Mitomycin C With Hyperthermia and Intravesical Mitomycin C to Treat Recurrent Bladder Cancer

• Sponsor: Mark Dewhirst (Other)
• Overall Status: Completed
• CT.gov ID: NCT00734994
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 35
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Hypothesis: In selected patients external hyperthermia will be used in combination with intravesical Mitomycin-C (MMC) to treat recurrent transitional cell carcinoma (TCC) of the bladder after local resection and standard adjuvant therapy and thus prevent or delay recurrence and the need for radical cystectomy.

Condition or Disease	Intervention/Treatment	Phase
Transitional Cell Carcinoma of Bladder; Superficial Bladder Cancer	Device: Hyperthermia System; Drug: Mitomycin C	Early Phase 1

Detailed Description

It is well established that tumor cells are sensitive to heat and when combined with a chemotherapeutic agent, drug uptake and intracellular distribution of drug within malignant cells is improved due to increased cellular permeability. Further, hyperthermia inhibits deoxyribonucleic acid (DNA) repair as a result of increased reaction between DNA and chemotherapy. By heating bladder tissue and accelerating the necessary series of reactions to link agents such as mitomycin C to cell DNA, this effect may be optimized. Depending on the extent of resection (and location, size, and depth of invasion of remaining tumor) after transurethral resection of the bladder tumor(TURBT), recommended adjuvant therapy consists of intravesical chemotherapy. MMC has been studied at doses as high as 80 mg without producing significant or irreversible side effects. The most commonly used dose of mitomycin is 40 mg.2

This pilot study proposes to use Mitomycin C at a dose of 40 mg in conjunction with deep hyperthermia to enhance the effect intravesical chemotherapy as second-line treatment of recurrent TCC (Stage Ta, T1, or Tis) of the bladder after surgical resection and standard adjuvant therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of External Hyperthermia and Intravesical Mitomycin-C To Treat Recurrent Bladder Cancer After Resection and Standard Adjuvant Therapy
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hyperthermia system, Mitomycin C Pilot study single arm study to test the safety, tolerability and clinical benefit of regional hyperthermia and mitomycin-C intravesical chemotherapy to treat non-invasive Transitional Cell carcinoma (TCC) of the bladder that has recurred after standard resection and adjuvant therapy.

Device: Hyperthermia System; Hyperthermia applied to heat the bladder to a temperature of 42 degrees Celsius for 40-60 minutes concurrent with mitomycin Treatment Schedule: 6 Weekly Sessions (Induction) followed by 4 Monthly Sessions (Maintenance) until documented second recurrence; Other Names: BSD 2000 Hyperthermia system ; Drug: Mitomycin C; 40 mg in 40 ml sterile water instilled into bladder; Other Names: Mutamycin

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability [During Treatment Phase average 6 weeks]

   Number of patient treatments stopped due to safety concerns or treatment intolerability. All events below are grade 1/2 toxicity. No grade 3-5 toxicity was observed.

Secondary Outcome Measures

1. Median Recurrence Free-survival [Median follow-up 3.18 years]

   Time to first recurrence of cancer in the bladder.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Non-muscle invasive transitional cell carcinoma (TCC) of the bladder (Ta, T1, Tis) recurrent after initial surgery and at least one round of adjuvant treatment (i.e. 6 weeks of intravesical biological therapy with Bacillus Calmette Guerin (BCG) solution); or

• An inability to tolerate BCG

• Age > 18

• Eastern Cooperative Oncology Group(ECOG) Performance Status 0-2

• Laboratory tests performed within 14 days of study enrollment:

• Leukocytes ≥ 3,200, Absolute Neutrophil count ≥ 1,500, Platelets ≥ 100,000

• Hemoglobin ≥ 9.0 gm/dL, Total bilirubin ≤ institution upper limit of normal *(ULN), Asparate Aminotransferase(AST) and Alanine Aminotransferase(ALT) ≤ 2.5 times ULN, Alkaline phosphatase ≤ 2.5 times ULN

• Creatinine ≤ 1.5 times ULN

• Women of child bearing potential must have a negative pregnancy test

• If post-menopausal - Amenorrhea for ≥ 12 months

Exclusion Criteria:

• Pregnancy or breastfeeding

• Muscle invasive disease (T2-T4)

• Prior radiation to the pelvis

• Peripheral neuropathy (any grade)

• Thrombocytopenia, coagulation disorder or an increase in bleeding tendency due to other causes

• Known bladder fistula

• Hypersensitive or idiosyncratic reaction to mitomycin-C or its components in the past

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Mark Dewhirst

Investigators

• Principal Investigator: Zelko Vujaskovic, MD, Duke University
• Principal Investigator: Brant A Inman, MD, MS, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Juang T, Stauffer PR, Craciunescu OA, Maccarini PF, Yuan Y, Das SK, Dewhirst MW, Inman BA, Vujaskovic Z. Thermal dosimetry characteristics of deep regional heating of non-muscle invasive bladder cancer. Int J Hyperthermia. 2014 May;30(3):176-83. doi: 10.3109/02656736.2014.898338. Epub 2014 Mar 26.
• Yuan Y, Cheng KS, Craciunescu OI, Stauffer PR, Maccarini PF, Arunachalam K, Vujaskovic Z, Dewhirst MW, Das SK. Utility of treatment planning for thermochemotherapy treatment of nonmuscle invasive bladder carcinoma. Med Phys. 2012 Mar;39(3):1170-81. doi: 10.1118/1.3679839.

• Responsible Party: Mark Dewhirst, Professor, Duke University
• ClinicalTrials.gov Identifier: NCT00734994
• Other Study ID Numbers: Pro00003239
• First Posted: Aug 14, 2008
• Last Update Posted: Jun 29, 2015
• Last Verified: Jun 1, 2015

• Additional relevant MeSH terms: Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Hyperthermia; Mitomycins; Mitomycin

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 09/2008-09/2010 Location: Urology and Radiation Oncology Clinics

Arm/Group Title	Mitomycin C With Hyperthermia and Recurrent Bladder Cancer
Arm/Group Description	Mitomycin C with Hyperthermia to Treat Recurrent Bladder Cancer
Period Title: Overall Study
STARTED	15
COMPLETED	14
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Mitomycin C With Hyperthermia
Arm/Group Description	Mitomycin C and Hyperthermia
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 46.7%
>=65 years	8 53.3%
Sex: Female, Male (Count of Participants)
Female	2 13.3%
Male	13 86.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	15 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Secondary Outcome

Title	Median Recurrence Free-survival
Description	Time to first recurrence of cancer in the bladder.
Time Frame	Median follow-up 3.18 years

Outcome Measure Data

Analysis Population Description

Entire cohort

Arm/Group Title	Hyperthermia System, Mitomycin C
Arm/Group Description	Pilot study single arm study to test the safety, tolerability and clinical benefit of regional hyperthermia and mitomycin-C intravesical chemotherapy to treat non-invasive Transitional Cell carcinoma (TCC) of the bladder that has recurred after standard resection and adjuvant therapy. Hyperthermia System: Hyperthermia applied to heat the bladder to a temperature of 42 degrees Celsius for 40-60 minutes concurrent with mitomycin Treatment Schedule: 6 Weekly Sessions (Induction) followed by 4 Monthly Sessions (Maintenance) until documented second recurrence Mitomycin C: 40 mg in 40 ml sterile water instilled into bladder
Measure Participants	15
Median (95% Confidence Interval) [Months]	15.4

2. Primary Outcome

Title	Safety and Tolerability
Description	Number of patient treatments stopped due to safety concerns or treatment intolerability. All events below are grade 1/2 toxicity. No grade 3-5 toxicity was observed.
Time Frame	During Treatment Phase average 6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mitomycin C With Hyperthermia
Arm/Group Description	Mitomycin C and Hyperthermia
Measure Participants	15
Measure Hyperthermia Treatments	132
Abdominal pain	5
Fatigue	2
Myalgia	1
Heat intolerance	1
Urethral pain	6
Chemical cystitis	4
Hematuria	3
Bladder spasm	2
Weak urinary stream	1
Vaginitis	1
Nausea	2
Constipation	1
Swelling	4
Pruritis	3
Rash	2
Bruising	1
Flushing	1
Dizziness	2
Confusion	1
Anxiety	1
Extrapyramidal symptoms	1
Urinary Tract Infection	2
Hypertension	3

Adverse Events

Arm/Group Title	Mitomycin C With Hyperthermia
Arm/Group Description	Mitomycin C and Hyperthermia
All Cause Mortality
	Mitomycin C With Hyperthermia
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Mitomycin C With Hyperthermia
	Affected / at Risk (%)	# Events
Total	0/15 (0%)
Other (Not Including Serious) Adverse Events
	Mitomycin C With Hyperthermia
	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)
Blood and lymphatic system disorders
Edema - localized	1/15 (6.7%)	1
Cardiac disorders
Hypertension	3/15 (20%)	7
Gastrointestinal disorders
Abdominal / pelvic discomfort	6/15 (40%)	11
Nausea	1/15 (6.7%)	2
constipation	1/15 (6.7%)	1
General disorders
Fatigue	2/15 (13.3%)	3
Heat intolerance	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Myalgia	1/15 (6.7%)	1
Nervous system disorders
Confusion	1/15 (6.7%)	1
Dizziness	2/15 (13.3%)	3
Extrapyramidal disorder	1/15 (6.7%)	1
Psychiatric disorders
Anxiety	1/15 (6.7%)	1
Renal and urinary disorders
Bladder spasms	2/15 (13.3%)	4
Cystitis	3/15 (20%)	4
Hematuria	3/15 (20%)	3
Urethral pain	5/15 (33.3%)	8
Urinary Tract Infection - suspected	3/15 (20%)	3
Reproductive system and breast disorders
Vaginitis	1/2 (50%)	1
Skin and subcutaneous tissue disorders
Bruising	1/15 (6.7%)	1
Flushing	1/15 (6.7%)	1
Induration	3/15 (20%)	3
Pruritus	3/15 (20%)	6
Rash	2/15 (13.3%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.