Hyperthermic Intra-Vesical Chemotherapy (HIVECII)

A Phase II, Open Label, Multicentre, Randomised Controlled Trial Comparing Hyperthermia Plus Mitomycin To Mitomycin Alone In Patients With Intermediate Risk Non-Muscle Invasive Bladder Cancer

The purpose of the HIVEC II trial is to find out if the combination of the new technology called hyperthermia (the use of heat) and a drug called mitomycin is more effective than mitomycin alone which is the standard treatment for bladder cancer in reducing the chances of bladder cancer returning.

Study Overview

• Status: Completed
• Conditions: Bladder Cancer
• Intervention / Treatment: Device: Hyperthermia will be delivered in combination with each instillation using the Combat BRS system

Detailed Description

The concept of hyperthermia plus MM has been demonstrated and a phase II randomized controlled trial of ablative HM versus MM using an alternative device (Synergo) has reported tumor ablation complete response (CR) rates in 66 % of tumors treated with hyperthermia plus mitomycin compared to 22% CR for MM mono-therapy.

Registered patients will be randomised to receive either Hyperthermia and Mitomycin or Mitomycin alone. Following treatment, patients will be followed up by surveillance cystoscopy for 24 months for disease recurrence. In the first year, the follow up visits will be every 3 months from the date of start of treatment and in the second year, the visits will be every 6 months.

The study also includes translational components to determine biomarkers of response to Heated Mitomycin. Urine samples will be collected prior to surveillance cystoscopies.

This study will address the problem of how to improve the disease free survival in patients with intermediate-risk NMIBC, the treatment must have acceptable side-effects, low toxicity, and show a significant benefit over MM alone.

• Study Type: Interventional
• Enrollment (Actual): 259
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Bath, United Kingdom
    • Royal United Hospitals Bath NHS Foundation Trust
  • Edinburgh, United Kingdom
    • Western General Hospital, Edinburgh
  • Guildford, United Kingdom, GU2 7XX
    • Royal Surrey County Hospital NHS Foudation Trust
  • Liverpool, United Kingdom
    • The Clatterbridge Cancer Centre
  • London, United Kingdom
    • St George's University Hospitals NHS Foundation Trust
  • London, United Kingdom
    • Barnet Hospital
  • London, United Kingdom
    • University College London Hospital, London.
  • Manchester, United Kingdom, M239QZ
    • University Hospital of South Manchester
  • Middlesborough, United Kingdom
    • South Tees NHS Trust - James Cook University Hospital
  • Norwich, United Kingdom
    • Norfolk & Norwich University Hospitals NHS Foundation Trust
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Portsmouth, United Kingdom
    • Portsmouth Hospitals NHS Trust - Queen Alexandra Hospital
  • Redhill, United Kingdom
    • East Surrey Hospital
  • Wolverhampton, United Kingdom
    • New Cross Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. New or Recurrence of intermediate risk NMIBC following TURBT defined as;

   • Grade 2 or grade 1 stage Ta or T1 disease*.
   • Any grade G2 or G1 other than Low risk
2. Age ≥ 18 yrs
3. WHO performance status 0, 1, 2, 3

4. Pre-treatment haematology and biochemistry values within acceptable limits:

   • Haemoglobin > or =10 g/dL
   • Neutrophil count > or =1.5 x 109/L
   • Platelets > or = 100 x 109/L
   • WBC > or = 3.0 x 109/L or ANC > or = 1.5 x 109/L
   • Serum creatinine < 1.5 x UNL
5. Negative pregnancy test for women of child-bearing potential.
6. Available for long-term follow-up.
7. Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 6 weeks after treatment discontinuation.
8. Written informed consent.

Exclusion Criteria:

1. Grade 3 TCC
2. Carcinoma in situ.
3. New solitary Ta G1 (small)
4. New solitary Ta G2 (small)
5. Previous intravesical chemotherapy in the past 6 months, other than single instillation post-TUR.
6. Bladder capacity <200cc.
7. UCC involving the prostatic urethra or upper urinary tract.
8. > or =T2 UCC
9. Known allergy to mitomycin
10. Pregnant or lactating women or women of childbearing potential unwilling or unable to use adequate non-hormonal contraception.
11. Other malignancy within the past five years, except: non-melanomatous skin cancer cured by excision, adequately treated carcinoma in situ of the cervix or DCIS/LCIS of the breast or prostate cancer with more than 5yrs life expectancy or any non lifethreatening tumours that have been curatively treated.
12. Concurrent chemotherapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Mitomycin; Patients will receive six consecutive weekly instillations of Mitomycin followed by surveillance
Experimental: Hyperthermia+Mitomycin; Patients will receive 6 weekly instillations of hyperthermia plus Mitomycin (HIVEC) using the COMBAT system, followed by surveillance cystoscopy.	Device: Hyperthermia will be delivered in combination with each instillation using the Combat BRS system; The Combat BRS system is a temperature controlled fluid recirculation system for the delivery of hyperthermic intravesical chemotherapy. The chemotherapy fluid is circulated in a closed system and warmed by an external isolated dry system using a novel innovative laminated aluminium foil heat exchanger with a small priming volume.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine if HIVEC increases disease-free survival at 24 months compared to the comparator arm of MM alone.	The interval in whole days between the date of randomisation into the trial and the earliest of date of detection of recurrent disease, or date (known as Disease- free survival) will be measured. of death from any cause.	After the last patient has completed 24 months follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine if HIVEC reduces the risk of recurrence at 3 months compared to the control arm, for patients with intermediate risk disease.	The recurrence of tumor at 3 months will be calculated as a time to event outcome. recurrence of tumor at 3 months can predict subsequent recurrence and as a surrogate outcome will be monitored as a secondary measure.	At the end of study - After all patients have been followed-up for at least 2 years
Progression Free Survival	Progression-free survival: Defined as the interval in whole days between the date of randomisation into the trial and the earliest of date of detection of disease progression, or date of death from any cause	At the end of study - After all patients have been followed-up for at least 2 years
Recurrence-free survival.	Recurrence free survival will be measured in patients with papillary disease only. It is defined in the same way as disease free survival, with the important distinction that CIS at the first three-month post-treatment will not be included as an event, but rather considered a treatment failure and will be censored.	At the end of study - After all patients have been followed-up for at least 2 years
To determine if Heated Mytomycin reduces the risk of progression to invasive disease compared to the control arm.	Progression Free Survival will be compared between the 2 arms. Progression free survival is defined as the interval in whole days between the date of randomisation into the trial and the earliest of date of detection of disease progression, or date of death from any cause.	After all patients have been followed-up for at least 2 years
To compare overall and disease-specific survival between the Heated Mytomycin and the control arm.	Overall and Disease specific survival will be measured in terms of time interval. Overall survival: Defined as the interval in whole days between the date of randomisation into the trial and date of death from any cause; patients who do not die during the course of the trial will be censored at the last follow-up date. Disease specific survival: Defined as the interval in whole days between the date of randomisation into the trial and date of death due to bladder cancer. Patients who do not die during the course of the trial will be censored at the last follow-up date. Patients who die of other causes will be censored at date of death due to other cause.	At the end of study - After all patients have been followed-up for at least 2 years
To define the safety and tolerability of Heated Mytomycin in this patient population.	Safety and Tolerability will be reported through the number of adverse events. This will include assessment of frequency, severity and nature of adverse events and the treatment received	At the end of study - After all patients have been followed-up for at least 2 years
To compare QOL between the Heated Mytomycin and the control arms.	Quality of life will be assessed at study entry and every three months using the questionnaires. The questionnaires collects information about side effects and symptoms as well as measures of function and overall well being. For each part, a set scale will be used.	After all patients have been followed-up for at least 2 years

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Investigators: Principal Investigator: Dr John Kelly, Queen Mary University of London

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2014
• Primary Completion (Actual): May 27, 2020
• Study Completion (Actual): May 27, 2020

Study Registration Dates

• First Submitted: August 25, 2017
• First Submitted That Met QC Criteria: January 6, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 6, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: BL-2013-04

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No