift Tables of Clinical Laboratory Results : Chemistry 
Safety Set 
Part 1 of 2 
 
 
Baseline [1]
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Most Abnormal Post Baseline Result [2] 
High 
Normal
Low
High
Normal
Low
High
Normal 
Low
High
Normal
Low
High
Normal
Low
 
 
 
Sodium (unit) 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
Potassium (unit) 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
Chloride (unit) 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
… 
 
 
… 
 
 
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 


 
 
 
39
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 11.2 
Shift Tables of Clinical Laboratory Results : Chemistry 
Safety Set 
Part 2 of 2 
 
Baseline [1] 
Total (N=) 
Most Abnormal Post Baseline Result [2]
High
Normal 
Low
 
Sodium (unit)
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
Potassium (unit)
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
Chloride (unit)
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
…
 
…
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 
 


 
 
 
40
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 11.3 
Shift Tables of Clinical Laboratory Results : Urinalysis 
Safety Set 
Part 1 of 2 
 
 
Baseline [1] 
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Most Abnormal Post Baseline Result [2] 
High 
Normal
Low
High
Normal
Low
High
Normal 
Low
High
Normal
Low
High
Normal
Low
 
 
 
Specific Gravity 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
pH 
n 
n
n
 
n
n
High 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Low 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. 
 
path\t_program.sas 
date 
time  
 
Programmer note  In most cases, baseline will be Week 1, Day 1.  Also, only those analytes with numeric results will be considered. 
 


 
 
 
41
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 11.3 
Shift Tables of Clinical Laboratory Results : Urinalysis 
Safety Set 
Part 2 of 2 
 
Baseline [1] 
Total (N=) 
Most Abnormal Post Baseline Result [2]
High
Normal 
Low
 
Specific Gravity
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
pH
n
 
High
n (%)
n (%) 
n (%)
Normal
n (%)
n (%) 
n (%)
Low
n (%)
n (%) 
n (%)
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. 
 
path\t_program.sas 
date 
time  
 
Programmer note  In most cases, baseline will be Week 1, Day 1.  Also, only those analytes with numeric results will be considered.


 
 
 
42
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 12 
Physical Examination [1] 
Safety Set 
 
 
Pre-Study Drug 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
Post-Study Drug 
Normal 
Abnormal
Normal
Abnormal
Normal
Abnormal
Normal 
Abnormal
Normal
Abnormal
Normal
Abnormal
 
 
 
Respiratory 
n 
 
n
n
n 
n
n
Normal 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Abnormal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
Cardiovascular 
n 
 
n
n
n 
n
n
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
Abnormal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
Gastrointestinal 
n 
 
n
n
n 
n
n
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
Abnormal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
… 
… 
…
…
…
…
…
… 
…
…
…
…
…
 
 
 
 
[1] For both pre- and post baseline results, a patient is considered normal for body system unless a result of abnormal is reported for specified body system and time interval.   
 
path\t_program.sas 
date 
time  
 
 
 


 
 
 
43
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 13 
Vital Signs 
Safety Set 
Heart Rate (unit) 
 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
 
Result 
Change [2] 
Result
Change [2]
Result
Change [2]
Result 
Change [2]
Result
Change [2]
Result
Change [2]
 
 
 
Baseline [1] 
 
 
n 
n 
 
n
n
n 
n
n
Mean (SD) 
xx.x (xx.xx) 
 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
 
xx.x
xx.x
xx.x 
xx.x
xx.x
Min, Max 
xx, xx 
 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
 
 
 
Week 2, Day 8 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
Week 3, Day 15 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
 
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each vital sign at each time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1. 
 


 
 
 
44
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 14.1 
Shift Table of 12-Lead ECG 
Safety Set 
Part 1 of 2 
 
 
Screening  
 
20,000 U (N=)
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Week 8, Day 50 
Nor[1] 
Abn[2]
ACS[3]
Nor[1]
Abn[2]
ACS[3]
Nor[1]
Abn[2] 
ACS[3]
Nor[1]
Abn[2]
ACS[3]
Nor[1]
Abn[2]
ACS[3]
 
 
 
 
n 
n
n
 
n
n
Normal 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Abnormal, not Clinically Significant 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
Abnormal , Clinically Significant 
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%) 
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
n (%)
 
 
 
 
[1] Nor= Normal   
[2] Abn= Abnormal, not Clinically Significant 
[3] ACS= Abnormal, Clinically Significant 
 
path\t_program.sas 
date 
time  
 


 
 
 
45
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 14.1 
Shift Table of 12-Lead ECG 
Safety Set 
Part 2 of 2 
 
Screening  
Total (N=) 
Week 8, Day 50
Nor[1]
Abn[2] 
ACS[3]
 
n
 
Normal
n (%)
n (%) 
n (%)
Abnormal, not Clinically Significant
n (%)
n (%) 
n (%)
Abnormal , Clinically Significant
n (%)
n (%) 
n (%)
 
 
[1] Nor= Normal   
[2] Abn= Abnormal, not Clinically Significant 
[3] ACS= Abnormal, Clinically Significant 
 
path\t_program.sas 
date 
time  
 


 
 
 
46
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 14.2 
12-Lead ECG 
Safety Set 
 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
 
Result 
Change [1] 
Result
Change [1]
Result
Change [1]
Result 
Change [1]
Result
Change [1]
Result
Change [1]
QT (unit) 
 
 
Screening 
 
 
n 
n 
 
n
n
n 
n
n
Mean (SD) 
xx.x (xx.xx) 
 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
 
xx.x
xx.x
xx.x 
xx.x
xx.x
Min, Max 
xx, xx 
 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
 
 
 
Week 8, Day 50 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
QTc (unit) 
 
 
Screening 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
 
 [1] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each ECG parameter. 


 
 
 
47
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 15 
Karnofsky Performance Status 
Safety Set 
 
 
20,000 U (N=) 
60,000 U (N=)
200,000 U (N=)
400,000 U (N=)
800,000 U (N=)
Total (N=)
 
Result 
Change [2] 
Result
Change [2]
Result
Change [2]
Result 
Change [2]
Result
Change [2]
Result
Change [2]
 
 
 
Baseline [1] 
 
 
n 
n 
 
n
n
n 
n
n
Mean (SD) 
xx.x (xx.xx) 
 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
 
xx.x
xx.x
xx.x 
xx.x
xx.x
Min, Max 
xx, xx 
 
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
 
 
 
100% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
90% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
80% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
70% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
60% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
50% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
40% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
30% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
20% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
10% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
0% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
 
 
 
Week 2, Day 8 
 
 
n 
n 
n 
n
n
n
n
n 
n
n
n
n
n
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx) 
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
xx.x (xx.xx)
Median 
xx.x 
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x 
xx.x
xx.x
xx.x
xx.x
xx.x
Min, Max 
xx, xx 
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx 
xx, xx
xx, xx
xx, xx
xx, xx
xx, xx
 
 
 
100% 
n (%) 
 
n (%)
n (%)
n (%) 
n (%)
n (%)
…
… 
… 
… 
…
…
…
…
… 
…
…
…
…
…
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each available time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1.  Categories may collapsed as requested by client. 
  
 


 
 
 
48
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 16 
Long-Term Follow-Up- Vital Signs 
Safety Set 
Heart Rate (unit) 
 
 
MTD Cohort  (N=)
 
Result
Change [2]
 
 
Baseline [1]
 
n
n 
Mean (SD)
xx.x (xx.xx)
Median
xx.x
Min, Max
xx, xx
 
 
Month 4 ½ 
 
n
n 
n
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
Median
xx.x
xx.x
Min, Max
xx, xx
xx, xx
 
 
Month 7 ½ 
 
n
n 
n
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
Median
xx.x
xx.x
Min, Max
xx, xx
xx, xx
 
 
… 
… 
…
… 
… 
…
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each vital sign parameter for each long-term follow-up time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1 and should exactly match baseline expressed in table 13 (Vital Signs). 
 


 
 
 
49
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 17 
Long-Term Follow-Up- Targeted Physical Examination 
Safety Set 
 
Reported at least one instance of abnormality [1]:
MTD Cohort 
(N=)
 
Pre-Study Drug 
Respiratory 
n (%)
Cardiovascular 
n (%)
Gastrointestinal 
n (%)
Hepatic 
n (%)
… 
 
Post-Study Drug up to and including Week 12 Visit
Respiratory 
n (%)
Cardiovascular 
n (%)
Gastrointestinal 
n (%)
Hepatic 
n (%)
… 
 
Post-Study Drug during Long-Term Follow-Up Starting with Month 6 until Study Discontinuation
Respiratory 
n (%)
Cardiovascular 
n (%)
Gastrointestinal 
n (%)
Hepatic 
n (%)
… 
 
 
 
Patients reporting more than one abnormality for the same system will be only counted once per time period (pre-study drug/ post-study drug). 
 
path\t_program.sas 
date 
time  
Programmer note  The first two endpoints should match up exactly with first two endpoints on table 12 (Physical Examination) 
 


 
 
 
50
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 18 
Long-Term Follow-Up- Cystoscopy 
ITT Set 
Month 4 ½ 
 
 
MTD Cohort 
(N=)
Cystoscopy 
Result 
Normal 
n (%)
Abnormal, Not Clinically Significant
n (%)
Abnormal, Clinically Significant
n (%)
 
Estimated Bladder Capacity Volume (mL)
n 
n
Mean (SD) 
xx.x (xx.xx)
Median 
xx.x
Min, Max 
xx, xx
… 
 
 
 
path\t_program.sas 
date 
time  
 
Repeat table for each time point. 
 


 
 
 
51
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 19 
Long-Term Follow-Up- Hematology 
Safety Set 
WBC (unit) 
 
 
MTD Cohort  (N=)
 
Result
Change [2]
 
 
Baseline [1]
 
n
n 
Mean (SD)
xx.x (xx.xx)
Median
xx.x
Min, Max
xx, xx
 
 
Month 4 ½
 
n
n 
n
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
Median
xx.x
xx.x
Min, Max
xx, xx
xx, xx
 
 
Month 7 ½
 
n
n 
n
Mean (SD)
xx.x (xx.xx)
xx.x (xx.xx)
Median
xx.x
xx.x
Min, Max
xx, xx
xx, xx
 
 
… 
… 
…
 
 
 
[1] Baseline defined as measurement taken most closely prior to first study drug administration.   
[2] Change= Change from Baseline 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each long-term follow-up time point. 
Programmer note  In most cases, baseline will be Week 1, Day 1 and should exactly match baseline expressed in table 10.1 (Hematology Results). 


 
 
 
52
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 20 
Long-Term Follow-Up- Study Drug Administration 
Safety Set 
 
 
Visit 
MTD Cohort 
(N=)
 
Month 4 ½ 
Chemophase 
Units Instilled- Mean (SD)
xx.x (xx.xx)
Volume Instilled- Mean (SD)
xx.x (xx.xx)
 
Sterile Saline 
Volume Instilled- Mean (SD)
xx.x (xx.xx)
 
MMC 
Dose Instilled- Mean (SD)
xx.x (xx.xx)
Volume Instilled- Mean (SD)
xx.x (xx.xx)
 
Total Volume Instilled- Mean (SD)
xx.x (xx.xx)
 
Any Interruptions or Adjustments Due to DLTs?
Yes 
n (%)
No 
n (%)
 
Length of Time Patient Retain Solution in their Bladder
2 Hours 
n (%)
>= 90 Minutes, < 2 Hours
n (%)
< 90 Minutes 
n (%)
 
5 mL Urine Sample Collected and Frozen?
Yes 
n (%)
No 
n (%)
 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each long-term follow-up time point. 
 
 
 
 
 
 


 
 
 
53
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 21 
Long-Term Follow-Up- NMP22 BladderChek Biomarker Test 
Safety Set 
 
 
 
MTD Cohort 
(N=xx)
 
Month 3 
Negative 
n (%)
Positive 
n (%)
No Valid Result 
n (%)
Not Done 
n (%)
 
Month 6 
Negative 
n (%)
Positive 
n (%)
No Valid Result 
n (%)
Not Done 
n (%)
 
… 
 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each long-term follow-up time point. 
 
 


 
 
 
54
 Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 22 
Long-Term Follow-Up- UroVysion FISH Biomarker Test 
Safety Set 
 
 
 
MTD Cohort 
(N=xx)
 
Month 3 
Negative 
n (%)
Positive 
n (%)
Equivocal 
n (%)
Other 
n (%)
Not Done 
n (%)
 
Month 6 
Negative 
n (%)
Positive 
n (%)
Equivocal 
n (%)
Other 
n (%)
Not Done 
n (%)
… 
 
 
path\t_program.sas 
date 
time  
 
Table will repeat for each analyte for each long-term follow-up time point.


 
 
 
55
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Table 23 
Long-Term Follow-Up- Time to Tumor Recurrence from First Study Drug Administration (Months) 
Safety Set 
 
 
Category, n (%) 
MTD Cohort 
(N=xx)
 
Number Patients with Tumor Recurrence 
n
Number Patients Censored 
n
 
Quartiles (95% CI): 
   25th Percentile 
x.x (x.x, x.x)
  50th Percentile (median)
x.x (x.x, x,x)
  75th Percentile 
x.x (x.x, x.x)
 
Kaplan Meier Estimate (# at Risk) 
   6 Months 
   12 Months 
   18 Months 
   24 Months 
 
x.x (n) 
x.x (n) 
x.x (n) 
x.x (n)
 
Range  (Patients with Tumor Recurrence)
xx, xx
Range  (All Patients)
xx, xx
 
 
path\t_program.sas 
date 
time  
 
 


 
 
 
56
 
 
APPENDIX C: LISTING LAYOUTS 
 


 
 
 
57
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 1 
Patient Disposition 
(N=) 
 
Cohort X/ 
Chem Units 
Patient ID 
Received MMC Only? 
Safety 
Set [1]
ITT Set [2]
Per Protocol 
Set [3]
Date of Study Discontinuation/ 
Study Termination
Completed 
Study?
Reason for 
Discontinuation [4]
Date of Investigator’s 
Signature
Name of 
Investigator
 
 
[1] Received at least one dose of Chemophase. 
[2] Received at least one dose of Chemophase with MMC. 
[3] Satisfied Inclusion Criteria 1 and 2; received at least 4 doses of Chemophase with MMC over an interval that did not exceed 8 weeks;  retained at least 4 intravesical instillations for at least 90 
minutes.  Note: the criterion “monitored to the time of tumor recurrence, or at least 5 years, whichever occurs first” was not applied for the generation of this table. 
[4] Reasons for discontinuation include: Did not receive all expected instillations of study drug. Protocol Violation, Lost to Follow-up, Adverse Event, Non-compliance, Patient Decision, Investigator 
Decision, Other. 
path\t_program.sas 
date 
time 
 


 
 
 
58
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 2 
Inclusion Criteria 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Date Informed 
Consent Signed 
Inclusion Criteria
1a 
1b
2
3
4
5
6 
7
8
9
10
11
12
 
 
 
path\t_program.sas 
date 
time 
 
Programmer Note   Inclusion criteria to be shown on separate page. 


 
 
 
59
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 3 
Exclusion Criteria 
(N=) 
 
Cohort X/ 
Chem Units 
Patient ID 
Date Informed 
Consent Signed 
Exclusion Criteria
1 
2
3
4
5
6
7
8 
9
10
11
12
13
14
15
16
 
 
 
path\t_program.sas 
date 
time 
 
Programmer Note   Exclusion criteria to be shown on separate page. 


 
 
 
60
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 4 
Criteria Waiver 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Patient Comply with All 
Entry Criteria? 
If No, Criteria Not Met
Criteria Not Met
Criteria Number
Exemption Explanation
Exemption Granted By
Date of Exemption
 
                                                                                                 Inclusion/Exclusion 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
61
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 5 
Demographics 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Date of Birth 
Day 1 Dose
Age on Day 1
Sex
Ethnicity
Race
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
62
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 6 
Medical History 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if No Medical 
History 
 
Site / System
 
Description
 
Year of Diagnosis / Onset
 
Ongoing
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
63
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 7 
Urologic History / Bladder Cancer History 
Part 1 of 3 (Cancer Recurrences) 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Bladder Cancer 
Date of Initial Diagnosis
Date of Recurrences
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
64
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 7 
Urologic History / Bladder Cancer History 
Part 2 of 3 (Estimation of Bladder Capacity) 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Bladder Capacity 
Date of Estimation
Method of Estimation 
Volume (mL)
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
65
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 7 
Urologic History / Bladder Cancer History 
Part 3 of 3 (Bladder Symptoms) 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
 
Frequent Urination? 
 
Nighttime Urinations?
 
Urinary Urgency? 
 
Urinary Incontinence?
 
Use Pads?
 
Yes/No 
Average 
Urinations/Day
 
Yes/No
Average 
Urinations/Night
 
Yes/No
Average 
Urinations/Week
 
Yes/No
Average 
Urinations/Week
 
Yes/No
Average 
Pads/Day
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
66
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 8 
Previous Bladder Tumor Treatments 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
 
 
Medication / Treatment 
 
Start Date / 
Stop Date
 
 
Dose / Units 
 
 
Route
 
 
Toxicities
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
67
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 9 
Previous Bladder Surgeries / Cystoscopies with Tumors Detected 
Part 1 of 2 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if None 
                                                                    Procedure
Tumor # from 
CRF 
 
Date
 
Type
Tumor Size 
(mm)
Histological 
Grading
 
Location
 
TNM Staging
                                                                                                                                             Surgery 
                                                                                                                                          Cystoscopy 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
68
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 9 
Previous Bladder Surgeries / Cystoscopies with Tumors Detected 
Part 2 of 2 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if None 
Tumor # from 
CRF 
 
Biopsy Performed?
If Yes, 
Biopsy Findings 
 
Gross Appearance of Tumor
Depth of Involvement of Bladder 
Mucosa or Not Applicable
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
69
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 10 
Previous Bladder Cystoscopies without Tumors 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None 
Cystoscopy # from CRF
 
Date of Procedure 
 
Abnormal Findings
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
70
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 11 
Previous Bladder Fibrosis / Contracture 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None 
Date
 
Diagnosis
 
Etiology
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
71
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 12 
Previous Cystometrogram 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None 
Test Date
 
Result
 
Test(s) Used
If Abnormal, 
Specify Abnormality
 
 
 
path\t_program.sas 
date 
time 
 


 
 
 
72
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 13 
Instillation of Chemophase and MMC 
Page 1 of 2 
(N=) 
 
  
 
Refrain From Drinking Fluids?
 
Pre-Instillation
 
Instillation
 
Post-Instillation
Cohort X/ 
Chem Units 
Patient 
ID 
For >= 8 Hours 
Before Instillation 
During 
Instillation
Fully 
Voided Before?
Volume Obtained by 
Catheter (mL)
 
Date
Start 
Time 
End 
Time
Elapsed Time 
(min) [1]
Time of 
Voiding
Dwell Time 
(min) [2]
Voided 
Volume (mL)
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
[1] Elapsed Time= End Time of Instillation – Start Time of Instillation 
[2] Dwell Time= Time of Voiding – End Time of Instillation 
  
path\t_program.sas 
date 
time   
 


 
 
 
73
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 13 
Instillation of Chemophase and MMC 
Page 2 of 2 
(N=) 
 
  
 
Chemophase Instilled 
 
Saline 
Instilled
 
MMC Instilled
  
  
  
Cohort X/ 
Chem Units 
Patient 
ID 
Volume 
(mL) 
Units 
(U) 
Volume 
(mL)
Volume 
(mL)
Dose 
(mg)
Total Volume 
Instilled (mL)
Interrupt/ Adjust 
due to DLTs? 
If Yes, Specify
Time Solution 
Retained [1]
Post Drug Instillation 
Urine Sample Collected? 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
                             
[1] Possible responses for Time Solution Retained include: 2 Hours, 90 Minutes to <2 Hours,  <90 Minutes 
path\t_program.sas 
date 
time   
 


 
 
 
74
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 14 
Blood Collection and Results for MMC, rHuPH20 and Neutralizing Antibodies (NAB) to rHuPH20 
(N=) 
 
 
 
Collection
Results
Neutralizing 
Antibodies (NAB) to 
rHuPH20 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if 
Not Done 
Date Drawn
Scheduled Time
Actual Time 
MMC (ng/mL) 
or Not Done
rHuPH20 (U/mL)
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
path\t_program.sas 
date 
time   
  


 
 
 
75
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 15 
Urine Cytology 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if Not 
Done
 
Collection Date
Diagnosis
Microscopic Description
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 


 
 
 
76
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 16 
Cystoscopy 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if 
Not Done 
Cystoscopy 
Date
Result
If Abnormal, Specify 
Abnormality:
Estimated Bladder Capacity (mL)
Absence of Bladder Cancer 
Verified?
 
 
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 
 


 
 
 
77
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 17 
Urine Dipstick 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit 
#
Mark if Not 
Done
Collection Date
Collection Time 
Do Results Indicate Possible UTI?
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 


 
 
 
78
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 18.1 
NMP22 BladderChek Biomarker Test 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if 
Not Done
Test
Collection Date
Collection Time
Result
If Invalid, Was Test Repeated?
 
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 
Programmer Note  Test column will indicate whether test conducted is an initial test or a retest. 


 
 
 
79
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 18.2 
UroVysion FISH Biomarker Test 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit #
Mark if Not 
Done
Test
Collection Date
Collection Time
Result
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 
Programmer Note  Test column will indicate whether test conducted is an initial test or a retest. 
 


 
 
 
80
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 19.1 
Adverse Events (Treatment-Emergent) 
(N=) 
 
 
 
 
 
 
Action Taken with:
 
Relationship to:
 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark 
if 
None 
AE # 
 
Preferred Term/ 
Verbatim Term
 
Start 
Date
Stop 
Date
Serious 
?
Severity 
(CTC)
 
 
MMC
 
 
Chemophase
 
 
MMC
 
 
Chemophase
 
 
Other Action
 
 
Outcome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
* Treatment-Emergent Adverse Events are defined as those adverse events that occurred after initial study drug dosing and those existing AE’s that worsened after initial study drug dosing.  Adverse 
Events that occurred after the first dose of MMC but prior to first dose of Chemophase will be indicated with a “*”. 
  
path\t_program.sas 
date 
time   
 
Programmer Note  Abbreviations may be needed for some of the columns.  If so, add a footnote to define the abbreviations. 


 
 
 
81
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 19.2 
Pre-Treatment-Emergent Adverse Events 
(N=) 
 
 
 
 
 
 
Action Taken with:
 
Relationship to:
 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark 
if 
None 
AE # 
 
Preferred Term/ 
Verbatim Term
 
Start 
Date
Stop 
Date
Serious 
?
Severity 
(CTC)
 
 
MMC
 
 
Chemophase
 
 
MMC
 
 
Chemophase
 
 
Other Action
 
 
Outcome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
* Only Adverse Events that occurred between the time the patient signed the informed consent and prior to the first dose of MMC and Chemophase are included. 
  
path\t_program.sas 
date 
time   
 
Programmer Note  Abbreviations may be needed for some of the columns.  If so, add a footnote to define the abbreviations.  
 


 
 
 
82
Page 1 of x 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 20 
Serious Adverse Events (Treatment-Emergent) 
(N=) 
 
 
 
 
 
 
Action Taken with:
 
Relationship to:
 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark 
if 
None 
AE # 
 
Preferred Term/ 
Verbatim Term
 
Start 
Date
Stop 
Date
Serious 
?
Severity 
(CTC)
 
 
MMC
 
 
Chemophase
 
 
MMC
 
 
Chemophase
 
 
Other Action
 
 
Outcome
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Treatment-Emergent Adverse Events are defined as those adverse events that occurred after initial study drug dosing and those existing AE’s that worsened after initial study drug dosing.  Adverse 
Events that occurred prior to first dose of MMC but prior to first dose of Chemophase will be indicated with a “*”. 
  
path\t_program.sas 
date 
time   
 
Programmer Note  Abbreviations may be needed for some of the columns.  If so, add a footnote to define the abbreviations. 
 


 
 
 
83
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 21 
Reference Range Lab Normals – Hematology 
 
 
 
 
 
 
Age
 
Lab (Both or Male) 
 
Lab (Female)
 
 
Site ID 
 
Lab ID 
Date 
Effective 
 
Lab Test
 
Low
 
High
 
Low
 
High 
 
Low
 
High
 
Units
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 
Programmer Note  Order the lab tests in the same order as on the CRF. 


 
 
 
84
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 22 
Reference Range Lab Normals – Chemistry 
 
 
 
 
 
 
Age
 
Lab (Both or Male) 
 
Lab (Female)
 
 
Site ID 
Date 
Effective 
 
Lab Test
 
Low
 
High
 
Low
 
High 
 
Low
 
High
 
Units
COVANCE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
path\t_program.sas 
date 
time   
 
Programmer Note  Order the lab tests in the same order as on the CRF. 


 
 
 
85
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 23 
Reference Range Lab Normals – Urinalysis 
 
 
 
 
 
Age
 
Lab (Both or Male) 
 
Lab (Female)
 
 
Site ID 
Test 
Code 
Lab 
Test 
Occu 
Seq 
Date Effective
 
Low
 
High
 
Low
 
High
 
Low
 
High
Units
COVANCE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 
Programmer Note  Order the lab tests in the same order as on the CRF. 


 
 
 
86
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 24 
Hematology Results 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Lab Test 
Visit # 
Lab ID
Mark if Not 
Done
Collection 
Date
Collection 
Time
 
Result [1]
 
Unit
 
Abnormal, not CS
 
Abnormal and CS
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CS = Clinically Significant. 
[1] H indicates a value above the normal range. L indicates a value below the normal range. 
 
path\t_program.sas 
date 
time   
 
 Programmer Note  Put an “H” next to results that are above the normal range. Put an “L” next to results that are below the normal range. 
                               Sort the lab tests in the same order as on the CRF. 
 
 


 
 
 
87
 
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 25 
Chemistry Results 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Lab Test 
Visit # 
Lab ID
Mark if Not 
Done
Collection 
Date
Collection 
Time
 
Result [1]
 
Unit
 
Abnormal, not CS
 
Abnormal and CS
 
 
 
 
 
 
 
COVANCE 
 
 
 
 
 
 
 
CS = Clinically Significant. 
[1] H indicates a value above the normal range. L indicates a value below the normal range. 
 
path\t_program.sas 
date 
time   
 
 Programmer Note  Put an “H” next to results that are above the normal range. Put an “L” next to results that are below the normal range. 
                               Sort the lab tests in the same order as on the CRF. 
 


 
 
 
88
 
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
  
Listing 26 
Urinalysis Results 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Lab ID 
Lab Test 
Visit 
#
Lab ID
Mark if 
Not Done
Collection 
Date
Collection 
Time
 
Result [1]
 
Unit
 
Abnormal, not CS
 
Abnormal and CS
 
 
 
 
 
 
 
COVANCE 
 
 
 
 
 
 
 
CS = Clinically Significant. 
[1] H indicates a value above the normal range. L indicates a value below the normal range. 
 
path\t_program.sas 
date 
time   
 
 Programmer Note  Put an “H” next to results that are above the normal range. Put an “L” next to results that are below the normal range. 
                               Sort the lab tests in the same order as on the CRF. 


 
 
 
89
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
Listing 27 
Physical Examination 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if 
Not Done
Exam 
Date
New, Changed or 
Resolved Abnormality?
PE 
#
System 
 
Description of Abnormality
 
Clinically Significant?
  
 
  
  
  
  
  
 
  
  
  
  
path\t_program.sas 
date 
time   
 
Programmer Note  For  System’, add footnotes to explain abbreviations as needed. 
                               If Physical Exam was not done, put “Not Done” for Exam Date ’.  
                               Sort System by System code #.


 
 
 
90
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 28 
Vital Signs and Karnofsky Performance Status 
(N=) 
 
 
 
Blood Pressure 
(mmHg)
Temperature
Weight
Height
Cohort X/ 
Chem Units 
Patient 
ID 
Visit 
# 
Mark if 
Not 
Done 
Date of 
Vital 
Collected
Heart Rate 
(bpm)
Respiration 
(breaths/min)
 
Systolic
 
Diastolic
 
Result 
Unit
Coll. 
Type
 
Result
 
Units
 
Result
 
Units
Karnofsky 
Score
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral 
Aural 
 
 
 
 
 
 
path\t_program.sas 
date 
time   
 
Programmer Note  If vitals were  not done put “Not Done” for Date. 
 


 
 
 
91
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
 
  
Listing 29 
12-Lead ECG 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if 
Not Done
ECG 
Date
Result
If Abnormal, CS, 
Specify:
QT 
(msec) 
QTc 
(msec)
HR 
(bpm)
P-R Interval (msec)
QRS (msec)
  
 
 
 
 
 
 
  
  
  
  
 
  
  
  
  
 
  
path\t_program.sas 
date 
time   
 


 
 
 
92
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 30 
Pregnancy 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Visit # 
Mark if 
Not Done
Date
 
Reason, If Not Done
 
Result
  
 
  
  
  
  
  
  
  
  
  
  
path\t_program.sas 
date 
time   
 


 
 
 
93
 
  
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
 
  
Listing 31 
Concomitant Medications 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None 
Con 
Med # 
Medication
 
Dose
 
Unit
 
Route
 
Regimen
Date of 
Day 1
Start Date 
Stop Date
 
Indication
Given for 
AE?
If Yes, AE 
#s
  
 
 
 
 
 
 
  
  
  
  
 
  
  
  
  
 
 
path\t_program.sas 
date 
time   
 
Programmer Note  If there are no concomitant medications put “NONE” for Medication’. 
                               Add footnotes to explain abbreviations as needed. 
 
 
 


 
 
 
94
 
  
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 32 
Procedures 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None 
Procedure 
#
Procedure
 
 
Date
 
 
Findings / Results
 
Related to 
AE?
 
If Yes, 
AE #s
 
 
 
 
 
 
  
  
  
  
 
  
path\t_program.sas 
date 
time   
 
Programmer Note  If there are no procedures put “NONE” for Procedure’. 
 
 


 
 
 
95
 
  
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 33 
Comments 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None
Comment #
 
Pertains to Visit 
Date
 
 
CRF Page
 
 
Comment
  
 
 
 
 
 
 
  
  
  
  
  
path\t_program.sas 
date 
time  
 
Programmer Note  If there are no comments put “NONE” for Comment #’.  
 


 
 
 
96
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 34 
Death Report 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Date of 
Death 
Date Death 
Reported to Site
 
Primary Cause
 
Autopsy 
Performed?
Comments
Investigator 
Signed?
Date of Signature
  
 
 
 
 
 
 
  
  
  
  
 
  
                                
path\t_program.sas 
date 
time   
 


 
 
 
97
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 35 
Tumor Recurrence 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
None 
Procedure 
Date 
Procedure 
Type
Tumor Size 
(mm)
Histopathological 
Grading
Tumor 
Location
TNM 
Staging 
Biopsy 
Performed?
If Yes, 
Biopsy 
Findings
Gross 
Appearance 
of Tumor
Involvement of 
Bladder 
Mucosa, or NA
  
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
  
                                
path\t_program.sas 
date 
time   
 


 
 
 
98
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
 
 
Listing 36 
Long-Term Follow-Up 
Part 1 of 5 
(N=) 
 
 
Bladder Cancer Treatments
Cohort X/ 
Chem Units 
Patient 
ID 
Contact/ 
Visit Date
Method of 
Contact
Patient 
Status at 
Contact
Source of 
Information
Treatment 
Mark if 
None
Start 
Date
Stop 
Date
Ongoing?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                
path\t_program.sas 
date 
time   


 
 
 
99
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 36 
Long-Term Follow-Up 
Part 2 of 5 
(N=) 
 
NMP22 BladderChek Test 
Cohort X/ 
Chem Units 
Patient 
ID
Contact/ Visit 
Date
Mark if 
None
Collection 
Date/Time
Result
  
 
 
 
 
 
 
  
  
  
  
 
 
  
                                
path\t_program.sas 
date 
time   
 


 
 
 
100
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 36 
Long-Term Follow-Up 
Part 3 of 5 
(N=) 
 
UroVysion FISH Biomarker Test
Cohort X/ 
Chem Units 
Patient 
ID
Contact/ Visit 
Date
Mark if 
None
Collection 
Date/Time
Result
  
 
 
 
 
 
 
  
  
  
  
 
 
  
                                
path\t_program.sas 
date 
time   
 


 
 
 
101
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 36 
Long-Term Follow-Up 
Part 4 of 5 
(N=) 
 
 
Cystoscopy
Urine Cytologies 
Bladder Biopsies
Cohort X/ 
Chem Units 
Patient ID 
Contact/ 
Visit Date 
Mark if 
None 
Date
Result
If Abnormal, 
Specify 
Abnormality
Mark if 
None
Date
Diagnosis 
Microscopic 
Description
Mark if 
None
Date
Findings
  
 
 
 
 
 
 
  
  
  
  
 
  
                                
path\t_program.sas 
date 
time   
 


 
 
 
102
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 36 
Long-Term Follow-Up 
Part 5 of 5 
(N=) 
 
 
Tumor Recurrence
Cohort X/ 
Chem Units 
Patient ID 
Contact/ 
Visit Date
Mark if None
Date Confirmed
Investigator Signed?
  
 
 
 
 
 
 
  
  
  
  
 
  
                                
path\t_program.sas 
date 
time   
 


 
 
 
103
 
Halozyme Therapeutics, Inc. 
Protocol Number: HZ2-05-01 
  
  
Listing 37 
Utility Database Panel for Dose-Limiting Toxicities (DLTs) 
(N=) 
 
Cohort X/ 
Chem Units 
Patient 
ID 
Mark if 
No DLT 
Date 
Reported
Adverse Event Considered 
to be DLT?  If so, Name 
Adverse Event
PK Lab Assessment of 
MMC Level Considered 
to be DLT?
Treatment 
Emergent Bladder 
Fibrosis?
 
Reason Given for Discontinuation on 
Termination Page
  
 
 
 
 
 
 
  
  
  
 
 
 Protocol defined DLTs are AEs with a CTC grade greater than or equal to 3, Plasma MMC Concentration >=100 ug/mL and Diagnosis of treatment-emergent bladder fibrosis. 
                                
path\t_program.sas 
date 
time   
 


 
 
 
104
APPENDIX D: INTERNATIONALLY AGREED ORDER FOR SOC 
Infections and infestations 
Neoplasms benign and malignant (including cysts and polyps) 
Blood and the lymphatic system disorders 
Immune system disorders 
Endocrine disorders 
Metabolism and nutrition disorders 
Psychiatric disorders 
Nervous system disorders 
Eye disorders 
Ear and labyrinth disorders 
Cardiac disorders 
Vascular disorders 
Respiratory, thoracic and mediastinal disorders 
Gastrointestinal disorders 
Hepato-biliary disorders 
Skin and subcutaneous tissue disorders 
Musculoskeletal, connective tissue and bone disorders 
Renal and urinary disorders 
Pregnancy, puerperium and perinatal conditions 
Reproductive system and breast disorders 
Congenital and familial/genetic disorders 
General disorders and administration site conditions 
Investigations 
Injury and poisoning 
Surgical and medical procedures 
Social circumstances 
 
 
This list is from an EMEA Guideline, ‘A Guideline on Summary of Product Characteristics’, October 2005.