Neoadjuvant Concomitant Modulated Electro-hyperthermia in HER2-negative Breast Cancer (NeoHTerMa)

• ClinicalTrials.gov Identifier: NCT05889390
• Recruitment Status: Recruiting
• First Posted: June 5, 2023
• Last Update Posted: June 5, 2023
• Sponsor: Semmelweis University
• Information provided by (Responsible Party): Marcell Szasz, Semmelweis University

Tracking Information

• First Submitted Date: March 3, 2023
• First Posted Date: June 5, 2023
• Last Update Posted Date: June 5, 2023
• Actual Study Start Date: February 20, 2023
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 25, 2023)

Residual size of the primary tumor, determined by imaging techniques (in percentage) [ Time Frame: change from baseline at 6 months ]

Using breast MR measurements, the the residual size of the primary tumor will be specified for all patients (in percentage). The comparison of these between the two study arms will serve as the primary outcome measure. Calculation: The tumor size after the 6-months treatment period (in mm) will be divided by the size measured prior treatment (in mm). The quotient will be given as a percentage and subtracted from 100.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: May 25, 2023)

• Percentage of complete pathological response [ Time Frame: 9 months ]
  Comparison of the percentage of complete pathological responses between the two groups
• Treatment response patterns [ Time Frame: 9 months ]
  Comparison of the pathological response categories (pCR : pPR : pNR) between the two groups
• Comparison of surgical procedure ratios [ Time Frame: 9 months ]
  It will be compared whether the ratio of two main breast surgery types (breast-conserving surgery vs. total mastectomy) differ between the two study arms.
• Effect of treatment on white blood cell counts [ Time Frame: through study completion, an average of ~8 months ]
  White blood cell counts (in G/L) will be measeured at every patient visit, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques.
• Effect of treatment on red blood cell counts [ Time Frame: through study completion, an average of ~8 months ]
  Red blood cell counts (in T/L) will be measeured at every patient visit, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques.
• Effect of treatment on platelet counts [ Time Frame: through study completion, an average of ~8 months ]
  Platelet counts (in G/L) will be measeured at every patient visit, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques.
• Effect of treatment on hemoglobin levels [ Time Frame: through study completion, an average of ~8 months ]
  Hemoglobin level of patients (in g/L) will be measeured at every patient visit, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques.
• Effect of treatment on hematocrit levels [ Time Frame: through study completion, an average of ~8 months ]
  Hematocrit level of patients (in L/L) will be measeured at every patient visit, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques.
• Number of treatments where the planned power output of the Oncotherm EHY-2030 device could not be reached [ Time Frame: 3 months ]
  For an optimal treatment, the Oncotherm EHY-2030 device must reach its maximum output for 30 minutes. The number of treatments where this optimal outpur could not be reached will be reported.
• Longitudinal analysis of the EORTC QLQ-C30 questionnaire's total scores [ Time Frame: through study completion, an average of ~8 months ]
  The European Organisation for Research and Treatment of Cancer 30-item quality of life questionnaire for cancer patients (EORTC QLQ-C30) total scores will be calculated as per the official quidelines, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques. Scoring of the questionnaire will be performed as per the official instructions of EORTC
• Longitudinal analysis of the EORTC QLQ-BR23 questionnaire's total scores [ Time Frame: through study completion, an average of ~8 months ]
  The European Organisation for Research and Treatment of Cancer 23-item quality of life questionnaire for breast cancer patients (EORTC QLQ-BR23) total scores will be calculated as per the official quidelines, and their longitudinal change will be analyzed using mixed-effect statistical modeling techniques. Scoring of the questionnaire will be performed as per the official instructions of EORTC
• Longitudinal analysis of the EQ-5D-5L questionnaire scores [ Time Frame: through study completion, an average of ~8 months ]
  The questionnaire will be assessed as per official guidelines. EuroQol's 5-dimension health-related quality of life instrument (EQ-5D-5L) questionnaire scores' longitudinal change will be analyzed using mixed-effect statistical modeling techniques. Scoring of the questionnaire will be performed as per the official instructions of EuroQol.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 25, 2023)

Incidence of Treatment-Emergent Adverse Events as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. [ Time Frame: through study completion, an average of ~8 months ]

All adverse events will be assessed and classified by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Using descriptive statistics, the number of occurrances will be listed for both study arms.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Neoadjuvant Concomitant Modulated Electro-hyperthermia in HER2-negative Breast Cancer
• Official Title: [A Prospective, Randomized Trial to Assess the Added Value of Concomitant Modulated Electro-hyperthermia in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy - an Investigator Initiated Study]
• Brief Summary: The aim of this study is to investigate whether the application of concomitant modulated electro-hyperthermia in a neoadjuvant chemotherapeutic setting is beneficial for patients with HER2-negative, stage II-III breast cancer.

Detailed Description

This study is a pivotal, randomized (1:1), open-label, two-treatment group, single-centre trial of Oncotherm EHY-2030, a modulated electro-hyperthermia (mEHT) device. Female patients aged 18 years or older with locally advanced, unilaterally localized HER2-negative breast cancer requiring neoadjuvant treatment are eligible for the study.

In the study, the wTAX (+ carboplatin) +AC neoadjuvant chemotherapy protocol will be administered according to the routine daily regimen, with or without mEHT three times a week during the wTAX (+ carboplatin) period. Carboplatin will be administered for patients with triple-negative breast cancer only.

Primary objective: to compare whether the percentage of tumor size decrease determined by imaging techniques is different in the two treatment groups?

Secondary and other objectives:

• Is complete pathological response (pCR) more common in the mEHT-treated group?
• Does the pattern of treatment response (pCR : pPR : pNR) differ between the two groups?
• Is the quality of life of patients different in the two study groups?
• Is there any treatment-related changes in the routine laboratory parameters such as blood count, liver enzymes, renal function? And do these differ in the two study arms?
• Safety and tolerability analysis of the device.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HER2-negative Breast Cancer

Intervention

• Device: Oncotherm EHY-2030
  Oncotherm EHY-2030 is a non-invasive electromagnetic devices with known anti-tumoral effects. It operates in a precision capacitive coupled impedance matched way, working on a radiofrequency of 13.56 MHz. mEHT exploits various biophysical differences of cancer cells. For example, energy absorption on the membrane rafts is different than those of healthy host cells, and damage-associated molecular patterns (DAMPS) will also occur leading to programmed or immunogenic tumor cell death. mEHT can enhance DNA fragmentation of tumor cells, increase the fraction of cells with low mitochondrial membrane potential, increase the concentration of intracellular Ca2+, increase the Fas, c-Jun N-terminal kinases and MAPK/ERK signaling pathways, increase the expression of pro-apoptotic Bcl-2 family proteins and can up-regulate the expression of genes associated with the molecular function of cell death (EGR1, JUN, and CDKN1A) and silencing others associated with cytoprotective functions.
• Drug: Paclitaxel
  weekly paclitaxel for 12 weeks
• Drug: Carboplatin
  added to weekly paclitaxel if patient has triple-negative breast cancer
• Drug: Cyclophosphamide/Doxorubicin
  according to the AC protocol
• Procedure: Breast cancer removal surgery
  Either breast-conserving surgery or total mastectomy after the neoadjuvant chemotherapy with or without mEHT (if feasible)

Study Arms

• Active Comparator: wTAX (+ carboplatin) +AC
  1. wTAX: Weekly paclitaxel (+ carboplatin in the case of triple-negative breast cancer) for 12 weeks
  2. AC: Doxorubicin/Cyclophosphamide every three-weeks, 4x
  3. Breast cancer tumor removal surgery (if feasible)
  Interventions:

  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Drug: Cyclophosphamide/Doxorubicin
  • Procedure: Breast cancer removal surgery
• Experimental: wTAX (+ carboplatin) +AC + mEHT

  1. wTAX + mWEHT

     1. wTAX: Weekly paclitaxel (+ carboplatin in the case of triple-negative breast cancer) for 12 weeks
     2. mEHT: Concomitant modulated electro-hyperthermia using the Oncotherm EHY-2030 device, 3 times per week, for 12 weeks
  2. AC: Doxorubicin/Cyclophosphamide every three-weeks, 4x
  3. Breast cancer tumor removal surgery (if feasible)
  Interventions:

  • Device: Oncotherm EHY-2030
  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Drug: Cyclophosphamide/Doxorubicin
  • Procedure: Breast cancer removal surgery

Publications *

• Szasz AM, Minnaar CA, Szentmartoni G, Szigeti GP, Dank M. Review of the Clinical Evidences of Modulated Electro-Hyperthermia (mEHT) Method: An Update for the Practicing Oncologist. Front Oncol. 2019 Nov 1;9:1012. doi: 10.3389/fonc.2019.01012. eCollection 2019.
• Herold Z, Szasz AM, Dank M. Evidence based tools to improve efficiency of currently administered oncotherapies for tumors of the hepatopancreatobiliary system. World J Gastrointest Oncol. 2021 Sep 15;13(9):1109-1120. doi: 10.4251/wjgo.v13.i9.1109.
• Petenyi FG, Garay T, Muhl D, Izso B, Karaszi A, Borbenyi E, Herold M, Herold Z, Szasz AM, Dank M. Modulated Electro-Hyperthermic (mEHT) Treatment in the Therapy of Inoperable Pancreatic Cancer Patients-A Single-Center Case-Control Study. Diseases. 2021 Nov 3;9(4):81. doi: 10.3390/diseases9040081.
• Szasz AM, Arrojo Alvarez EE, Fiorentini G, Herold M, Herold Z, Sarti D, Dank M. Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas. Cancers (Basel). 2023 Jan 31;15(3):880. doi: 10.3390/cancers15030880.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 25, 2023): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 30, 2025
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. At least 18 years of age
2. Female patient
3. Life expectancy ≥ 6 months
4. De novo histological/cytological diagnosis of HER2-negative (triple-negative or ER/PR+) breast tumor involving one breast
5. Diagnosis of breast tumor ≤ 40 days

6. Locally advanced stage disease (stage II and III) requiring neoadjuvant treatment - according to the following criteria:

   1. Primary breast tumor ≥ 20 mm in size and/or
   2. Presence of axillary lymph node metastases
   3. Optimal surgical intervention without neoadjuvant chemotherapy is not feasible
7. ECOG status: 0-2
8. Suitable for and designated by the investigator for neoadjuvant therapy with wTAX + (carboplatin) + AC chemotherapeutic agent
9. Willingness to participate in the trial and signed the informed consent form for the protocol

Exclusion Criteria:

1. Patient is ≤ 18 years of age.
2. Tumor of both breasts.
3. Diagnosis of breast tumor > 40 days
4. HER2 positive breast tumor
5. Has already received some anticancer therapy
6. Any previous cancer requiring anti-tumor treatment within 5 years prior to selection, except: in situ cervical or uterine cancer and non-melanoma skin cancer.

7. Co-existing serious diseases:

   1. Presence of severe neuropathy requiring medical treatment, diabetic neuropathy.

   2. Clinically significant hematological, hepatic or renal dysfunction, as defined below:

      • Neutrophil count < 1.5 G/L and platelet count < 100 G/L
      • bilirubin > 1.5 times the upper limit of normal range (ULN), except for known Gilbert's disease
      • AST and/or ALT > 2.5 times the upper limit of the normal range
      • Serum creatinine > 1.5 times the upper limit of the normal range.
   3. Clinically significant cardiovascular disease in the medical history, unless the disease is adequately controlled. E.g. New York Heart Association (NYHA) Class II or worse congestive heart failure (moderate limitation of physical activity; well-being at rest but normal activity is associated with fatigue, rapid heart rate or dyspnoea).
   4. Uncontrolled hypertension with resting systolic ≥ 180 mmHg, resting diastolic ≥ 110 mmHg.
   5. Resting sinus tachycardia with a pulse ≥ 110/min.
   6. History of sympathetic or treatment-naive cardiac arrhythmia. Atrial fibrillation or flutter controlled with medication is not an exclusion for participation in the study.
   7. Major cardiovascular event (e.g. myocardial infarction, unstable angina, cerebral vascular accident (CVA), etc.) in the 6 months prior to randomisation.

   8. Active infection or severe underlying disease that renders the patient unfit for treatment according to the study protocol.

      • A current diagnosis of chronic hepatitis, Hepatitis B surface antigen positive, Hepatitis C antibody positive and/or other clinically active liver disease requiring treatment.
      • Known HIV infection.
      • Untreated thyroid disease.
      • Systemic autoimmune disease.
   9. Any psychiatric condition in the medical history that may result in the patient being unable to understand or comply with the requirements of the study, having reduced communication skills or being unable to give informed consent.
8. Need for concomitant anti-tumor therapy in addition to wTAX + (carboplatin) + AC protocol
9. Any active medical device implanted in the anatomical area, such as pacemakers.
10. Known severe hypersensitivity to any of the chemotherapies used in the study.
11. Pregnancy or breast-feeding (patients of childbearing potential must use effective contraception throughout the study and for 3 months after the end of treatment). The method of effective contraception is at the discretion of the investigator.
12. History of drug or alcohol dependence within 6 months prior to screening.
13. Unable to comply with the study plan for medical, psychological, family, geographical or other reasons.
14. Institutionalisation by administrative or judicial decision.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Attila M Szasz, M.D./Ph.D.; +3614591500 ext 51618; szasz.attila_marcell@med.semmelweis-univ.hu

Contact: Zoltan Herold, Ph.D.; +3614591500; herold.zoltan@med.semmelweis-univ.hu

• Listed Location Countries: Hungary

Administrative Information

• NCT Number: NCT05889390
• Other Study ID Numbers: NeoHTerMa
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Marcell Szasz, Semmelweis University
• Original Responsible Party: Same as current
• Current Study Sponsor: Semmelweis University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Magdolna Dank, M.D./Ph.D.; Semmelweis University

• PRS Account: Semmelweis University
• Verification Date: May 2023