Neoadjuvant Concomitant Modulated Electro-hyperthermia in HER2-negative Breast Cancer

Study Overview
=================
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.

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]

Conditions
-----------------
HER2-negative Breast Cancer

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At least 18 years of age Female patient Life expectancy ≥ 6 months De novo histological/cytological diagnosis of HER2-negative (triple-negative or ER/PR+) breast tumor involving one breast Diagnosis of breast tumor ≤ 40 days Locally advanced stage disease (stage II and III) requiring neoadjuvant treatment - according to the following criteria: Primary breast tumor ≥ 20 mm in size and/or Presence of axillary lymph node metastases Optimal surgical intervention without neoadjuvant chemotherapy is not feasible ECOG status: 0-2 Suitable for and designated by the investigator for neoadjuvant therapy with wTAX + (carboplatin) + AC chemotherapeutic agent Willingness to participate in the trial and signed the informed consent form for the protocol Exclusion Criteria: Patient is ≤ 18 years of age. Tumor of both breasts. Diagnosis of breast tumor > 40 days HER2 positive breast tumor Has already received some anticancer therapy 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. Co-existing serious diseases: Presence of severe neuropathy requiring medical treatment, diabetic neuropathy. 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. 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). Uncontrolled hypertension with resting systolic ≥ 180 mmHg, resting diastolic ≥ 110 mmHg. Resting sinus tachycardia with a pulse ≥ 110/min. History of sympathetic or treatment-naive cardiac arrhythmia. Atrial fibrillation or flutter controlled with medication is not an exclusion for participation in the study. Major cardiovascular event (e.g. myocardial infarction, unstable angina, cerebral vascular accident (CVA), etc.) in the 6 months prior to randomisation. 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. 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. Need for concomitant anti-tumor therapy in addition to wTAX + (carboplatin) + AC protocol Any active medical device implanted in the anatomical area, such as pacemakers. Known severe hypersensitivity to any of the chemotherapies used in the study. 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. History of drug or alcohol dependence within 6 months prior to screening. Unable to comply with the study plan for medical, psychological, family, geographical or other reasons. Institutionalisation by administrative or judicial decision.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: wTAX (+ carboplatin) +AC<br>wTAX: Weekly paclitaxel (+ carboplatin in the case of triple-negative breast cancer) for 12 weeks AC: Doxorubicin/Cyclophosphamide every three-weeks, 4x Breast cancer tumor removal surgery (if feasible) | Drug: Paclitaxel<br>* weekly paclitaxel for 12 weeks<br>Drug: Carboplatin<br>* added to weekly paclitaxel if patient has triple-negative breast cancer<br>Drug: Cyclophosphamide/Doxorubicin<br>* according to the AC protocol<br>Procedure: Breast cancer removal surgery<br>* Either breast-conserving surgery or total mastectomy after the neoadjuvant chemotherapy with or without mEHT (if feasible)<br>|
| Experimental: wTAX (+ carboplatin) +AC + mEHT<br>wTAX + mWEHT wTAX: Weekly paclitaxel (+ carboplatin in the case of triple-negative breast cancer) for 12 weeks mEHT: Concomitant modulated electro-hyperthermia using the Oncotherm EHY-2030 device, 3 times per week, for 12 weeks AC: Doxorubicin/Cyclophosphamide every three-weeks, 4x Breast cancer tumor removal surgery (if feasible) | Device: Oncotherm EHY-2030<br>* 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.<br>Drug: Paclitaxel<br>* weekly paclitaxel for 12 weeks<br>Drug: Carboplatin<br>* added to weekly paclitaxel if patient has triple-negative breast cancer<br>Drug: Cyclophosphamide/Doxorubicin<br>* according to the AC protocol<br>Procedure: Breast cancer removal surgery<br>* Either breast-conserving surgery or total mastectomy after the neoadjuvant chemotherapy with or without mEHT (if feasible)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Residual size of the primary tumor, determined by imaging techniques (in percentage) | 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. | change from baseline at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of complete pathological response | Comparison of the percentage of complete pathological responses between the two groups | 9 months | 
| Treatment response patterns | Comparison of the pathological response categories (pCR : pPR : pNR) between the two groups | 9 months | 
| Comparison of surgical procedure ratios | 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. | 9 months | 
| Effect of treatment on white blood cell counts | 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. | through study completion, an average of  8 months | 
| Effect of treatment on red blood cell counts | 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. | through study completion, an average of  8 months | 
| Effect of treatment on platelet counts | 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. | through study completion, an average of  8 months | 
| Effect of treatment on hemoglobin levels | 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. | through study completion, an average of  8 months | 
| Effect of treatment on hematocrit levels | 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. | through study completion, an average of  8 months | 
| Number of treatments where the planned power output of the Oncotherm EHY-2030 device could not be reached | 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. | 3 months | 
| Longitudinal analysis of the EORTC QLQ-C30 questionnaire's total scores | 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 | through study completion, an average of  8 months | 
| Longitudinal analysis of the EORTC QLQ-BR23 questionnaire's total scores | 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 | through study completion, an average of  8 months | 
| Longitudinal analysis of the EQ-5D-5L questionnaire scores | 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. | through study completion, an average of  8 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hyperthermia, modulated electro-hyperthermia, oncothermia, breast cancer