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Modulated Electro-Hyperthermia Plus Chemo-radiation for Locally Advanced Cervical Cancer Patients in South Africa (mEHT)

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ClinicalTrials.gov Identifier: NCT03332069
Recruitment Status : Unknown
Verified November 2017 by Jeffrey Kotzen, University of Witwatersrand, South Africa.
Recruitment status was:  Recruiting
First Posted : November 6, 2017
Last Update Posted : November 7, 2017
Sponsor:
Collaborators:
National Research Foundation of South Africa
NTP Radioisotopes SOC Ltd
Information provided by (Responsible Party):
Jeffrey Kotzen, University of Witwatersrand, South Africa

Study Description
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Brief Summary:
This is a phase III randomised clinical trial. The aim is to investigate the clinical effects of the addition of modulated electro-hyperthermia (mEHT) to standard treatment protocols (chemoradiotherapy, CRT) for Human Immunodeficiency Virus (HIV) positive and negative locally advanced cervical cancer patients (LACC). SAMPLE: The investigators aim to enrol 236 HIV negative and HIV positive women with LACC, FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) Stages IIB (distil) to stage III. Participants will be randomly assigned to a control group (N=118) and a study group (N=118). METHODOLOGY: Randomisation is based on age, stage and HIV. Participants from both groups will receive the standard treatment for cervical cancer at the hospital at the Charlotte Maxeke Johannesburg Academic Hospital in South Africa: Up to three doses of 80mg/m2 cisplatin, administered three weeks apart; 50Gy external beam radiation (EBR) in fractions of 2Gy; Three doses of 8Gy High Dose Rate (HDR) brachytherapy. The study group will have two 55 minute mEHT treatments per week, at 130W, directly before the EBR using the EHY 2000 Device. OUTCOMES: 1) Determine the local disease control after treatment at 6 months using a Positron Emission Tomography (PET) and computerised tomography (CT) scans. 2) Determine the progression-free survival (PFS) at 6, 12, 18 and 24 months after the last treatment date. PFS will be assessed in all registered participants, regardless of completion (Intent to Treat-ITT) as well as only in the subset of participants who complete the prescribed CRT. 3) Overall survival at two years will be assessed. 4) To evaluate the adverse events associated with mEHT. 5) The effect of mEHT on chemotherapy and radiotherapy tolerability and toxicity will be evaluated. 6) The quality of life of enrolled participants will be assessed before, at 6 weeks, and at 3, 6, 9, 12, 18 and 24 months after completion of therapy using the EORTC (European Organisation for Research and Treatment of Cancer) and EuroQoL forms. 7) To evaluate the economic viability of the addition of mEHT to standard treatment protocols for LACC. 8) The effect, if any, of mEHT treatments on the HIV disease status of HIV positive patients will be assessed by the presence of Autoimmune Deficiency Syndrome (AIDS) defining illnesses before and after treatment. 9) The cancer recurrence patterns will be described and compared in all the participants.

Condition or disease Intervention/treatment Phase
Cervical Cancer Device: Modulated electro-hyperthermia Radiation: External beam radiation Drug: Cisplatin Radiation: Brachytherapy Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 236 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Care Provider, Outcomes Assessor)
Masking Description: Clinicians conducting follow up evaluations, radiographers and nuclear medicine physicians reporting on the PET/CT investigations are unaware of the group that the participants have been assigned to.
Primary Purpose: Treatment
Official Title: A Phase III Randomised Trial Investigating the Benefits of the Addition of Modulated Electro-hyperthermia to Chemo-radiation for Cervical Cancer in HIV Positive and Negative Women in South Africa
Actual Study Start Date : January 9, 2014
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : July 31, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Study
50 Gy external beam radiation administered in fractions of 2 Gy 3 Doses of 8 Gy High Dose Rate brachytherapy up to 3 doses of 80mg/m2 of Cisplatin 10 modulated electro-hyperthermia treatments (55 minutes at a maximum of 150W)
 Device: Modulated electro-hyperthermia
Modulated electro-hyperthermia device used is the EHY 2000 by Oncotherm GmbH
Other Names:
  • Oncothermia
  • Nanothermia

Radiation: External beam radiation
Other Name: Radiotherapy

Drug: Cisplatin
Other Name: Chemotherapy

Radiation: Brachytherapy
High Dose Rate
Other Name: Radiation therapy
Active Comparator: Control
50 Gy external beam radiation administered in fractions of 2 Gy 3 Doses of 8 Gy High Dose Rate brachytherapy up to 3 doses of 80mg/m2 of Cisplatin
 Radiation: External beam radiation
Other Name: Radiotherapy

Drug: Cisplatin
Other Name: Chemotherapy

Radiation: Brachytherapy
High Dose Rate
Other Name: Radiation therapy


Outcome Measures
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Primary Outcome Measures :
  1. Change in Local Disease Control [ Time Frame: 6 months post treatment ]
    Assessed by PET/CT using the RESIST/PERSIST criteria: complete response, complete metabolic response, partial response, stable disease, progressive disease.


Secondary Outcome Measures :
  1. Progression Free Survival [ Time Frame: 24 months post treatment ]

    To determine the progression-free survival (PFS) at 6, 12, 18 and 24 months after the last treatment date.

    1. Determine PFS in all registered participants, regardless of completion (Intent To Treat-ITT)
    2. Determine PFS in the subset of participants who complete the prescribed chemo-radiotherapy

  2. 2 Year Survival [ Time Frame: 24 months post treatment ]
    Determine the overall survival at two years and the cause of death (i.e. cancer-related, HIV-related, treatment related or other).

  3. Incidence of Adverse Events Attributed to mEHT as assessed by CTCAE version 4.0 [ Time Frame: 6 months post treatment ]
    To evaluate the adverse events that can be directly attributed to mEHT treatments.

  4. Incidence of Treatment Related Adverse Events Attributed to Cisplatin as assessed by CTCAE version 4.0 [ Time Frame: Up to 3 months post treatment completion ]
    The incidence of treatment-emergent adverse events which can be attributed to Cisplatin in each arm will be compared in order to identify any potential effect of mEHT on the frequency and severity of adverse events attributed to Cisplatin.

  5. Number of participants with Early Treatment Related Adverse Events as assessed by CTCAE version 4.0 [ Time Frame: Up to 6 months post treatment completion ]
    The incidence of early toxicity symptoms (graded using the CTCAE version 4 criteria) associated with radiotherapy in each arm of the study will be compared to identify any potential effect of the mEHT on the incidence and severity of early toxicity.

  6. Number of participants with Late Treatment Related Adverse Events as assessed by CTCAE version 4.0 [ Time Frame: Up to 24 months post treatment completion ]
    The incidence of late toxicity symptoms (graded using the CTCAE version 4 criteria) associated with radiotherapy in each arm of the study will be compared to identify any potential effect of the mEHT on the incidence of late toxicity in the sample group.

  7. Visual Analogue Scale On the EuroQoL EQ-5D-5L form [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Visual Analogue Scale on the EuroQoL EQ-5D-5L form

  8. Mobility On the EuroQoL EQ-5D-5L form [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Mobility on the EuroQoL EQ-5D-5L form

  9. Self-Care On the EuroQoL EQ-5D-5L form [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Self-Care on the EuroQoL EQ-5D-5L form

  10. Usual Activities On the EuroQoL EQ-5D-5L form [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Usual Activities on the EuroQoL EQ-5D-5L form

  11. Pain/Discomfort On the EuroQoL EQ-5D-5L form [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Pain/Discomfort on the EuroQoL EQ-5D-5L form

  12. Anxiety/Depression On the EuroQoL EQ-5D-5L form [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline value at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of Anxiety/Depression on the EuroQoL EQ-5D-5L form

  13. Score on the EORTC-QLQ 30 for Global Health Status [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Global Health Status

  14. Score on the EORTC-QLQ 30 for Physical Functioning [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Physical Functioning

  15. Score on the EORTC-QLQ 30 for Role Functioning [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Role Functioning

  16. Score on the EORTC-QLQ 30 for Emotional Functioning [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Emotional Functioning

  17. Score on the EORTC-QLQ 30 for Cognitive Functioning [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Cognitive Functioning

  18. Score on the EORTC-QLQ 30 for Social Functioning [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Social Functioning

  19. Score on the EORTC-QLQ 30 for Fatigue [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Fatigue

  20. Score on the EORTC-QLQ 30 for Nausea and Vomiting [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Nausea and Vomiting

  21. Score on the EORTC-QLQ 30 for Pain [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Pain

  22. Score on the EORTC-QLQ 30 for Dyspnoea [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Dyspnoea

  23. Score on the EORTC-QLQ 30 for Insomnia [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Insomnia

  24. Score on the EORTC-QLQ 30 for Appetite Loss [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Appetite Loss

  25. Score on the EORTC-QLQ 30 for Constipation [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Constipation

  26. Score on the EORTC-QLQ 30 for Diarrhoea [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Diarrhoea

  27. Score on the EORTC-QLQ 30 for Financial Difficulties [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Financial Difficulties

  28. Score on the EORTC-QLQ 24 for Symptom Experiences [ Time Frame: Up to 24 months post treatment completion ]
    To evaluate the changes from baseline scores at set time points (6 weeks, 3 months, 6 months, 9 months, 12 months,18 months, 24 months) of the Score on the EORTC-QLQ 30 for Symptom Experiences


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participants (who have been adequately clinically staged by standard clinical guidelines) with biopsy proven primary, untreated, histologically confirmed invasive squamous and aden-squamous cell carcinoma of the uterine cervix, FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) stages advanced IIB (invasion of the distal half of the parametrium), IIIA and IIIB.
  2. HIV positive participants will be accepted.

  3. The following laboratory tests will be done prior to enrolment in the study and the values must be in the following ranges:

    • Haemoglobin >10 g/dL;
    • Platelet count >150/mm3;
    • Absolute neutrophil count (ANC) >3000/mm3
    • Creatinine clearance>60 mL/min
    • Liver function tests
  4. Females between the ages of 18 and 70 years.
  5. Ability to understand and the willingness to sign a written informed consent document.
  6. Eastern Cooperative Oncology Group (ECOG) score of not more than 2.
  7. Participants of childbearing potential must have a negative urine or serum pregnancy test prior to enrolment and use an effective form of contraception (e.g. barrier contraception, highly effective hormonal contraception).
  8. At the investigators' discretion, participants must be suitable for treatment with radical intent using concurrent chemotherapy and pelvic radiation. Subjects who undergo emergency RT in the form of brachytherapy for haemostasis, prior to enrolment will be allowed to be screened and enrolled provided they meet all other eligibility criteria.
  9. Life expectancy of greater than 12 months.

  10. Participants must have a body mass index (BMI) that is within normal ranges.

    -

Exclusion Criteria:

  1. Participants who have undergone hysterectomy.
  2. Exclude para-aortic lymph involvement on planning CT (without contrast)
  3. Patients with life-threatening AIDS defining illnesses (other than cervical carcinoma) will be excluded, as will patients with a CD4 count < 200/µL and not on ARVs.
  4. Patients with acute active (such as tuberculosis or malaria), serious, uncontrolled infections will be excluded.
  5. Participants will be excluded if there is evidence of resistance to antiretroviral therapy (i.e. HIV viral load > 400 copies/mL despite combination antiretroviral therapy for at least 4 months).
  6. Prior invasive malignancy other than cervical cancer, diagnosed within the past 24 months, excluding in situ anal dysplasia or carcinoma in situ, non-melanoma skin carcinoma, or Kaposi's sarcoma that has not required systemic chemotherapy within the past 24 months.
  7. Pregnant or breast-feeding women.
  8. A medical or psychiatric illness that prevents the participant from being able to sign an informed consent or would affect the participant's ability to comply with the protocol stipulations.
  9. Participants with circumstances that will not permit completion of the study or required follow-ups. For instance if travel to and from treatment site is an issue.
  10. Participants with carcinoma of the cervical stump.

  11. Participants with a history of cardiovascular disease manifested as

    1. History of myocardial infarction
    2. Unstable angina
    3. Currently taking medication for treatment of angina
    4. History of coronary artery bypass surgery

  12. Participants with contraindications to modulated electro-hyperthermia treatment:

    1. Pace makers and other implanted devices which rely on current and charges.
    2. Large metal implants, such as hip replacements.
    3. Inability to feel temperature in the region.
    4. Inability to express or vocalise discomfort or heat at the treatment site.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03332069


Contacts
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Contact: Carrie A Minnaar, PhD student +27721234292 cazzminn1@gmail.com
Contact: Jeffrey A Kotzen, MBCHB +27825747985 jkotzen@yahoo.com

Locations
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South Africa
Charlotte Maxeke Johannesburg Academic Hospital Recruiting
Johannesburg, Gauteng, South Africa, 2163
Contact: Jeffrey A Kotzen, MBBCH    +27825747385      
Contact: Carrie A Minnaar, Masters    +27721234292      
Sponsors and Collaborators
Jeffrey Kotzen
National Research Foundation of South Africa
NTP Radioisotopes SOC Ltd
Investigators
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Study Chair: Carrie A Minnaar, Msc Student - PhD Candidate
Principal Investigator: Jeffrey A Kotzen, MBBCH Senior Radiation Oncologist
Study Chair: Ans Baeyes, PhD Head of Department of Radiobiology
More Information
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Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Jeffrey Kotzen, Senior Radiation Oncologist, University of Witwatersrand, South Africa
ClinicalTrials.gov Identifier: NCT03332069    
Other Study ID Numbers: LACC-OT
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: November 7, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jeffrey Kotzen, University of Witwatersrand, South Africa:
Hyperthermia
cervix
HIV
Additional relevant MeSH terms:
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Uterine Cervical Neoplasms
Hyperthermia
Fever
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
 Genital Diseases, Female
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Genital Diseases
Body Temperature Changes
Heat Stress Disorders
Wounds and Injuries
Cisplatin
Antineoplastic Agents