Safety Study of Recombinant Human Hyaluronidase (Chemophase) in Combination With Mitomycin in Participants With Superficial Bladder Cancer

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00318643
• Collaborator: (none)
• Enrollment: 27
• Locations: 5
• Arms: 5
• Actual Duration (Months): 40.4
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer	Drug: Mitomycin C; Drug: Chemophase	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase 1-2a, 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
• Actual Study Start Date: Mar 30, 2006
• Actual Primary Completion Date: Aug 11, 2009
• Actual Study Completion Date: Aug 11, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: MMC plus Chemophase 20,000 U 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.	Drug: Mitomycin C; intravesical administration; Drug: Chemophase; intravesical administration
Experimental: Cohort 2: MMC plus Chemophase 60,000 U 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.	Drug: Mitomycin C; intravesical administration; Drug: Chemophase; intravesical administration
Experimental: Cohort 3: MMC plus Chemophase 200,000 U 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.	Drug: Mitomycin C; intravesical administration; Drug: Chemophase; intravesical administration
Experimental: Cohort 4: MMC plus Chemophase 400,000 U 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.	Drug: Mitomycin C; intravesical administration; Drug: Chemophase; intravesical administration
Experimental: Cohort 5: MMC plus Chemophase 800,000 U 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.	Drug: Mitomycin C; intravesical administration; Drug: Chemophase; intravesical administration

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Chemophase in Combination With MMC [5 weeks (Week 2 to Week 6)]

   The MTD was defined as the maximum dose level at which no more than two of six participants experienced dose-limiting toxicities (DLT). DLT was defined as any of the following: Plasma MMC concentration greater than or equal to (>=) 100 nanograms (ng)/milliliter (mL) Adverse event (AE) with a Common Toxicity Criteria (CTC) grade greater than or equal to 3 New, treatment-emergent diagnosis of bladder fibrosis.

2. Number of Participants With Dose Limiting Toxicities (DLTs) [5 weeks (Week 2 to Week 6)]

   DLT was defined as any of the following: Plasma MMC concentration >= 100 ng/mL AE with a CTC grade greater than or equal to 3 New, treatment-emergent diagnosis of bladder fibrosis.

3. Recommended Dose of Chemophase With MMC For Future Studies [5 weeks (Week 2 to Week 6)]

Secondary Outcome Measures

1. Number of Participants With a Quantifiable MMC Plasma Concentration Value [0 (predose), 1, 2, and 3 hours postdose at Weeks 1, 2, 5, and 6]

   A quantifiable MMC plasma concentration value was a value that was not below the quantifiable limit (BQL) of <10.0 nanogram/milliliter (ng/mL).

2. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Baseline up to 2 years]

   TEAEs were defined as any AE that occurred after the first administration of the study drug and until the end of the study. AEs were defined as any untoward medical occurrence in a participant administered study drug and that did not necessarily have a causal relationship with the study drug. SAEs were defined as any AE that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes as fatal, life-threatening, required in-participant hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, an important medical event. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in 'Reported Adverse Events' Section.

3. Number of Participants Who Remained Tumor Free at the End of the Study [Baseline up to 2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants with initial presentation or recurrence of Stage Ta, T1 or Tis, any grade, bladder cancer after transurethral resection of bladder tumor (TURBT).

• TURBT within 42 days prior to Day 1/Week 1

• Karnofsky Performance Status greater than or equal to 80%

• Life expectancy at least 3 years

• 18 years or older

• A negative pregnancy test (if female of child-bearing potential)

• Acceptable liver function within 7 days defined as: bilirubin less than or equal to 1.5 times upper limit of normal, and aspartate aminotransferase (AST) Glutamic-oxalacetic transaminase (SGOT), alanine aminotransferase (ALT), glutamic-pyruvic transaminase (SGPT), and alkaline phosphatase <= 2.5 times upper limit of normal

• Acceptable renal function within 7 days defined as: serum creatinine less than or equal to 1.5 times upper limit of normal, or calculated creatinine clearance greater than or equal to 40 milliliter (mL)/minute/1.73 meter^2

• Acceptable hematologic status within 7 days defined as: absolute neutrophil count (ANC) greater than or equal to 2,500 cells/millimeter^{3, platelet count greater than or equal to 150,000/millileter}3, and hemoglobin greater than or equal to 10.0 grams/deciliter.

• Urinalysis showing no clinically significant abnormalities except those attributable to bladder cancer.

• For men and women of child-producing potential, agreement to use an effective contraceptive method during the treatment period of the study.

• Signed, written Institutional Review Board (IRB)-approved informed consent

Exclusion Criteria:

• History or previous diagnosis of bladder fibrosis

• Total bladder capacity estimated at cystoscopy to be less than 150 mL

• Urinary incontinence of a severity that would compromise the ability of the participant to retain the study drug intravesical instillation for two hours.

• Severe irritative voiding symptoms such as urgency, frequency, or nocturia

• 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.

• Major surgery, other than TURBT and diagnostic surgery, within 28 days prior to Day 1/Week 1.

• Active, uncontrolled bacterial, viral, or fungal infections, including urinary tract infection.

• Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within one month prior to Day 1/Week 1 on study (two months for nitrosureas 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.

• Known infection with human immunodeficiency virus (HIV)

• Known active infection with hepatitis B or hepatitis C

• 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).

• History of a hypersensitivity or idiosyncratic reaction to, or other contraindication to, mitomycin.

• Known allergy to bee or vespid venom

• Known coagulation disorder or bleeding tendency

• Treatment with heparin or anticipation of heparin treatment during the treatment period in this study.

• Unwillingness or inability to comply with procedures required in this protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	BCG Oncology	Phoenix	Arizona	United States	85032
2	MedResearch	La Mesa	California	United States	91942
3	Malcolm Randall Veterans Administration Urology Section (112-C)	Gainesville	Florida	United States	32608
4	Advanced Research Institute	New Port Richey	Florida	United States	34652
5	James A. Haley Veterans Hospital	Tampa	Florida	United States	33612

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Feb 26, 2009
• Statistical Analysis Plan - Jan 11, 2008

More Information

Additional Information:

• Sponsor's website

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT00318643
• Other Study ID Numbers: HZ2-05-01
• First Posted: Apr 27, 2006
• Last Update Posted: Oct 29, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Halozyme Therapeutics: Non-invasive bladder cancer; Chemophase; Intravesical administration; Superficial Bladder Cancer
• Additional relevant MeSH terms: Urinary Bladder Neoplasms; Mitomycins; Mitomycin

Study Results

Participant Flow

Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U	Cohort 2: MMC Plus Chemophase 60,000 U	Cohort 3: MMC Plus Chemophase 200,000 U	Cohort 4: MMC Plus Chemophase 400,000 U	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 40 milligrams (mg) mitomycin C (MMC) intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 20,000 Units (U) Chemophase intravesically once weekly from Weeks 2 through 6.	Participants received 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.	Participants received 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.	Participants received 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.	Participants received 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.
Period Title: Overall Study
STARTED	3	3	6	3	12
Received at Least 1 Dose of Study Drug	3	3	6	3	12
COMPLETED	3	3	6	3	9
NOT COMPLETED	0	0	0	0	3

Baseline Characteristics

Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U	Cohort 2: MMC Plus Chemophase 60,000 U	Cohort 3: MMC Plus Chemophase 200,000 U	Cohort 4: MMC Plus Chemophase 400,000 U	Cohort 5: MMC Plus Chemophase 800,000 U	Total
Arm/Group Description	Participants received 40 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.	Participants received 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.	Participants received 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.	Participants received 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.	Participants received 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.	Total of all reporting groups
Overall Participants	3	3	6	3	12	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.7 (11.24)	67.0 (8.54)	65.7 (10.33)	73.7 (3.79)	68.0 (10.54)	67.9 (9.44)
Sex: Female, Male (Count of Participants)
Female	0 0%	2 66.7%	2 33.3%	0 0%	3 25%	7 25.9%
Male	3 100%	1 33.3%	4 66.7%	3 100%	9 75%	20 74.1%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Chemophase in Combination With MMC
Description	The MTD was defined as the maximum dose level at which no more than two of six participants experienced dose-limiting toxicities (DLT). DLT was defined as any of the following: Plasma MMC concentration greater than or equal to (>=) 100 nanograms (ng)/milliliter (mL) Adverse event (AE) with a Common Toxicity Criteria (CTC) grade greater than or equal to 3 New, treatment-emergent diagnosis of bladder fibrosis.
Time Frame	5 weeks (Week 2 to Week 6)

Outcome Measure Data

Analysis Population Description

The Intent-To-Treat (ITT) Set included all participants who received one or more doses of Chemophase with MMC.

Arm/Group Title	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 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.
Measure Participants	12
Number [Units]	800000

2. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs)
Description	DLT was defined as any of the following: Plasma MMC concentration >= 100 ng/mL AE with a CTC grade greater than or equal to 3 New, treatment-emergent diagnosis of bladder fibrosis.
Time Frame	5 weeks (Week 2 to Week 6)

Outcome Measure Data

Analysis Population Description

ITT Set included all participants who received one or more doses of Chemophase with MMC.

Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U	Cohort 2: MMC Plus Chemophase 60,000 U	Cohort 3: MMC Plus Chemophase 200,000 U	Cohort 4: MMC Plus Chemophase 400,000 U	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 40 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.	Participants received 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.	Participants received 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.	Participants received 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.	Participants received 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.
Measure Participants	3	3	6	3	12
Count of Participants [Participants]	0 0%	0 0%	1 16.7%	0 0%	0 0%

3. Primary Outcome

Title	Recommended Dose of Chemophase With MMC For Future Studies
Time Frame	5 weeks (Week 2 to Week 6)

Outcome Measure Data

Analysis Population Description

ITT Set included all participants who received one or more doses of Chemophase with MMC.

Arm/Group Title	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 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.
Measure Participants	12
Number [Units]	800000

4. Secondary Outcome

Title	Number of Participants With a Quantifiable MMC Plasma Concentration Value
Description	A quantifiable MMC plasma concentration value was a value that was not below the quantifiable limit (BQL) of <10.0 nanogram/milliliter (ng/mL).
Time Frame	0 (predose), 1, 2, and 3 hours postdose at Weeks 1, 2, 5, and 6

Outcome Measure Data

Analysis Population Description

ITT Set included all participants who received one or more doses of Chemophase with MMC.

Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U	Cohort 2: MMC Plus Chemophase 60,000 U	Cohort 3: MMC Plus Chemophase 200,000 U	Cohort 4: MMC Plus Chemophase 400,000 U	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 40 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.	Participants received 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.	Participants received 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.	Participants received 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.	Participants received 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.
Measure Participants	3	3	6	3	12
Week 1: Predose	0 0%	0 0%	0 0%	0 0%	0 0%
Week 1: 1 hour	0 0%	0 0%	0 0%	0 0%	1 8.3%
Week 1: 2 hours	0 0%	0 0%	0 0%	0 0%	1 8.3%
Week 1: 3 hours	0 0%	0 0%	0 0%	0 0%	0 0%
Week 2: Predose	0 0%	0 0%	0 0%	0 0%	0 0%
Week 2: 1 hour	0 0%	0 0%	0 0%	0 0%	0 0%
Week 2: 2 hours	0 0%	0 0%	0 0%	0 0%	0 0%
Week 2: 3 hours	0 0%	0 0%	0 0%	0 0%	0 0%
Week 5: Predose	0 0%	0 0%	0 0%	0 0%	0 0%
Week 5: 1 hour	0 0%	0 0%	0 0%	0 0%	0 0%
Week 5: 2 hours	0 0%	0 0%	1 16.7%	0 0%	0 0%
Week 5: 3 hours	0 0%	0 0%	1 16.7%	0 0%	0 0%
Week 6: Predose	0 0%	0 0%	0 0%	0 0%	0 0%
Week 6: 1 hour	0 0%	0 0%	0 0%	1 33.3%	0 0%
Week 6: 2 hours	0 0%	0 0%	0 0%	1 33.3%	0 0%
Week 6: 3 hours	0 0%	0 0%	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	TEAEs were defined as any AE that occurred after the first administration of the study drug and until the end of the study. AEs were defined as any untoward medical occurrence in a participant administered study drug and that did not necessarily have a causal relationship with the study drug. SAEs were defined as any AE that, in the view of either the Investigator or Sponsor, resulted in any of the following outcomes as fatal, life-threatening, required in-participant hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, an important medical event. A summary of all SAEs and Other AEs (nonserious) regardless of causality is located in 'Reported Adverse Events' Section.
Time Frame	Baseline up to 2 years

Outcome Measure Data

Analysis Population Description

The Safety Set included all participants who received one or more doses of Chemophase.

Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U	Cohort 2: MMC Plus Chemophase 60,000 U	Cohort 3: MMC Plus Chemophase 200,000 U	Cohort 4: MMC Plus Chemophase 400,000 U	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 40 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.	Participants received 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.	Participants received 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.	Participants received 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.	Participants received 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.
Measure Participants	3	3	6	3	12
TEAEs	1 33.3%	1 33.3%	4 66.7%	2 66.7%	10 83.3%
SAEs	1 33.3%	0 0%	2 33.3%	0 0%	2 16.7%

6. Secondary Outcome

Title	Number of Participants Who Remained Tumor Free at the End of the Study
Time Frame	Baseline up to 2 years

Outcome Measure Data

Analysis Population Description

ITT Set included all participants who received one or more doses of Chemophase with MMC.

Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U	Cohort 2: MMC Plus Chemophase 60,000 U	Cohort 3: MMC Plus Chemophase 200,000 U	Cohort 4: MMC Plus Chemophase 400,000 U	Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 40 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.	Participants received 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.	Participants received 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.	Participants received 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.	Participants received 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.
Measure Participants	3	3	6	3	12
Count of Participants [Participants]	2 66.7%	0 0%	2 33.3%	1 33.3%	6 50%

Adverse Events

Time Frame	Baseline up to 2 years
Adverse Event Reporting Description	The Safety Set included all participants who received one or more doses of Chemophase.
Arm/Group Title	Cohort 1: MMC Plus Chemophase 20,000 U		Cohort 2: MMC Plus Chemophase 60,000 U		Cohort 3: MMC Plus Chemophase 200,000 U		Cohort 4: MMC Plus Chemophase 400,000 U		Cohort 5: MMC Plus Chemophase 800,000 U
Arm/Group Description	Participants received 40 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.		Participants received 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.		Participants received 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.		Participants received 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.		Participants received 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.
All Cause Mortality
	Cohort 1: MMC Plus Chemophase 20,000 U		Cohort 2: MMC Plus Chemophase 60,000 U		Cohort 3: MMC Plus Chemophase 200,000 U		Cohort 4: MMC Plus Chemophase 400,000 U		Cohort 5: MMC Plus Chemophase 800,000 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1: MMC Plus Chemophase 20,000 U		Cohort 2: MMC Plus Chemophase 60,000 U		Cohort 3: MMC Plus Chemophase 200,000 U		Cohort 4: MMC Plus Chemophase 400,000 U		Cohort 5: MMC Plus Chemophase 800,000 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/3 (0%)		2/6 (33.3%)		0/3 (0%)		2/12 (16.7%)
Cardiac disorders
Acute myocardial infarction	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Angina unstable	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
General disorders
Chest pain	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Infections and infestations
Pneumonia	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to bone	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Neoplasm	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Small cell lung cancer stage unspecified	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Nervous system disorders
Syncope	1/3 (33.3%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1: MMC Plus Chemophase 20,000 U		Cohort 2: MMC Plus Chemophase 60,000 U		Cohort 3: MMC Plus Chemophase 200,000 U		Cohort 4: MMC Plus Chemophase 400,000 U		Cohort 5: MMC Plus Chemophase 800,000 U
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/3 (33.3%)		4/6 (66.7%)		2/3 (66.7%)		10/12 (83.3%)
Blood and lymphatic system disorders
Iron deficiency anaemia	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Cardiac disorders
Acute myocardial infarction	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Cardiac failure congestive	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Coronary artery disease	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Eye disorders
Diabetic retinopathy	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Dry eye	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Eye pain	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Diarrhoea	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Diverticulum	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
General disorders
Chest pain	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Malaise	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Suprapubic pain	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Infections and infestations
Urinary tract infection	0/3 (0%)		1/3 (33.3%)		2/6 (33.3%)		0/3 (0%)		2/12 (16.7%)
Asymptomatic bacteriuria	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Cellulitis	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/12 (0%)
Folliculitis	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Helicobacter infection	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Influenza	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Nasopharyngitis	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Onychomycosis	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Investigations
Blood creatine phosphokinase increased	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/12 (8.3%)
Red blood cells urine positive	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/12 (0%)
White blood cells urine positive	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/12 (0%)
Alanine aminotransferase increased	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Aspartate aminotransferase increased	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Blood urine present	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/12 (0%)
False positive laboratory result	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Haemoglobin decreased	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Liver function test abnormal	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
White blood cells urine	0/3 (0%)		0/3 (0%)		0/6 (0%)		1/3 (33.3%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Plantar fasciitis	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Nervous system disorders
Cerebral ischaemia	0/3 (0%)		1/3 (33.3%)		0/6 (0%)		0/3 (0%)		0/12 (0%)
Headache	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Renal and urinary disorders
Dysuria	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		2/12 (16.7%)
Pollakiuria	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		2/12 (16.7%)
Bladder spasm	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Calculus urethral	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Haematuria	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Micturition urgency	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Nocturia	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Urethral disorder	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Urtheral haemorrhage	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Reproductive system and breast disorders
Genital rash	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/12 (8.3%)
Balanitis	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/12 (0%)
Prostatitis	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		1/12 (8.3%)
Cough	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)
Nasal congestion	0/3 (0%)		0/3 (0%)		0/6 (0%)		0/3 (0%)		1/12 (8.3%)

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