A Phase II Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib as Second-line Therapy For Patients With Advanced Hepatocellular Carcinoma.
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Wake Forest University Health Sciences

A Phase II Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib 
as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
 
 
 
Protocol Version Date: 06/07/21 
Page 1 of 81 
 
Principal Investigator(s):  
Ravi Paluri, M.D. 
Radiation Oncology 
Comprehensive Cancer Center Wake Forest 
University 
 
 
 
Co-Investigator(s):  
 
George Yacoub, M.D. 
 
 
 
 
 
 
 
 
 
Section on Hematology and Oncology 
Comprehensive Cancer Center Wake Forest 
University 
  
 
 
Steve Sorscher, M.D.  
Section on Hematology and Oncology 
Comprehensive Cancer Center Wake Forest 
University 
  
 
 
Lance Miller, PhD. 
Department of Cancer Biology 
Comprehensive Cancer Center Wake Forest 
University 
  
 
 
Greg Hawkins, PhD. 
Department of Biochemistry 
Wake Forest School of Medicine 
 
 
 
Study Staff:  
 
 
Kojo Agyemang 
Graduate Student 
   

A Phase II Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib 
as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
 
 
 
Protocol Version Date: 06/07/21 
Page 2 of 81 
 
Allan Johansen 
Graduate Student 
   
 
 
Biostatistician: 
 
 
Scott P. Isom 
Biostatistician IV 
 
 
Comprehensive Cancer Center Wake Forest 
University 
 
 
 
 
Study Coordinators: 
 
Austin Humbert, CRC 
 
 
 
 
 
WFBCCC, CPDM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stacie N. Moore, CRN 
 
 
 
 
 
WFBCCC, CPDM 
 
 
 
 
 
 
 
 
 
 
 
 
 
Regulatory Contact: 
 
Emmanuel Vazquez 
WFBCCC, CPDM 
 
 
 
Protocol Writer: 
 
 
Kathy Walker, BA 
Comprehensive Cancer Center Wake Forest 
University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Institution(s): 
Wake Forest Baptist University Comprehensive Cancer Center 
 
Confidential 
Version Date (original IRB approved): 06/03/20 

A Phase II Study Of Intrabucally Administered Electromagnetic Fields and Regorafenib 
as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
 
 
 
Protocol Version Date: 06/07/21 
Page 3 of 81 
 
 
Amended:6.7.21 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
Page 4 of 81 
 
Table of Contents 
 1.0 Introduction and Background ................................................................................................. 7 
1.1 Current standard of care ..................................................................................................... 8 
1.2 Administration of amplitude-modulated radiofrequency electromagnetic fields (AM RF 
EMF) of low intensity ............................................................................................................... 10 
2.0 Objectives ............................................................................................................................. 32 
2.1 Primary Objective .............................................................................................................. 32 
2.2 Secondary Objectives ....................................................................................................... 32 
3.0 Patient Selection ................................................................................................................... 32 
3.1 Inclusion Criteria ................................................................................................................ 32 
3.2 Exclusion Criteria .............................................................................................................. 33 
3.3 Inclusion of Women and Minorities ................................................................................... 34 
3.4 Life Style Guidelines .......................................................................................................... 34 
4.0 Registration Procedures ....................................................................................................... 35 
5.0 Study Outcomes and Study Measures ................................................................................. 36 
5.1. Primary Outcome ............................................................................................................. 36 
5.2 Secondary Outcomes ........................................................................................................ 36 
6.0 Study-Related Activities ........................................................................................................ 37 
6.1 Description of Procedures ................................................................................................. 38 
6.2 Treatment with Regorafenib .............................................................................................. 40 
6.3 Treatment With TheraBionic .............................................................................................. 41 
6.4 General Concomitant Medication and Supportive Care Guidelines .................................. 43 
6.5 Duration of Therapy ........................................................................................................... 43 
6.6 Duration of Follow Up ........................................................................................................ 45 
7.0 
Dosing Delays/Dose Modifications ................................................................................... 45 
7.1 
TheraBionic Device ...................................................................................................... 46 
7.2 
Regorafenib .................................................................................................................. 46 
8.0 
Measurement of Effect - Radiological assessment .......................................................... 47 
8.1 Antitumor Effect-Solid Tumors .......................................................................................... 47 
8.2 Definitions for RECIST 1.1 ................................................................................................ 47 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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8.3 Definitions for mRECIST ................................................................................................... 48 
8.4 Methods for Evaluation of Measurable Disease ................................................................ 49 
8.5 Evaluation of Best Overall Response ................................................................................ 49 
8.6 Disease control .................................................................................................................. 49 
8.7 Tumor progression ............................................................................................................ 50 
8.8 Time to progression (TTP) ................................................................................................ 50 
8.9 Survival Outcomes ............................................................................................................ 50 
9.0 Adverse Events List and Reporting Requirements ............................................................... 51 
9.1 Potential toxicity ................................................................................................................ 51 
9.2 Adverse Events for Regorafenib ....................................................................................... 51 
9.3 Adverse Event Characteristics .......................................................................................... 52 
9.4 DSMC SAE Reporting Requirements ................................................................................ 53 
9.5 WFUHS IRB AE Reporting Requirements ........................................................................ 53 
9.6 Sponsor Reporting Requirements ..................................................................................... 54 
9.6.1.  Conflict of Interest Management Plan Summary ...................................................... 54 
10.0 Pharmaceutical Information ................................................................................................ 55 
10.1 Device Programming and treatment accountability ......................................................... 55 
10.2 AM RF EMF Device (TheraBionic® P1 Device) ............................................................... 56 
10.3 
Pharmaceutical Accountability ...................................................................................... 57 
10.4 
Regorafenib (STIVARGA) ............................................................................................ 57 
11.0 Laboratory Correlative Studies ........................................................................................... 57 
12.0 Data Management .............................................................................................................. 59 
13.0 Statistical Considerations .................................................................................................... 60 
13.1 Analysis of Primary Objective .......................................................................................... 60 
13.2 Analysis of Secondary Objectives ................................................................................... 60 
13.3 Power and Sample Size .................................................................................................. 61 
13.4 Interim Analysis ............................................................................................................... 62 
13.5 Estimated Accrual Rate ................................................................................................... 62 
Appendix A – Eligibility Checklist ................................................................................................ 63 
Appendix B – Protocol Registration Form ................................................................................... 66 
Appendix C - Race & Ethnicity Verification Form ........................................................................ 67 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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Appendix D Data and Safety Monitoring  Committee Requirements .......................................... 68 
Appendix E  Calculator: Child Pugh score for severity of liver disease (SI units) ....................... 75 
Appendix F- List of items/agents/compounds that block T-type channels ( Cav 3.1/2/3) ........... 76 
Reference List ............................................................................................................................. 78 
 
 
 
 
 
 
 
 
 
 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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Consent and Eligibility 
Assessment
Regorafenib + AM RF EMF
Regorafenib per standard of care plus AM 
RF EMF 3 times a day for one hour each 
session
Every 4 weeks
Clinic Assessments-Physical Exam/AE 
evaluation and Labwork
Treatment Compliance Assessments
Every 6 weeks
Clinic Assessments-Physical Exam/AE evaluation 
and Labwork
Treatment Compliance Assessments
CT/MRI
s
Primary Outcome: Progression Free Survival
Secondary Outcomes: Overall survival
Adverse Events
Alfa-fetoprotein levels
Study Follow Up

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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1.0 Introduction and Background  
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer death 
worldwide [1, 2]. This tumor is the fastest rising cancer in the United States. In 2019, it is 
estimated that 42,030 new cases will be diagnosed and there will be 26,810 deaths from 
HCC, i.e. 86% and 73% increase in the number of new cases and deaths since 2009, 
respectively[3, 4]. The prognosis of patients suffering from advanced HCC is poor with an 
average survival time of ten months [2]. Factors negatively influencing patient survival 
include: poor performance status, history of alcoholism, low albumin rate, hepatic 
cirrhosis, high level of alpha-fetoprotein (AFP), and an obstruction of the portal vein.  
Therapies for HCC are limited. Resection of the primary tumor is the therapeutic approach 
of first choice when possible [2]. Although this intervention results in long-term survival 
for some patients, the majority of patients are not surgical candidates due to tumor size, 
the patient’s overall condition, or presence of hepatic cirrhosis. Until 2017, only two 
therapeutic interventions had demonstrated survival benefit in such patients: 
chemoembolization [5] and sorafenib, a multikinase inhibitor [6] [7]. Systemic therapies 
for patients with advanced hepatocellular carcinoma have recently improved, with several 
new agents showing clinical efficacy in phase 3 trials: Regorafenib [8], Lenvatinib [9], 
Cabozantinib [10],and Ramucirumab [11]. Sorafenib, lenvatinib, and atezolizumab + 
bevacizumab are currently approved for first-line treatment; regorafenib, cabozantinib, 
ramucirumab, 
lenvatinib, 
nivolumab, 
nivolumab 
+ 
ipilumab, 
sorafenib, 
and 
pembrolizumab are approved for second-line treatment. While these new therapies 
provide additional options for patients with advanced hepatocellular carcinoma, the 
incremental survival benefits are limited to approximately 3 months. Additional therapies 
for this disease are sorely needed, especially for the large number of patients with 
advanced disease who progress after first line therapy. 
 
1.1 Current standard of care  
The current standard of care is described in the following Figure 1 [2].  
 
 
 
 
 
 
 
 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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Regimens recommended by the NCCN guidelines version 1.2020 
 
 
Figure 1: Clinical algorithm for the management of hepatocellular carcinoma 
The algorithm is based on the Barcelona clinic liver Cancer (BCLC) algorithm, which 
classifies patients in one of 5 stages, and European Association for the Study of the Liver 
guidelines [12] [13]. Depicted is the estimated survival time in each stage once the 
recommended therapy has been administered or performed. As of March 23, 2020, the 
combination of atezolizumab together with bevacizumab is an additional preferred 
regimen recommended by the NCCN Guidelines Version 1.2020. Additionally, nivolumab, 
nivolumab plus ipilumab, and pembrolizumab are FDA approved second line therapies 
for advanced hepatocellular carcinoma. 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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1.2 Administration of amplitude-modulated radiofrequency electromagnetic fields 
(AM RF EMF) of low intensity  
 
1.2.1 Electromagnetic fields and tumor cell growth  
 
Until a decade ago little was known regarding the kHz to THz electromagnetic 
interactions with biological systems, which do not result in changes in temperature 
within tumor tissues or in tumor cell membrane electroporation. Recent studies provide 
growing experimental and clinical evidence that alternating electric fields (Tumor 
Treating Fields) and amplitude-modulated radiofrequency electromagnetic fields (AM 
RF EMF) are capable of blocking tumor growth [14].  
 
In 2001, Pasche and Barbault hypothesized [15] and subsequently provided 
experimental evidence that intrabuccal delivery of 27 MHz radiofrequency 
electromagnetic fields, which are amplitude-modulated at tumor-specific frequencies 
(AM RF EMF), has anticancer activity. Using noninvasive patient-based approaches, 
Barbault et al. were the first to identify tumor-specific modulation frequencies, i.e., 
changes in pulse amplitude upon exposure to specific AM RF EM, in patients with 
cancer that were not found in healthy individuals [16].They subsequently determined 
that these frequencies had anticancer effects both in vitro and in vivo [17, 18] They 
conducted first a feasibility study in 28 patients with advanced cancer and no 
therapeutic options [19] then a phase I/II in patients with advanced HCC without 
therapeutic options [20]. These studies showed that treatment with AM RF EMF results 
in clinical benefits with minimal risks, even after several years of continuous daily use 
[20] [21, 22].  These clinical and translational findings led to the European regulatory 
approval of the TheraBionic P1 medical device for the treatment of advanced HCC [15].  
The TheraBionic P1 medical device received European approval as a class IIa low risk 
medical device in 2018 and is indicated for patients with advanced hepatocellular 
carcinoma who have failed or are intolerant to first line and second lines therapies. In 
2019, the FDA granted Breakthrough Designation to the same medical device for use in 
patients with advanced hepatocellular carcinoma who have failed or are intolerant to 
first line and second line therapies for HCC.  
 
1.2.2 Administration of electromagnetic fields of low intensity in human beings 
 
Intrabuccal administration of tumor-specific AM RF EMF as a single anticancer 
treatment modality has yielded objective tumor shrinkage in the femur [16], adrenal 
gland [16], liver [20], lungs [20] and brain [23] of patients suffering from unresectable or 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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metastatic cancer, which suggests that intrabuccally-administered 27 MHz AM RF EMF 
have systemic anticancer effects distant from the point of administration, i.e., the buccal 
mucosa. Jimenez et al. recently demonstrated that intrabuccal administration of AM RF 
EMF results in absorption throughout the body because contact between the spoon-
shaped “antenna” applicator and the anterior part of the patient’s tongue results in the 
patient’s body acting as an extension of the antenna.  The AM RF EMF reach the whole 
body because of the 27 MHz carrier frequency, which has a wavelength of 11 m. 
Optimal antenna absorption by living systems is achieved at one third of the 
wavelength, i.e., 3.6 m, which is very close to the length of the human body (1.4-2.2 m). 
Additionally, because the carrier wave is 27.12 MHz and the electrical charge is so low, 
the signal (AM RF EMF) extends throughout the body and thereby in effect allowing the 
body to become an extension of the coaxial cable delivering treatment systemically.  
 
The RF output of the TheraBionic P1 medical device is adjusted to 100 mW into a 50 Ω 
load using a sinusoidal test signal [16, 20, 22]. The Specific Absorption Rate (SAR) 
level and distribution inside the human body  during treatment (Fig. 1a and 1b) was 
assessed and the variability depending on device positioning and patient posture (Fig. 
1c) was quantified. Homogeneous and inhomogeneous model simulations show similar 
SAR distribution pattern (Fig. 1d and 1e). The whole-body (wbSAR) and the peak 
spatial SAR (psSAR) over any 10 g (psSAR10g) and 1 g (psSAR1g) of major organs 
according to IEEE standard[24] are listed in Table 1. 
 
 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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Intrabuccal delivery of 27 MHz AM RF EMF results in whole-body absorption from head 
to toe and the highest peak spatial SAR (psSAR) is at the interface between the tongue 
and the spoon-shaped applicator. As shown in Table 1b, there is more radiated power 
when the device is far away from the body. Conversely, the wbSAR is slightly higher 
when the device touches the body, regardless of position (Table 1c). Experimental 
validation measurements based on a tank phantom (Fig. 1f) show that the SAR 
distribution inside the tank is similar to that of the homogeneous human model.[22].  
The wbSAR is 1.35 mW/kg with psSAR over 1 g from 146 to 352 mW/kg when the 
applicator spoon is perfectly matched, which is significantly below the International 
Commission on Non-Ionizing Radiation Protection [25] standard safety limits of 80 
mW/kg wbSAR, or psSAR of 2,000 mW/kg (Table 2).[25] Organ-specific SAR ranges 
from 0.02 to 1 mW/kg (Table 2). Liver-specific SAR ranges from 0.05 to 0.5 mW/kg 
(Table 2). 
 
Uncertainty and variation assessments were 
conducted with the patient sitting with the 
device placed away from the body. The posture 
variation based on sitting positions as shown in 
introduces 0.06 dB deviation. A ±10 kg variation 
in body weight introduces 0.39 dB deviation, the 
biggest contribution, 2.19 dB comes from the 
variation of the applicator spoon impedance with posture and device position and its 
effect on the power delivered to the patient. Therefore, the total variation of 2.21 dB, as 
shown in Table 1d, mainly depends on the delivered power.  
 
In summary, dosimetry analysis shows that 27 MHz AM RF EMF administered by 
means of a spoon-shaped applicator results in systemic EMF absorption, which is more 
than one hundred fold lower than the SAR generated by cell phones and does not result 
in heating of any body part. In all conditions studied, the device complies with the 
standard for human exposure to RF EMF. [26] The results also demonstrate that the 
human body acts as an antenna resulting in head to toe delivery of AM RF EMF. These 
findings provide a biophysical rationale for the antitumor effects documented in patients 
with metastases in the femur, liver, adrenal glands, lungs, and brain receiving 
intrabuccally-administered treatment with the TheraBionic device. Tumor-specific AM 
RF EMF appear to have a broad therapeutic window as tumor shrinkage was observed 
in humans,[16] [20] in human xenografts [23], and in vitro [17] at SARs ranging from 
0.02 mW/kg to 400 mW/kg.  
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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Figure 1. Intrabuccal delivery results in systemic absorption of AM RF EMF. a Patient with 
advanced hepatocellular carcinoma receiving first treatment with the AM RF EMF emitting 
device. The concentric lines represent AM RF EMF emission from the spoon-shaped 
antenna placed on the patient’s tongue. Red: primary and metastatic tumors. Blue arrows: 
depiction of antitumor activity location.  b Same patient several months later with evidence 
of shrinkage or disappearance of the primary tumor and its metastases [18, 27], Brown: 
shrunken tumor following AM RF EMF treatment, c,1) Patient sitting with device on thigh, 
2) Patient sitting with device on the abdomen, 3) Patient sitting with device placed away 
from the body, 4) Patient in supine position to test the hypothesis that the body can act 
as one half of a short dipole antenna while the cable and device form the other half, or for 
treatment lying down while the device is behind the head. The device and coaxial cable 
are shown in blue. The electric dipole is shown in green. d, SAR slice views in the 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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homogeneous human model: the images are normalized to 5 W/kg/W, with 3 dB/contour. 
1) Patient sitting with device on thigh, 2) Patient sitting with device on the abdomen, 3) 
Patients sitting with device placed away from the body, 4) Patient in supine position. e, 
SAR slice views in the inhomogeneous model: the images are normalized to 5 W/kg/W, 
with 3 dB/contour. Left panels: patient sitting with device on thigh. Right panels: patient 
sitting with device located away from the body. f, Experimental validation measurements 
setups and results.1) The device is located at one extremity underneath the tank, 2) The 
device is in the middle underneath the tank, 3) The device is beside the tank, 4) The 
device is as far away from the tank as possible. 
 
1.2.3 Clinical effects of amplitude-modulated electromagnetic fields of low 
intensity (Low Emitting Therapy Emission: LEET) on sleep and insomnia.  
 
In 1986, the Food and Drug Administration authorized the first tests of LEET technology 
in humans indicating that the device was a nonsignificant risk device (NSR). The emitting 
device was a precursor of the TheraBionic device, which had identical emitting power as 
the TheraBionic P1 medical device, which was adjusted to 100 mW into a 50 Ω load using 
a sinusoidal test signal 100 mW.[28] As a result, clinical studies were allowed to proceed 
upon local IRB approval. After approval by Swiss and American ethical committees (local 
IRBs), the first study using LEET was carried out on 104 volunteers at 2 different centers 
(Montreux, Switzerland and Denver, Colorado, United States). All subjects received in a 
blinded fashion one 15-minute active treatment and one 15-minute placebo treatment at 
least one week apart. An analysis of the electroencephalograms obtained immediately 
after treatment showed that active treatment decreased sleep latency and allowed healthy 
volunteers to reach a deeper sleep stage following active treatment than following 
placebo treatment [28, 29]. Active treatment also caused a feeling of relaxation when 
compared with placebo treatment[30].  
 
The effects of LEET on chronic insomnia were assessed with polysomnography (PSG) 
on a total of 106 patients at two U.S. sleep disorder centers (Scripps Clinic, La Jolla, CA 
and University of Colorado Health Sciences Center, Denver, CO) [31] [32]. Active or 
inactive LEET was administered for 20 minutes in late afternoon three times a week for a 
total of 12 treatments. There was a significant increase in total sleep time as assessed by 
polysomnography (PSG) between baseline and post-treatment values for the active 
treatment group (76.0 ± 11.1 minutes, p = 0.0001). The increase in total sleep time for 
the inactive group was not statistically significant (20.0 ± 13.5, p = 0.15). There was a 
significant decrease in sleep latency as assessed by polysomnography between baseline 
and post-treatment values for the active treatment group (-21.6 minutes ± 5.9 minutes, p 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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= 0.0006), whereas the decrease noted for the inactive treatment group was not 
statistically significant (- 6.0 ± 6.0 minutes, p = 0.32). Interestingly, the number of 
physiological sleep cycles per night increased by 30 % (0.84 ± 0.19) after active treatment 
(p = 0.0001), but was unchanged (0.23 ± 0.21) following inactive treatment. Subjects did 
not experience rebound insomnia, and there were no significant side effects. Lastly, the 
number of sleep cycles increased by 30% in the active group (0.84 ± 0.19, p = 0.0001), 
whereas it did not change in the placebo group (0.23 ± 0.21, p = 0.27).(31) Hence, LEET 
was able to effectively improve the sleep of chronic insomniacs by increasing the number 
of sleep cycles without altering the percentage of the various sleep stages during the 
night. The therapeutic action of LEET differs from that of currently available therapies in 
that the sleep patterns noted in insomniacs following LEET treatment more closely 
resembles nocturnal physiological sleep. More than 1000 patients were treated with this 
therapy in Europe and in the United States between 1982 and 2003 [33]. The only 
recorded side effects reported were an increase in dreams (likely related to the observed 
increase in the number of physiological cycles of the sleep).  
 
1.2.4 Low levels of amplitude-modulated radiofrequency electromagnetic fields 
(AM RF EMF) in the treatment of cancer.  
Barbault and Pasche have developed a patient-based, noninvasive biofeedback 
approach to measure physiological reactions upon exposure to high-frequency carrier 
signals, which are amplitude- modulated at various frequencies. Frequency discovery 
consists in the measurement of variations in pulse amplitude and blood flow [15, 16]. 
These measurements are conducted while individuals are exposed to low and safe levels 
of amplitude-modulated frequencies emitted by a handheld device or while holding the 
spoon antenna in the mouth. Exposure to these frequencies results in minimal absorption 
by the human body, which is well below the Institute of Electrical and Electronics 
Engineers [24] limits [26].  These frequency detection methods allowed them to identify 
specific modulation frequencies commonly encountered in patients suffering from cancer 
but not encountered in healthy controls [16]. In collaboration with Professor Niels Kuster 
and his team from the Swiss Federal Institute of Technology in Zurich, Pasche and 
Barbault developed new devices (OncoBionic P1 used for clinical trials; TheraBionic P1 
device for European registration according to ISO 13485:2016 and 93/42 EWG 
guidelines) for the administration of radiofrequency electromagnetic fields, which are 
amplitude-modulated with a precision reaching 10 -7 Hz. These devices differ from the 
older Symtonic devices used for the treatment of insomnia in that the precision of the 
emitted modulation frequencies has been significantly improved [15, 16].  The 
TheraBionic P1 devices, which received the CE mark in 2018 will be available for the 
proposed study. Importantly, the emitting power and the levels of absorbed 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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electromagnetic fields of the TheraBionic P1 and OncoBionic P1 are identical to those of 
the Symtonic device. 
 
In 2002, after having identified frequencies likely to have a therapeutic effect in the 
treatment of cancer, Pasche and Barbault initiated a feasibility study to evaluate the 
tolerability of this approach in the treatment of patients with solid tumors. A total of 28 
patients with advanced cancer were offered compassionate experimental treatment [16]. 
Independent review of the imaging studies by U.S. Board certified radiologists using 
RECIST criteria [34] showed a complete response lasting 11 months in a patient with 
breast cancer metastatic to the adrenal gland and bone, and a partial response lasting 
13.5 months in another patient with breast cancer metastatic to the liver and bone. The 
tumor of a patient suffering from pancreatic cancer metastatic to the liver was stable for 
4.0 months. The tumor of a patient with stage IV non-small cell lung cancer was stable 
for 5.1 months. One patient with recurrent follicular thyroid cancer metastatic to the lungs 
enrolled in August 2006 is still on therapy as of November 2019, more than 13 years and 
three months after enrollment into the study [21]. None of the patients have experienced 
any serious side effects as a result of the administration of electromagnetic fields, even 
after more than 13 years of continuous treatment. These preliminary results indicated that 
a therapeutic approach based on low intensity electromagnetic fields administered daily 
for three hours does not entail major health risks, even after several years of exposure, 
and is potentially effective in the treatment of advanced cancer.  
 
1.2.5 Specific frequencies in HCC  
By means of the above described methods and devices, Barbault and Pasche have 
identified potentially effective frequencies for the treatment of HCC [16]. Given the fact 
that there was no effective therapy for the treatment of advanced HCC resistant to 
conventional therapies, Dr. Frederico Costa initiated in 2005 a phase I/II study at the 
University of Sao Paulo in Brazil [20]. The main goal of this phase I/II study was to assess 
the safety and effectiveness of low levels of radiofrequency electromagnetic fields 
amplitude-modulated at HCC-specific frequencies and administered by means of an 
intrabuccal spoon-shaped probe in patients with advanced HCC. The primary efficacy 
end point was progression-free survival (PFS) ≥ 6 months. Secondary efficacy end points 
were progression-free survival and overall survival (OS). Three daily 60 min outpatient 
treatments were administered until disease progression or death. Imaging studies were 
performed every eight weeks. From October 2005 to July 2007, 41 patients with advanced 
HCC and Child-Pugh A or B were enrolled in this study. Thirty-one patients (75.6%) had 
radiological evidence of disease progression at the time of enrollment as defined by 
comparison of baseline imaging studies with imaging studies obtained within the previous 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
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six months. Thirty-four (82.9%) patients had received therapy prior to enrollment. The 
majority of patients had severely impaired liver function as demonstrated by the fact that 
22 patients had Child-Pugh B disease.  Six of the first 23 patients (26.1%) had 
progression-free survival ≥ 6 months, which led the study team to continue enrolling 
patients up to the pre-planned total of 41 patients. In total, fourteen patients (34.1%) had 
stable disease for more than 6 months. Median progression- free survival was 4.4 months 
(95% CI 2.1-5.3) and median overall survival was 6.7 months (95% CI 3.0-10.2). One 
patient with evidence of disease progression at the time of enrollment remained on 
therapy for 63 months. Estimated survival at 12, 24 and 36 months was 27.9% (SE = 
7.1%), 15.2% (SE = 5.7%) and 10.1% (SE = 4.8%). A total of 28 patients were evaluable 
for tumor response. Four (14.3%) patients had a partial response assessed with CT with 
or without contrast-enhanced ultrasound. All partial responses were independently 
reviewed by two radiologists. Serial alpha-fetoprotein (AFP) measurements, which predict 
radiological response and survival in patients with HCC [20], were available for 23 
patients. AFP decreased by 20% or more in four (17.3%) patients following initiation of 
therapy.  
Overall, there were six long-term survivors with an overall survival greater than 24 
months, and four long-term survivors with an overall survival greater than three years. 
Importantly, five of the six (83%) long-term survivors had radiological evidence of disease 
progression at the time of study enrollment. The two patients with the longest survival 
(48.4 and 63 months) had BLCL stage C disease and portal vein thrombosis, predictors 
of short survival [20].  Eleven patients reported pain prior to treatment initiation, three 
patients reported grade 3, five grade 2, and three reported grade 1. Five patients reported 
complete disappearance of pain and two patients reported decreased pain shortly after 
treatment initiation. Two patients reported no changes and two patients reported 
increased pain. There was no treatment-related grade 2, 3 or 4 toxicities. The only 
treatment-related adverse events were grade I mucositis (1 patient) and grade I 
somnolence (1 patient). 
 
1.2.6   In vivo effects of amplitude-modulated radiofrequency electromagnetic fields 
Having characterized SAR levels delivered to patients during treatment with the AM RF 
EMF emitting device, Jimenez et al. set out to replicate human exposure conditions in 
vivo.  They used a custom-designed small animal AM RF EMF exposure system [35] [18] 
and exposed tumor-bearing mice with tumors developing in subcutaneous tissue 
predominantly surrounded by fat. The exposure system RF output was set for delivery of 
a SAR level of 67 mW/kg. This SAR was selected so that it was 1) within the range of 
previously demonstrated in vitro activity (30 - 400 mW/kg) [36] and 2) within the range of 
wbSAR1g and psSAR1g in patients receiving treatment with the TheraBionic device (1 - 

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352 mW/kg) (Table 2).  Huh7 and patient-derived tumor cells were used as subcutaneous 
cellular xenograft models of HCC [23, 37], [38]. Thirty-seven of 40 mice injected with Huh7 
cells developed palpable tumors and were exposed to HCC-specific AM RF EMF 
(HCCMF), randomly chosen AM RF EMF (RCF), or were not exposed to EMF (SHAM) 
as controls. Both control subsets (RCF and no exposure) were compared to the group 
exposed to HCC-specific frequencies (N = 20). The treatment by time interaction was 
highly significant (p<0.001) showing that tumor growth curves were different among the 
three groups. Comparison between the two control subsets showed no statistical 
difference over the course of six weeks; P = 0.655. The two groups were therefore 
combined as control group. Comparison between the pooled control group (N = 17) and 
the HCCMF (N = 20) group shows beginning separation between groups at week four (p 
= 0.08), and significant separation at week five (p = 0.045), and week six (p = 0.019) 
(Figure 2a). The commonly used RECIST 1.1 criteria [39] were applied to assess 
response to treatment. At week six, the volume of 8 (42.1%) of the 19 tumors exposed to 
HCCMF had decreased by 30% or more. At the same time point none of the 17 tumors 
of the control group had evidence of shrinkage [22]. 
 

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To characterize in vivo the temporal relationship between exposure to HCCMF and HCC 

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Figure 2. Antiproliferative effects of HCCMF in vivo. a, Mice were exposed to either 
HCCMF exposure with a xenograft-specific SAR of 67 mW/kg or are assigned to the 
control treatment group three hours per day. Control group is comprised of mice receiving 
either randomly chosen frequencies (RCF) with a xenograft-specific SAR of 67 mW/kg 
and those receiving no exposure (SHAM). Tumor volume is measured three times per 
week and volume is calculated as (Length x (Width)2) / 2.  After six weeks of exposure, 
statistical significance between treated and control groups has been achieved; [Week five 
(p = 0.045), Week six (p = 0.019) Student’s two-tailed t-test] and [Test for treatment by 
time interaction (p < 0.001)].  b, Sequential exposure to randomly chosen and HCCMF. 
Five mice carrying Huh7 xenografts were exposed to RCF (grey line) three hours per day 
for ten weeks during which the average tumor volume increased by 48%. Exposure was 
switched to HCCMF (blue line) after ten weeks. Exposure to EMF was discontinued for 
one week after four weeks exposure, then resumed. Mice were sacrificed at the end of 
week 16. c, Patient-derived HCC xenografts (PDX) exposed to HCCMF or not exposed 
to EMF. Patient derived xenografts from a 63-year-old male with hepatocellular 
carcinoma. Mice received either HCCMF exposure (HCCMF; N = 6) or received no 
treatment (SHAM; N =4). Tumor volume measured three times per week and volume is 
calculated as (Length x Width2) / 2. After eight weeks of exposure, statistical significance 
had been achieved; [Week four (p = 0.0176), Week five (p = 0.0211) Student’s two-tailed 
t-test]. At week six, all mice in the Sham group expired and tumor volume was imputed, 
Week six (p = 0.0553) [student’s t-test].  [Test for treatment by time interaction (p = 
0.0006)]. d, Ki-67 staining of SHAM, RCF and HCCMF treated tumors. [Anova: F = (2, 
33) 67.55, P = <0.0001].  [Post-Hoc Tukey Test: Sham vs RCF p = 0.2067, SHAM vs 
HCCMF p <0.0001, RCF vs HCCMF p < 0.0001.] e, Cyclin D1 staining of SHAM, RCF 
and HCCMF treated tumors. [Anova: F = (2, 33) 23.29, p < 0.0001]. [Post-Hoc Tukey test: 
Sham vs RCF p = 0.1379, SHAM vs HCCMF p <0.0001, RCF vs HCCMF p = 0.0005]. f, 
p21 staining of SHAM, RCF and HCCMF treated tumors [Anova: F = (2, 33) 6.907, p = 
0.0031]. [Post-Hoc Tukey test: Sham vs RCF p = 0.7373, Sham vs HCCMF p = 0.0411, 
RCF vs HCCMF p = 0.0049]. g, IHC of Huh-7 Xenograft tumors and all images at 20X 
(Lens; scale bar is 50 um). Tumor and intestinal crypt cell proliferation in mice exposed 
to HCCMF, RCF, and mice not exposed to EMF. Representative figures and graphs (d-f) 
represent mean +/- SEM (SHAM: N = 3; RCF: N = 3; HCCMF: N = 6) and three randomly 
selected fields of view per slide were used to quantify all staining. BRDU staining of 
SHAM, RCF and HCCMF treated tumors showed positive staining in all crypts; no 
statistics performed.  
 
To characterize in vivo the temporal relationship between exposure to HCCMF and HCC 
growth, we randomly selected and studied five mice, which had been exposed to RCF 

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three hours daily for ten weeks, all of which had evidence of tumor growth while  
exposed to RCF. As shown in Fig. 2b, the growth of Huh7 xenografts stopped within one 
week of switching from exposure RCF to exposure to HCCMF (week 11) and the tumors 
shrank by 62% within three weeks of exposure to HCCMF. To assess the carry-over effect 
of HCCMF, exposure was stopped at the end of week 14. As shown in Fig. 2b, the 
average volume of Huh7 xenografts increased by 109% within two weeks. To determine 
whether repeat exposure to HCCMF could again block tumor growth, mice were re-
exposed to HCCMF at week 15. As shown in Fig. 2b tumor growth was, again, effectively 
blocked within one week of re-exposure.  Lastly, to assess in vivo the effect of HCCMF 
on patient-derived xenografts (PDX), 6 PDX mice were exposed to HCCMF. Four PDX 
mice were observed as controls. As shown in Fig. 2c, tumor growth was significantly 
inhibited by HCCMF, test for treatment by time interaction (p = 0.0006). 
 
In summary, there was significant tumor shrinkage ranging from near complete and partial 
responses to tumor stabilization in two different mouse models of HCC, which establishes 
that HCCMF exert sustained control over the growth of HCC tumors in vivo at SAR levels 
corresponding to the levels delivered in patients with advanced HCC. In contrast, there 
was no shrinkage in any tumors exposed to randomly chosen frequencies or not exposed 
to any EMF. 
 
1.2.7 Tumor shrinkage is associated with HCC cell differentiation into quiescent 
cells with spindle morphology 
 
Having demonstrated that exposure to HCCMF results in shrinkage of Huh7 tumor 
xenografts, similarly to what has been observed in patients receiving treatment with 
HCCMF, we examined the histology of shrunken tumors and tumors from the control 
group. The first difference between tumors treated with HCC-specific AM RF EMF 
compared with control tumors was the absence of necrosis [22] Second, we consistently 
observed accumulation of fibroblast-like cells around and intermeshed with the shrunken 
HCC xenografts suggesting that fibroblast-like cells had replaced HCC cells (Fig. 3a). To 
identify the origin of these cells, we used green-fluorescent protein (GFP) tagged Huh7 
cells. 

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As shown in Fig. 3b, there was strong GFP 
staining 
of 
the 
fibroblast-like 
cells 
surrounding and intermeshed with residual 
Huh7 cells demonstrating their HCC origin. 
To further characterize these cells, we 
performed immunohistochemistry analysis 
of several fibroblast cell markers. As 
shown in Fig. 3c-d, marker analysis 
identified two separate subpopulations of 
fibroblast-like cells in shrunken tumors 
compared to control tumors, a peripheral 
region surrounding a distinct central 
region. The peripheral cells were positive 
for E-cadherin, fibronectin, and TWIST, 
weakly positive for smooth muscle actin 
(SMA) and faintly positive for SNAIL while 
the centrally located cells were more 
intensely positive for fibronectin and SMA 
but did not stain for E-cadherin, N-cadherin 
and SNAIL and had decreased staining for 
TWIST (Fig. 3c).  
 
Figure 3. Histological analysis of Huh7 xenograft tumors.  
Tumors were exposed to either no treatment (SHAM), or randomly chosen frequencies 
(RCF) or HCC-specific frequencies (HCCMF) three hours daily at a SAR of 67 mW/kg. 
The selected control tumors (SHAM & RCF) grew in size while tumors exposed to HCCMF 
shrank by approximately 70%. a, Fibroblast-like cells intermeshed with tumor cells 
following HCCMF mediated tumor shrinkage. Histological analysis 10X (Lens; scale bar 
is 100um)  shows residual tumor cells () surrounded by layers of fibroblast-like cells (#) 
and occasional lipocytes. b, Epithelial neoplasm (Huh7-GFP tagged cells) intermeshed 
with vector red positive cells () of spindle morphology demonstrating the same cell of 
origin for the two morphologically different populations 10X (Lens; scale bar is 100um). 
c, IHC summary of multiple IHC stains for SHAM, RCF, and HCCMF treated tumors. d, 
IHC staining images of Huh7 tumors following treatment. Images at 20X (Lens; scale bar 
is 50 um) with upper right embedded image at 60X (lens).  
 
These findings suggest that centripetal tumor shrinkage during exposure to HCCMF 

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results in the differentiation of HCC cells into quiescent cells with spindle morphology at 
the centre with residual carcinoma-like cells at the periphery of the shrunken tumor.  
 
To test the hypothesis that HCCMF only targets the proliferation of HCC cells in mice 
carrying tumor xenografts, we assessed tumor Ki67 as well as intestinal crypt BrdU 
staining in mice in which HCCMF had yielded at least 55% tumor shrinkage as well as in 
control mice. As shown in Fig. 2d-f, Ki67 and cyclin D1 staining was decreased and p21 
increased in the tumors of mice exposed to HCCMF compared to control mice. However, 
there was no difference in intestinal crypt BrdU staining between mice exposed to 
HCCMF and control mice (Fig. 2g). Similarly, there were no differences in white blood 
cells, red blood cells and platelets between HCCMF-exposed and control mice at the time 
of sacrifice [22].  In summary, HCCMF target HCC cell proliferation in vivo without 
affecting the proliferation of other cells and tumor shrinkage occurs through HCC cells 
differentiation into quiescent cells with spindle morphology. 
 
1.2.8 HCCMF antiproliferative effects require calcium influx through Cav3.2 T-type 
Voltage Gated Calcium Channels (CACNA1H) 
 
To agnostically assess the impact of HCCMF on HCC, we performed a combined review 
of the previously published RNA-Seq data [40] and new microRNA array assays. 
Ingenuity pathway analysis identified the IP3/DAG signalling pathway through differential 
expression of several genes and microRNAs. Differential expression of several key genes 
and microRNAs modulating this pathway was confirmed in Huh7 cells (Jimenez, 2019 
#217) Ca2+ modulates several steps of this pathway,(Albarran, 2016 #280)  and several 
investigators have shown that Ca2+ flux from brain tissue is enhanced upon exposure to 
RF EMF but only when modulated at specific frequencies, irrespective of the carrier 
frequency used (50, 147, and 450 MHz).[41, 42].We therefore postulated that Ca2+ is 
involved in HCCMF antiproliferative effects on HCC cells. To begin to test this hypothesis, 
we added BAPTA, a chelator of Ca2+, during each HCCMF exposure. As shown in Fig. 
5a, chelation of extracellular Ca2+ abrogates HCCMF antiproliferative effects without 
affecting the proliferation of Huh7 cells exposed to RCF demonstrating that extracellular 
Ca2+ plays a central role in this process. 
 
Next, we sought to determine if extracellular Ca2+ enters HCC cells upon exposure to 
HCCMF. We validated changes in intracellular Ca2+ following exposure to HCCMF with 
Fluo-4 calcium imaging. As shown in Fig. 4, intracellular Ca2+ was significantly increased 
after exposure of HCC cells (Huh7) to HCCMF for 30 min, one hour, three-hour, and six-
hour. We additionally validated increased intracellular Ca2+ in a second HCC cell line 

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(Hep3B) at the three-hour time point (Fig. 4). However, no increase in intracellular Ca2+ 
was observed after exposure to either RCF or breast cancer-specific AM RF EMF (data 
not shown). Moreover, there were no changes in intracellular Ca2+ levels when culturing 
cells in Ca2+-free medium demonstrating that HCCMF-mediated increase in intracellular 
Ca2+ is due to Ca2+ influx from the extracellular to the intracellular compartment, not by 
mobilization of intracellular Ca2+ stores. Lastly, HCCMF exposure did not have an impact 
on intracellular Ca2+ levels in human non-malignant hepatocytes (THLE2; ATCC), human 
microglia cells (HMC3; ATCC) or Rat myocardium cells (H9c2; ATCC) (data not shown) 
demonstrating that Ca2+ influx is both tumor- and tissue-specific as it only occurs when 
HCC cells are exposed to HCCMF.  
 
Having demonstrated that extracellular Ca2+ influx was necessary for HCCMF inhibition 
of HCC cell proliferation, we sought to identify how Ca2+ enters the cells. Ca2+ entry is 
mainly controlled by voltage-gated Ca2+ channels (VGCCs) [43-45]. We used inhibitors of 
L-type and T-type VGCCs to determine whether these VGCCs are involved in HCCMF 
Ca2+ influx and inhibition of cell proliferation. Amlodipine, which blocks L-type VGCCs, did 
not alter Ca2+ influx (data not shown). In contrast, ethosuximide, which blocks all three T-
type VGCCs (Cav 3.1, 3.2, 3.3), (Gomora, Daud et al. 2001) abrogated HCCMF’s Ca2+ 
influx as well as inhibition of Huh7 cell proliferation (Fig. 5b). Having identified T-type 
VGCCs as the necessary mediators of HCCMF Ca2+ influx and inhibition of HCC cell 
proliferation,we asked which of the three T-type VGCCs isoforms accounted for this 
effect. While knockdown of Cav3.1 (CACNA1G) and Cav3.3 (CACNA1I) did not affect  
HCCMF-mediated inhibition of HCC cell proliferation, knockdown of Cav3.2 (CACNA1H) 
abrogated HCCMF antiproliferative effects in Huh7 and Hep3B cell lines (Fig. 5c).   
In summary, HCCMF exert their selective antiproliferative effects on HCC cells by 
targeting CACNA1H, an event contingent on Ca2+ influx into HCC cells, an event restricted 
to HCC cells. 
  

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Figure 4. Intracellular Ca2+ measurement in Huh7 and Hep3B cells following 
exposure to AM RF EMF. a, Huh7: 30 min HCCMF exposure results in 50.2% increase 
in fluorescence (p = 0.0296), N =6 per group. b, Huh7: one-hour HCCMF results in 18.6% 
increase in fluorescence (p = 0.0337), N =5. c, Huh7: three-hour HCCMF results in 29.2% 

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increase in fluorescence (p = 0.0394), N =5 per group. d, Huh7: three-hour HCCMF 
exposure results in 23.2% increase in fluorescence (p = 0.0201), N =5 per group. 
Measured by Flow Cytometry. e, Huh7 six-hour HCCMF exposure of Huh7 cells results 
in 14.3% increase in fluorescence (p = 0.0089), N =5 per group. f, Huh7 three-hour 
HCCMF results in 72.8% increase in fluorescence (p = 0.0016), N = 6 per group. There 
was no increase in intracellular Ca2+ in the presence of 0.5 mM Ethosuximide (Ethos) (p-
value 0.3872). g, Hep3B three-hour HCCMF exposure of Hep3B cells results in 11.68% 
increase in fluorescence (p = 0.0400), N =11 SHAM & N = 10 HCCMF. All fluorescent 
data was read using a Fluostar fluorescent plate reader (unless otherwise stated i.e. flow 
cytometry) with 485 excitation/520 emission and calcium staining was accomplished 
using the Fluo-4 calcium imaging kit (Molecular Probes). All experiments performed at 
least twice with representative experiments shown. [Student’s one-tailed t-test was used 
to identify statistical significance as Ca2+ influx (directionality) was identified and 
established]. 
 
 

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Figure 5. HCCMF antiproliferative effects on HCC cells and downregulation of CSCs 
are mediated by Cav 3.2 T-type voltage gated calcium channels (CACNA1H). a, Ca2+ 
chelation abrogates AM RF EMF-mediated inhibition of Huh7 cell proliferation. Huh7 cells 
were exposed to either randomly chosen (RCF) or hepatocellular carcinoma-specific 
(HCCMF) AM RF EMF three hours daily for seven days prior to cell proliferation assays 
with tritiated thymidine incorporation. ANOVA followed by Tukey post hoc-test: [Anova: F 
= (3, 20) 8.258, P = 0.0009] showed that proliferation of cells exposed to HCCMF was 
significantly lower than cells exposed to RCF [Post-Hoc Tukey Test p = 0.0023]. b, T-type 
voltage gated calcium channel blockade with ethosuximide abrogates HCCMF inhibition 
of Huh7 cell proliferation. Huh7 cells were exposed to HCCMF three hours daily for seven 
days prior to cell proliferation assays. Huh7 cells not exposed to AM RF EMF (SHAM) 
were used as controls. Experiments were performed in the presence or absence of 
ethosuximide (Ethos). ANOVA followed by Tukey Post Hoc-Test [Anova: F = (3, 36) = 
13.06, P < 0.0001] indicates that only HCCMF block Huh7 cell proliferation [Post-Hoc 
Tukey Test: SHAM vs HCCMF p < 0.0001]. c, Inhibition of cell proliferation by HCCMF in 
Huh7 and Hep3B cells with selective knockdown of Cav 3.1, 3.2 and 3.3 T-type voltage 

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gated calcium channels. The three T-type voltage-gated calcium channels Cav 3.1, Cav 
3.2, and Cav 3.3 were selectively knocked down using siRNA targeting the CACNA1G 
(sh3.1), CACNA1H (sh3.2), and CACNA1I (sh3.3) genes, respectively. CACNA1I (sh3.3) 
expression in Hep3B cells was not detectable by qPCR, as noted in Cav isoform relative 
expression graph, hence knockdown was not attempted. Cell proliferation was assessed 
after exposure to HCCMF three hours daily for seven days. Huh7 data (LEFT): 
shScramble (N=5 for both groups) [Student’s two-tailed T-test p value: 0.0092]; sh3.1 
(N=6 for both groups) [Student’s two tailed t-test p value: < 0.0001]; sh3.2 (N=6 for both 
groups) [Student’s two-tailed t test p value: 0.4948]; Sh3.3 (N=6 for both groups) 
[Student’s two-tailed t-test p-value: 0.0071]. Hep3B data [46].: shScramble (N=5 for 
SHAM and N=6 for HCCMF) [Student’s two-tailed t-test p-value: 0.0493]; sh3.1 (N=6 for 
SHAM and N=5 for HCCMF) [Student’s two-tailed t-test p-value: 0.0443]; sh3.2 (N=6 for 
both groups) [Student’s two-tailed t-test p-value: 0.1691]. (Lower): Basal expression 
levels of T-type voltage-gated calcium channels isoforms Cav 3.1, Cav 3.2, and Cav 3.3 
in multiple cell lines (RED circles signify targets with no detectable expression via qRT-
PCR). d, Antiproliferative effects of HCCMF on HBV positive HCC cells. Cell proliferation 
was assessed in HCC cells exposed to HCCMF using a [3H] thymidine incorporation 
assay as described before. e, Effect of HCCMF on HCC cancer stem cells. The cancer 
stem cell population of Huh7 (upper panel) and Hep3B (lower panel) cells was assessed 
after one-week exposure to HCCMF. Control cells were not exposed to EMF. The 
population of cancer stem cells was significantly lower following exposure to HCCMF. 
(UPPER PAIR) Huh7 %CSC Data: SHAM (N = 4) and HCCMF (N = 4); [Student’s two-
tailed t-test p-value = 0.0091]. Huh7 Sphere formation: SHAM (N = 5) and HCCMF (N = 
5); [Student’s two-tailed t-test p-value = 0.0011]. (LOWER PAIR) Hep3B %CSC Data: 
SHAM (N = 4) and HCCMF (N = 3); [Student’s two-tailed t-test p value = 0.0091]. Hep3B 
Sphere formation: SHAM (N = 7) and HCCMF (N = 6); [Student’s two-tailed t-test p-value 
= 0.0011]. f, Effect of HCCMF on Cav 3.2 knockdown HCC cancer stem cells. The cancer 
stem cell population of Huh7 Cav3.2 knockdown (upper panel) and Hep3B Cav 3.2 
knockdown (lower panel) cells was assessed after one week of exposure to HCCMF. 
Control cells were not exposed to EMF. The population of cancer stem cells was equal to 
or greater than the control group following exposure to HCCMF. (UPPER) Huh7 Cav 3.2 
knockdown sphere formation: SHAM (N = 5) and HCCMF (N = 5); [Student’s two-tailed t-
test p-value = 0.2364]. (LOWER) Hep3B Cav 3.2 knockdown sphere formation: SHAM (N 
= 6) and HCCMF (N = 7); [Student’s two-tailed t-test p-value = 0.0034]. 
 
 
1.2.9  HCCMF block HCC cancer stem cells 
 

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It has been shown that sorafenib and lenvatinib significantly improve the survival of 
patients with advanced HCC.[6] However, patients invariably develop resistance to both 
agents [6, 7, 47, 48]. There is growing evidence that HCC cancer stem cells (CSCs) are 
responsible for tumor recurrence and resistance to sorafenib [49-51] We have previously 
reported several long-term responses in patients with advanced HCC receiving 
intrabuccally administered AM RF EMF. Specifically, 6 (14.6%) of the 41 patients 
receiving treatment with the TheraBionic device, had an overall survival in excess of 26 
months, one patient was treated continuously for 44.6 months, and one patient was 
treated continuously for 62 months without any evidence of disease progression prior to 
expiring of causes unrelated to her malignancy.[20], [21] One additional off-study patient 
with rapidly progressive disease received continuous treatment with HCCMF for 74 
months prior to expiring with minimal progression of disease (section 1.2.10). These 
unexpectedly long-lasting responses, which have not been observed with the use of either 
sorafenib or lenvatinib [48], led us to test the hypothesis that HCCMF target CSCs as 
therapies affecting CSCs are associated with long-term survival [52]. 
 
We first assessed the anti-proliferative effects of HCCMF on hepatitis B virus (HBV) 
positive cell lines as 53% of HCC cases worldwide are attributable to HBV infection.[53]. 
As shown in Fig. 5d, the proliferation of HBV positive HCC cell lines from patients of Asian 
(HCCLM3 and MHCC97L) and African American (Hep3B) ancestry was effectively 
blocked by HCCMF. Next, we assessed the impact of HCCMF on HBV negative (Huh7) 
and HBV positive (Hep3B) CSCs. As shown on Fig. 5e, exposure to HCCMF led to 57% 
and 38% decreases in Huh7 and Hep3B CSCs (CD44+CD133+) cells, respectively. 
Sphere formation was similarly decreased by 26% and 28% in Huh7 and Hep3B cells, 
respectively. However, in the presence of ethosuximide, there were no changes in CSCs 
or sphere formation in either Huh7 or Hep3B cells demonstrating that inhibition of CSCs 
is also mediated by T-type VGCCs. The experiments were repeated with cells in which 
CACNA1H had been knocked down. As shown in Fig. 5f, knockdown of CACNA1H 
abrogated HCCMF downregulation of CSCs in Huh7 as well as Hep3B cells. 
 
1.2.10    Potential synergy between AM RF EMF tyrosine kinase inhibitors 
 
Figure 6: Long-term response in a patient with metastatic hepatocellular carcinoma 
receiving treatment with HCCMF (a) [22] A 79-year-old man was diagnosed in January 
2011 with hepatitis A and B negative hepatocellular carcinoma. He underwent left 
hepatectomy in February 2011, which revealed the presence of a poorly differentiated 
hepatocellular carcinoma. The tumors largest diameter was 10 cm and was staged as 
pT3NxMx. In May 2011, the patient had evidence of disease progression with four new 

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lesions identified within the right lobe of the liver and new mediastinal adenopathy. 
Chemoembolization with doxorubicin and lipiodol was performed in June 2011. A follow 
up MRI performed in July 2011 showed progression of disease. Treatment with sorafenib 
was initiated in August 2011 when the patient’s performance status was KPS 80%, ECOG 
1 with a Child Pugh of A6. Treatment with sorafenib was discontinued in February 2013 
because of intolerable side effects. Simultaneous compassionate treatment with the 
TheraBionic device was administered 3 hours a day from September 2011 until April 2017 
when the patient became unable to receive treatment on a regular basis because of hip 
fracture secondary to a fall, generalized weakness, and worsening renal failure. He 
passed away in October 2017. The patient had complete response by marker as the level 
of alpha foetal protein (AFP) decreased from 92,620 international units/ml (IU/ml) on 
August 12, 2011 prior to treatment initiation to 4.18 IU/ml on January 16, 2011. Following 
discontinuation of Nexavar in February 2013 the patient’s AFP level remained below 20 
IU/ml until May 2014 when it started to rise slowly and was 553.0 IU/ml in June 2017 prior 
to admission to the hospital for left femur fracture repair. 
 

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The AFP level began to rise more rapidly from the time the patient became unable to 
receive TheraBionic treatment until October 9, 2017, when it reached 2038.0 IU/ml. (b) 
Key imaging studies of the same patient. Imaging studies obtained prior (left panel: July 
2011) and during (Right panel: December 2011) treatment show partial response as 
assessed by RECIST criteria 
 

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2.0 Objectives  
The primary goal of this study is to gather efficacy data concerning the progression-free 
survival rate with EMF + Regorafenib when compared to historical data with Regorafenib 
alone as a second-line therapy in patients with advanced HCC who have received any 
first line systemic therapy either standard of care Sorafenib or Lenvatinib or any 
experimental therapy. Patients who have received any treatment that includes either EMF 
or Regorafenib will be excluded.  
 
2.1 Primary Objective  
 
2.1.1 To estimate progression-free survival rates according to the RECIST 
1.1{Eisenhauer, 2009 #7245} and modified RECIST (mRECIST) for HCC [54] 
 
2.2 Secondary Objectives  
 
 
2.2.1 To obtain information concerning Overall survival-defined as date of enrollment to 
date of death; progression-free survival at 4 months, 6- month survival rate, proportion 
of patients with disease control (complete or partial response or stable disease) 
according to RECIST 1.1 and modified RECIST (mRECIST) for HCC [54]  at 4 and 6 
months, and time to radiologic progression. 
 
2.2.2 To evaluate type, incidence, severity (graded by the National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 5.0), timing, 
seriousness, and relatedness of adverse events and laboratory abnormalities 
  
2.2.3 To evaluate the effect on levels of alpha-fetoprotein.  
 
3.0 Patient Selection  
3.1 Inclusion Criteria  
• Biopsy-proven HCC that is locally advanced or metastatic. Or 
 
• 
Patients without biopsy confirmation are also eligible if they meet the following: 
• 
Radiologic diagnosis of HCC as per the AASLD guidelines: 
• 
–liver cirrhosis AND 

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• 
–a liver mass confirmed by BICR that shows arterial phase hyperenhancement 
on triphasic CT or MRI, AND EITHER: 
• 
Is ≥20 mm with either non-peripheral portal washout or an enhancing capsule 
• 
OR is 10-19 mm with non-peripheral portal venous washout AND an enhancing 
capsule {Marrero, 2018 #302} 
 
• Patients must have been treated with at least one standard systemic treatment modality 
for advanced HCC such as sorafenib, lenvatinib, atezolizumab plus bevacizumab, or 
another approved or experimental systemic therapy prior to study entry.   
• Measurable disease according to RECIST version 1.1{Eisenhauer, 2009 #7245} and 
mRECIST for HCC [54].   
• At least one target lesion should not have previously received any local therapy, such 
as surgery, radiation therapy, hepatic arterial embolization, TACE, hepatic arterial 
infusion, radio-frequency ablation, percutaneous ethanol injection or cryoablation, unless 
it has subsequently progressed by 20% or more according to RECIST version 
1.1{Eisenhauer, 2009 #7245}  and mRECIST for HCC [54].  
• Patients with Child’s Pugh A (at time of enrollment), with compensated cirrhosis, as 
 defined by the parameters contained in the Child Pugh Calculator found in Appendix E 
[55]. 
• Performance status ECOG 0-2  
• Absence of medical or psychiatric contraindication which, in the opinion of the treating     
Investigator, would make the patient’s participation in this trial inappropriate.  
• Patient must not have curative treatment options, including surgery or radiofrequency 
 ablation, available.  
• Any extra-hepatic metastases, including treated CNS metastases but patients cannot 
have leptomeningeal disease.  
• At least 2 weeks must have elapsed since administration of any anti-cancer treatment.  
• Other anti-cancer treatments are not permitted during this study, including alternative 
 medicine and herbal therapies.  
• Patients must be 18+ years old and must be able to understand and sign an informed 
consent.  
• Patient must agree to be followed up according to the study protocol.  
 
3.2 Exclusion Criteria  
• Known leptomeningeal disease. 
• Fibro lamellar HCC.  
• Patients who had surgical resection of the disease and who do not have measurable 
disease.  

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• Patients with any of the following history within the 12 months prior to study drug 
administration: severe/unstable angina, myocardial infarction, coronary artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident, including transient 
ischemic attack, or pulmonary embolism.  
• Pregnant or breastfeeding women  
• Patients diagnosed with another type of cancer (excluding basal cell carcinoma) whose 
cancer diagnosed previously is not in remission.  
• Patients receiving calcium channel blockers and any agent blocking L-type or T-type 
Voltage Gated Calcium Channels, e.g. amlodipine, nifedipine, ethosuximide, etc. are not 
allowed in the study unless their medical treatment is modified to exclude calcium 
channel blockers prior to enrollment. (Refer to Appendix F for a complete list of 
excluded medications and/or pathways). 
• Patients allergic or intolerant to Sorafenib. 
 
3.3 Inclusion of Women and Minorities 
Men and women of all races and ethnicities who meet the above-described eligibility 
criteria are eligible to participate in this study.  
The study consent form will also be provided in Spanish for Spanish-speaking 
participants. Based on CCCWFU population estimates, we expect approximately 40% of 
participants to be women. We do not expect the percentage of Hispanic/Latino or racial 
minority cancer patients eligible for this study to be higher than the percentage of Hispanic 
or racial minority new cancer patients seen at CCCWFU (1.7% and 14.4%, respectively).  
Should we not meet or exceed these estimates, the PI will engage the Cancer Center 
Health Equity Advisory Group to discuss strategies to enhance recruitment in these target 
populations.  
 
3.4 Life Style Guidelines  
 
Female patients must be surgically sterile or be postmenopausal, or must agree to use 
adequate contraception during the period of therapy. Male patients must be surgically 
sterile, or must agree to use adequate contraception during the period of therapy. 
Adequate contraception is defined as double barrier contraception (i.e., condom plus 
spermicide in combination with a female condom, diaphragm, cervical cap or intrauterine 
device). List of adequate contraceptives in accordance with local regulations may be 
reported in the patient’s Informed Consent Document.  
If a female patient becomes pregnant while on therapy, treatment will stop immediately. 
The patient will be assisted by the investigator physician during her pregnancy. If the 
outcome of the pregnancy meets the criteria for immediate classification as a serious 

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adverse event, i.e. spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
(including that in an aborted fetus, stillbirth or neonatal death), the investigator should 
follow the procedures for reporting serious adverse events.  
In the case of a live birth, the “normality” of the newborn can be assessed at the time of 
birth. The “normality” of an aborted fetus can be assessed by gross visual inspection, 
unless pre- abortion test findings are suggestive of a congenital anomaly.  
Additional information about pregnancy outcomes that are classified as serious adverse 
events follows: “Spontaneous abortion” includes miscarriage and missed abortion. All 
neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the exposure in utero to the investigational 
treatment should be reported. Further follow-up of birth outcomes will be handled on a 
case-by-case basis (eg.. follow-up on preterm infants to identify developmental delays) 
4.0 Registration Procedures 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer 
control trial, must be linked to the study in EPIC within 24 hours of Informed Consent. 
Patients must be registered prior to the initiation of treatment.   
 
You must perform the following steps in order to ensure prompt registration of your 
patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix B) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed 
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, 
either by fax or e-mail. 
 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 

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Note: If labs were performed at an outside institution, provide a printout of the 
results. Ensure that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will:   
 
• assign a patient study number 
• assign the patient a dose 
• other appropriate actions 
• register the patient on the study 
5.0 Study Outcomes and Study Measures  
5.1. Primary Outcome  
Primary outcome is progression-free survival. This measure will be assessed throughout 
the trial. 
 
5.2 Secondary Outcomes  
5.2.1 Overall survival defined as date of enrollment to date of death; progression-free 
survival at 4 months, 6- month survival rate, proportion of patients with disease control 
(complete or partial response or stable disease) according to the modified RECIST 
(mRECIST) for HCC [54] at 4 and 6 months, and time to radiologic progression using 
standard RECIST v1.1 criteria. 
5.2.2 Type, incidence, severity (graded by the National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE], version 5.0), timing, 
seriousness, and relatedness of adverse events and laboratory abnormalities 
5.2.3 Alfa-fetoprotein levels.  
 
 

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6.0 Study-Related Activities 
 
Pre- 
Study a 
 
Baseline 
 
Phone call 
 
Clinic Visit  
 
Imaging 
End of 
Treatment 
Visit 
Long Term 
Follow Up 
 
 
(Cycle 1, Day 
1) 
(Cycle 1, day 
15) 
Week 5 and on 
the first day of 
subsequent 
cycles 
Week 7 & 
every 6 weeks 
thereafter 
Within 30 days of 
withdrawal or 
progression 
 
 
 
Week 1 
Week 3 
Week 5 
Week 7 
At 
progression 
 
Informed Consent 
X 
 
 
 
 
 
 
Baseline Documentation 
X 
 
 
 
 
 
 
Regorafenib 
 
X 
 
X 
 
 
 
Concomitant Medications 
and Treatments 
 
X 
 
 
 
 
 
X 
 
Pre-Toxicity 
X 
 
 
 
 
 
 
Medical/Oncologic History 
and Demographics 
 
X 
 
 
 
 
 
 
 
Physical Examination, 
including oral exam 
 
X 
X 
 
X 
X 
 
X 
 
Hematology and  
Blood Chemistry including 
Alpha-feto protein d 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Coagulation 
X 
 
 
 
 
X 
 
Pregnancy Test b 
X 
 
 
X 
 
X 
 
Correlative Blood Studies 
X 
 
 
 
 
X 
 
dynamic multiphase 
contrast-enhanced CT/MRI 
Scan h 
X 
 
 
 
X 
 
 
ECOG PS, body weight, 
and vital signs 
X 
 
 
X 
 
 
 
Bone Scan f 
X 
 
 
 
X 
 
 
Adverse Events Signs and 
Symptoms 
 
 
X 
 
 X 
X 
X 
X 
 
Treatment Compliance 
Diaryc 
 
 
 
X 
X 
 
 
X 
 
Device Reconciliation Form 
 
 
X 
X 
 
X 
 
Post-Study Anticancer 
Treatment g 
 
 
 
 
 
X 
 
X 
Post-Study Survival Status 
g 
 
 
 
 
 
X 
X 
EMF e  
 
X 
 
X 
 
 
 
a  Pre-study requirements listed in table must be completed within 14 days prior to treatment initiation with the exception of 
hematology and blood chemistry and pregnancy test which should be performed with 7 days prior to treatment initiation. 

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6.1 Description of Procedures  
 
Screening and Consent  
• The screening period is planned to last a maximum of 14 days prior to treatment 
initiation. All study procedures necessary for patient selection, determination of 
eligibility and treatment initiation should be performed within this period unless 
otherwise indicated.  
• Informed Consent must be obtained prior to undergoing any study procedure and 
should occur prior to the 14-day screening period. Pre-Study Assessments.  
• Medical/Oncology History and Demographics should include age, race, sex, hepatitis 
virus exposure, Child-Pugh score, Barcelona score (BLCL), CLIP score, 
information on prior cancer treatments, and histological diagnosis of HCC by 
previous or recent biopsy.  
• Concomitant medications and treatments and the amount per day will be recorded at 
registration.  
• Baseline Signs and Symptoms will include any signs or symptoms experienced within 
the past 14 days. Assessment of symptoms and symptom intensity will be per the 
National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0  
• Physical Examination should include examination of major body systems, body weight, 
height, abdominal diameter, ECOG performance status, and vital signs 
(temperature, blood pressure, resting heart rate, respiratory rate) and an intraoral 
examination.   
• Hematology and blood chemistry should include CBC with WBC differential count, 
platelet count, sodium, potassium, BUN, creatinine, fasting glucose, bilirubin 
(direct and indirect), transaminases (ASAT and ALAT), LDH, alkaline 
b  Serum pregnancy test (women of childbearing potential) + 7 days prior to treatment initiation 
c  All patients included in this study will be evaluated by a research nurse in order to monitor treatment compliance using a 
specific device as described in section 7.1., and conduct an initial assessment of symptoms and symptom intensity as per the 
National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0 
d  Hematology and blood chemistry should include CBC with WBC differential count, platelet count, sodium, potassium, BUN, 
creatinine, fasting glucose, bilirubin (direct and indirect), transaminases (ASAT and ALAT), LDH, alkaline phosphatase, gamma 
glutamyl transferase, albumin, PT and INR, AFP, and hepatitis B and C serology. Hematology and blood chemistry screening 
assessment is required within 7 days prior to the start of study treatment as is standard of care.  
e  At baseline visit, subject will receive device education, first 60 minute treatment, and be provided with treatment logs. 
f   Bone scan will be required only in case of clinical suspicion of central nervous system metastases or bone metastases at 
screening or subsequently. 
g  Post-Study Survival Status will be recorded after discontinuation of study treatment Any new post-study anticancer treatment 
will be recorded. This data will be collected by clinic visit or telephone contact approximately every 2 months until one year after 
end of treatment visit or death. 
h   Brain MRI/CT will be required only in case of clinical suspicion of central nervous system metastases or bone metastases at 
screening or subsequently. 

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phosphatase, gamma glutamyl transferase, albumin, PT and INR, AFP, and 
hepatitis B and C serology. Hematology and blood chemistry screening 
assessment is required within 7 days prior to the start of study treatment.  
• Pregnancy Test (Serum or Urine) is mandatory for women of reproductive potential and 
must be tested within 7 days prior to the start of study treatment.  
• Correlative blood tests will involve collection of 8.5 ml blood draw volumes from each 
patient. The blood samples will be collected into PAXgene Blood DNA Tubes 
(Qiagen) containing a proprietary blend of reagents that both prevents blood 
coagulation and stabilizes genomic DNA in white blood cells. The tubes are 
identified by a blue Hemogard stopper. Samples will be collected and transported 
at room temperature then refrigerated within 24 hours of collection. Samples will 
transported by study staff to the Pasche lab, NRC, 441. Samples may be stored at 
2-8° C refrigeration for 1-7 days, then moved to -80° C for longer storage as 
needed for batch DNA processing.  
• 
Tumor Imaging is required within 30 days of treatment initiation and will include 
dynamic multiphase contrast-enhanced CT with intravenous contrast abdomen, 
and pelvis, and other applicable sites of disease. If the evaluation by CT-scan does 
not highlight the lesions in a sufficiently clear way, magnetic resonance imaging 
studies (MRI) must be obtained within 30 days of treatment initiation. In this case, 
only MRI studies will be performed to evaluate changes in target lesions.  
• 
Brain CT or MRI Scan and Bone scan will be required only in case of clinical 
suspicion of central nervous system metastases or bone metastases at screening 
or subsequently.  
 
During Treatment  
• All assessments should be performed prior to cycle initiation unless otherwise indicated. 
Acceptable time window for performing each assessment is considered a maximum of 3 
(three) days. 
 
• Physical Examination should be performed on Day 1 of each cycle. This assessment 
should include examination of major body systems, ECOG performance status, 
body weight, abdominal diameter, and vital signs (temperature, blood pressure, 
heart rate, respiratory rate) and an intraoral examination.  
• Hematology and blood chemistry assessments should include: CBC with WBC 
differential, platelets, sodium, potassium, urea, creatinine, fasting glucose, bilirubin 
(direct and indirect), transaminases (ASAT and ALAT), LDH, alkaline 
phosphatase, gamma glutamyl transferase, albumin, PT and INR, and AFP.  
• For Cycle 1 Day 1, Hematology and blood chemistry assessments are not required if 

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acceptable screening assessment is performed within 7 days prior to the start of 
treatment with study treatment.  
• For the subsequent assessments, Day 1 acceptable assessment time window for 
hematology and blood chemistry is considered a maximum of 3 (three) days prior 
to starting each treatment follow-up visit.  
• 
Tumor Imaging will include dynamic multiphase contrast-enhanced CT or MRI 
scans of the chest, abdomen, and pelvis, and other applicable sites of disease, 
performed every 6 weeks during the study. The schedule of assessments should 
be fixed according to the calendar, regardless of treatment delays. Allowable time 
windows for on study tumor assessments are ±7 days.  
• Adverse Events must be followed from the first day of study treatment until at least 28 
days after the last on-study treatment administration, or until all serious or study 
treatment-related toxicities have resolved or are determined to be “chronic” or 
“stable,” whichever is later. Serious adverse events should be monitored and 
reported as described in the protocol.  
Baseline tumor-related signs and symptoms will be recorded as adverse events during 
the trial if they worsen in severity or increase in frequency.  
• At the beginning of each treatment cycle (Day 1) and at the completion of therapy, 
accountability and compliance will be verified and documented in CRF or other 
appropriate documents  
• Concomitant medications and treatments will be recorded at study entry and during the 
study. At the end of  the study and at follow-up  
• End of Treatment Visit- Device/Withdrawal assessment should be obtained during the 
last week on study or within 30 days from the patient’s exclusion date. This assessment 
should include: Physical Examination, including examination of major body systems, 
ECOG performance status, body weight, abdominal diameter, and vital signs 
(temperature, blood pressure, heart rate, respiratory rate).Signs and Symptoms as per 
the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 5.0. 
Concomitant medications and treatments should be recorded for 28 days or until all study 
treatment-related toxicities have resolved, whichever is later. 
• Post-Study Survival Status will be recorded after discontinuation of study treatment and 
any new post-study anticancer treatment will be recorded and post-study survival status 
will be collected by clinic visit or telephone contact approximately every 2 months until 
one year after end of treatment visit or death.  
 
6.2 Treatment with Regorafenib 
 
Patients will receive 160 mg regorafenib (four 40 mg tablets) orally once daily for the first 

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3 weeks of each 4-week cycle per approved prescribing information. Patients may 
continue on this schedule until they withdraw or experience progression. 
 
6.3 Treatment With TheraBionic 
 
Amplitude-modulated electromagnetic fields will be self-administered and given 
continuously to patients in three courses of 60-minute treatments per day, administered 
in the morning, at noon and in the evening at the patient's home, with the exception of the 
first 60-minute treatment, which will be delivered at the research site. Each 4 week 
treatment period will be considered a cycle of treatment.  
 
6.3.1 Selection of frequencies  
 
HCC-specific frequencies were identified by Barbault and Pasche using the methods 
described in section 1.2.4 and 1.2.5. These frequencies have previously been shown to 
block HCC in vitro,[36] [22] in vivo,[22] as well as in patients with advanced HCC as a 
single anticancer modality [20] and in combination with a tyrosine kinase inhibitor. 
 
6.3.2 Use of the TheraBionic P1 device  
 
Instructions for patient use: The patients included in the study will receive the TheraBionic 
P1 device free of charge for home use as well as the accompanying instructions manual. 
The device will be programmed with HCC-specific modulation frequencies and will be 
activated for more than 200 one-hour treatment sessions. 
 
Prior to treatment initiation the study coordinator for the study will recharge the device’s 
batteries for 24 h as described in section 4.2, page 14 of the User Manual (TheraBionic 
P1 User Manual, IFU_TheraBionic_P1_USEN_rev07_2018-06-20n). The exact number 
of HOURS:MINUTES available prior to administration of the first treatment will be 
documented and constitute the pre-treatment baseline. The total number of 
HOURS:MINUTES appears on the TheraBionic P1 device display after the device is 
switched on as shown in section 4.6, page 21 of the Instruction Manual and on the 
TheraBionic.com web site: . https://www.therabionic.com/use-of-the-therabionic-p1/.  
 
6.3.3 Treatment location  
 
With the exception of the first 60-minute treatment, which will be delivered at the clinic, 
all other treatments will be self-administered at the patient's home. Each treatment day 

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with consists of three courses of 60-minute treatments per day, administered in the 
morning, at noon and in the evening. It is not necessary to keep rigid treatment schedules. 
However, it is recommended to keep schedules consistent over time. Each treatment 
should be delivered without interruption. Each 4 week treatment period will be considered 
a cycle of treatment, similar to each regorafenib treatment cycle. 
 
6.3.4 Treatment interruption  
 
Treatment will be allowed to be interrupted temporarily in case of:  
• 
Limited toxicity  
• 
Potentially reversible clinical condition, which temporally prevents continuation of 
treatment, e.g. gastrointestinal bleeding.  
• 
Hospitalization that prevents continuation of treatment.  
• 
Technical problems related to the TheraBionic P1 device until replacement of a 
new TheraBionic P1 device. Treatment should be restarted, without modification 
in the above described treatment plan, if treatment was interrupted for at most 21 
days. In case of any treatment interruption of longer duration, the patient should 
be excluded from the study.  
 
6.3.5 Treatment compliance  
At each visit treatment compliance will be assessed by the research nurse. Patients will 
be asked how many treatments per day they received, and whether or not they 
completed treatment sessions. Treatment compliance will be further determined by 
determining the number of HOURS:MINUTES at each return visit. The total treatment 
time between clinic visit will be the difference in HOURS:MINUTES displayed by the 
device.  
 
If any technical problem related to the TheraBionic P1 device is suspected, a new 
TheraBionic P1 device programmed with the same treatment the patient is currently using 
will promptly replace the TheraBionic P1 device. 
  
If a lack of compliance is identified, the investigator will make every reasonable effort to 
keep the patient on therapy. The patient should be re-oriented how to use the device. The 
patient should be oriented that the re-incidence of lack of compliance will require the 
patient cease treatment. If the patient desires not to continue on therapy, the patient will 
be removed from the study protocol.  
 

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6.4 General Concomitant Medication and Supportive Care Guidelines  
 
No other experimental therapy may be used on this protocol. Simultaneous participation 
in another clinical treatment study protocol is not allowed. Additionally, as indicated 
above, the use of calcium channel blockers and any agent that could block calcium 
channels is strictly prohibited as there is in vitro evidence that calcium channel blockers 
antagonize the anticancer effect of AM RF EMF.  
 
External beam radiotherapy will be permitted during the study period only for palliative 
indication, i.e. symptomatic control, if it does not treat all target lesions. Any form of 
radiotherapy to the hepatic parenchyma (external or internal) will not be permitted during 
the study period.  
 
Concomitant loco-regional treatment, such as TACE, ethanol injection, microwave 
ablation, etc. is not allowed while on the study period.  
 
If a patient, while on the study period, receives any concomitant treatment not allowed in 
this protocol, the patient should come off study as a protocol violation.  
Anti-inflammatory or narcotic analgesics may be offered as needed. Packed red blood 
cell and platelet transfusions may be administered as clinically indicated. Prophylactic 
use of hematopoietic growth factors to support neutrophil or platelet counts may be used 
at the discretion of the treating Investigator. Patients may be supported with appropriate 
hormone replacement therapy in the event they develop adrenal or thyroid insufficiency 
in the absence of disease progression or unacceptable treatment-associated toxicity.  
 
Medications considered necessary for the patient's well-being may be given at the 
discretion of the investigator, i.e., chronic treatments for concomitant medical conditions, 
as well as agents required for life-threatening medical problems, etc. Patients should be 
advised to contact the physician before starting any new drug. All concomitant 
medications will be recorded on the appropriate CRF page.  
 
6.5 Duration of Therapy  
 
The Investigator will make every reasonable effort to keep each patient on their study 
treatment, unless it is in the patient’s best interest to discontinue from study treatment. 
Patients in the study will be removed from study intervention in the following situations:  
• 
If they received less than 50% of the prescribed AM RF EMF treatments at two 
consecutive visits (total of 16 weeks) as assessed by patient’s report and 

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confirmed by objective measurement of treatment compliance.  
• 
If they lost or damaged the equipment provided for this study due to a lack of care.  
• 
If they do not adhere to the treatment protocol and or planned protocol procedures.  
• 
If there is evidence of radiological progression of disease.  
• 
If the patients receive concomitant anti-tumor treatment (chemoembolization or 
tumor ablation by means of radiofrequencies, chemotherapy or any other 
anticancer agent) not allowed during the study period.  
• 
If they voluntarily withdraw informed consent.  
• 
If the physician responsible for the study decides to stop the treatment for medical 
reasons.  
• 
If the treatment is temporally interrupted for more than 21 days in a row.  
• 
In the instance of unacceptable toxicity or if the same serious adverse event recurs 
following resumption of treatment.  
• 
If the patient dies.  
• 
If the patient was unable to complete at least 4 weeks of therapy from the date of 
enrollment. 
6.5.1 Concomitant therapy exclusion  
 
If a patient, while on treatment, needs palliative radiotherapy for metastatic disease for 
symptomatic control without documentation of disease progression; the patient should 
NOT come off study (exception if the radiation is delivered to the only site of measurable 
disease) or discontinue study treatment. Any palliative radiotherapy given during the 
study should be recorded on the appropriate CRF page.  
If a patient, while on treatment, needs palliative surgery, the patient may stop study 
treatment at the discretion of the investigator. There is no need to delay the surgery to 
minimize the risk of impaired wound healing and bleeding. Postoperatively, the decision 
to reinitiate study treatment should be based upon a clinical assessment of satisfactory 
recovery from surgery within 21 days after stopping study treatment. If the timing for 
resuming study treatment is longer than 21 days, the patient should be removed from the 
study.  
 
6.5.2 Inclusion of discontinued patients  
 
All patients removed from the study after having measurement of efficacy performed will 
be considered eligible for the measurement of efficacy and should be evaluated regarding 
the status of disease at the time of exclusion. Those patients in whom measurement of 
efficacy was not performed prior to treatment discontinuation will be censored for 
progression free survival (PFS) and time to progression (TTP) at the date of 

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randomization.  
All patients who signed a consent form and were later removed from the study treatment 
should be classified, at the time of removal, into the following categories:  
• No evidence of disease.  
• Stable disease.  
• Objective response (partial or complete)  
• Progression of disease.  
• Death from other causes, e.g. hepatic failure, gastrointestinal bleeding. 
• Death from tumor progression.  
• Lost to follow up  
• Screen failure  
• Excluded patients classified as progression of disease or death will be considered as 
an event in the study analysis. 
•  Excluded patients classified as screen-failures will not be considered for study analysis. 
All other patients will be included in the analysis.  
 
6.6 Duration of Follow Up  
 
Adverse events monitoring will continue for a minimum of 30 days after removal from 
study or until death, whichever occurs first. Patients removed from study for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event.  
After discontinuation of study treatment and the mandated 30-day follow-up period, 
patients will be followed by phone every 2 months in order to collect information on further 
anti-tumor therapy and survival. Patients will be followed until death. Patients who 
discontinue study treatment without documented evidence of radiologic disease 
progression should continue tumor imaging and quality of life assessment at the same 
frequency until disease progression, or initiation of another anticancer treatment, 
whichever is earlier.  
 
 
 
 
 
 
7.0  Dosing Delays/Dose Modifications 

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7.1 TheraBionic Device 
7.1.1 There will be no dose modifications of the device. If the device 
causes severe or unwanted DLTs that cannot be tolerated by the 
patient, the patient will be removed from the study.   
 
7.2  Regorafenib 
7.2.1 The recommended daily dose of Regorafenib is 160 mg orally 
every day (qd) on days 1-21 of 28-day cycle (i.e. 3 weeks on, 1 
week off) 
7.2.2 Concomitant strong CYP3A4 inducers 
7.2.3 Management of suspected adverse drug reactions may require a 
dose reduction of Regorafenib. If dose modifications are required, 
reduce the dose in 40-mg (1 tablet) increments, the lowest 
recommended daily dose is 80 mg.  
7.2.4 If treatment with regorafenib is stopped for any reason, treatment 
with the TheraBionic device should continue as long as the patient 
is tolerating the AM RF EMF treatment. 
 
 

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8.0  Measurement of Effect - Radiological assessment  
Assessment will be made by independent radiologic review using RECIST version 1.1 
and mRECIST for HCC. 
 
8.1 Antitumor Effect-Solid Tumors 
Disease progression and response to treatment will be assessed using RECIST version 
1.1. and mRECIST for HCC [54] and response will be assessed using standard RECIST 
1.1 criteria and mRECIST for HCC.T 
 
 
For the purposes of this study, patients should be reevaluated for response every 6 
weeks.  
 
8.2 Definitions for RECIST 1.1 
Definitions 
At baseline, tumour lesions/lymph nodes will be categorised measurable or non-
measurable as follows: 
 
Measurable 
Tumour lesions: Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
 

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• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
8.3 Definitions for mRECIST 
• 
To be selected as a target lesion using mRECIST, an HCC lesion should meet all 
the following criteria:  
• 
The lesion can be classified as a RECIST measurable lesion (i.e., the lesion can 
be accurately measured in at least one dimension as 1 cm or more). 
• 
The lesion is suitable for repeat measurement. 
• 
The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or 
MRI. 
  
It is important to point out that only well-delineated, arterially enhancing lesions can 
be selected as target lesions for mRECIST. This may not be the case of infiltrative-
type HCC. Infiltrative-type HCC should be considered as a nontarget lesion when the 
mass shows ill-defined borders and therefore does not appear to be suitable for 
accurate and repeat measurements. HCC lesions previously treated with locoregional 
or systemic treatments may or may not be considered as suitable to be selected as 
target lesions for mRECIST: if the lesion shows a well-delineated area of viable 
(contrast enhancement in the arterial phase) tumor that is at least 1 cm in longest 
diameter, then it can be selected as a target lesion. In contrast, if the lesion is poorly 
demarcated or exhibits atypical enhancement as a result of the previous intervention, 
then it cannot be selected as a target lesion for mRECIST. 
 

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8.4 Methods for Evaluation of Measurable Disease 
 
Response Criteria for RECIST version 1.1 and mRECIST 
 
8.5 Evaluation of Best Overall Response  
 
The best overall response should be confirmed within 6 weeks with follow-up radiological 
assessment. The confirmation criteria described below will be applied:  
The serologic marker alpha-fetoprotein (AFP) will not be used primarily to evaluate 
effectiveness. However, pre-treatment and during treatment AFP measurements will be 
collected in all patients and changes in AFP constitute a secondary efficacy end point 
for this study. A rise in AFP will not be used as a criterion for progression of disease. 
 
8.6 Disease control 
 
Disease control will be defined as the percentage of patients who are alive and have 
documented response status of CR, PR or SD at 4 month and 6 months from the date of 
enrollment.  
 
Best early response  
(not yet confirmed)  
Best late response 
(confirmed)  
Best overall response  
CR  
CR  
CR   
CR  
No CR or not available  
SD  
PR  
CR or PR  
PR  
PR  
SD or PD or not available   
SD  
SD  
Not applicable  
SD  
PD  
Not applicable  
PD   

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8.7 Tumor progression  
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded on study).  
The duration of overall complete response is measured from the time measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented.  
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
 
8.8 Time to progression (TTP) 
 
Time-to-radiological progression assessment will be recorded in days and will represent 
the period starting at the date of enrollment date and finishing at the date of radiological 
assessment documenting tumor progression. Patients who initiate post-study anti-cancer 
therapy or die without documented progression will be censored at that time point.  
 
8.9 Survival Outcomes  
 
Overall survival assessment will be recorded in days and will represent the period starting 
at the date of randomization and finishing at the date of patient death. Living patients at 
the time of analysis will have the date of last contact (consultation visit or phone contact) 
used to define overall survival.  
Progression-free survival assessment will be recorded in days and will represent the 
period starting at the date of enrollment and finishing at the later of the date of 
documentation of radiologic tumor progression, date of last follow-up on study treatment 
or death, whichever comes first. Patients who initiate post-study anti-tumor therapy prior 
to radiologic progression will be censored for PFS at that date. 

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9.0 Adverse Events List and Reporting Requirements  
9.1 Potential toxicity  
The TheraBionic P1 device is a low risk device as it emits and results in the absorption 
of levels of radiowaves that are more than ten times lower than those of cellphones. The 
only known risks are irritation of the tongue, fatigue, and increased dreaming. 
Only minor adverse effects were observed in two studies of AM RF EMF in patients with 
cancer [16]. Four of the 69 (5.8%) patients enrolled in these two studies had grade 1 
somnolence after treatment and 1 had grade 1 mucositis (1.4%). There were no grade 
2, 3, or 4 toxicities in any patient, even among very long-term users. No changes in 
complete blood count, kidney function, or hepatic function were observed in any patient. 
Post Marketing Clinical Follow Up (PMCF) data collected since European Regulatory 
Approval have not revealed any additional adverse events (data on file, TheraBionic). 
 
9.2 Adverse Events for Regorafenib 
 
Based on the RESORCE study [8], the following AE’s were reported and could 
reasonably be expected in the current study: 

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9.3 Adverse Event Characteristics  
• 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov).  
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ for expedited reporting 
purposes only.  
• 
Attribution of the AE:  
  
 
-  Definite – The AE is clearly related to the study treatment.  

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-  Probable – The AE is likely related to the study treatment.  
  
 
-  Possible – The AE may be related to the study treatment.  
  
 
-  Unlikely – The AE is doubtfully related to the study treatment.  
  
 
-  Unrelated – The AE is clearly NOT related to the study treatment.  
 
9.4 DSMC SAE Reporting Requirements  
The Data and Safety Monitoring Committee (DSMC) is responsible for reviewing SAEs 
for WFBCCC Institutional studies as outlined in Appendix D. All Adverse Events that occur 
during protocol intervention and are coded as either 1) unexpected grade 4, 2) unplanned 
inpatient hospitalization > 24 hours (regardless of grade), or grade 5 (death) must be reported 
to the DSMC using the using the SAE console in WISER. All WFBCCC Clinical Protocol and 
Data Management (CPDM) staff members assisting a Principal Investigator in 
investigating, documenting and reporting an SAE qualifying for DSMC reporting are 
responsible for informing a clinical member of the DSMC as well as the entire 
committee via the email notification procedure of the occurrence of an SAE.  
 
9.5 WFUHS IRB AE Reporting Requirements  
Any unanticipated problems involving risks to subjects or others and adverse events shall 
be promptly reported to the IRB, according to institutional policy. Reporting to the IRB is 
required regardless of the funding source, study sponsor, or whether the event involves 
an investigational or marketed drug, biologic or device. Reportable events are not limited 
to physical injury, but include psychological, economic and social harm. Reportable 
events may arise as a result of drugs, biological agents, devices, procedures or other 
interventions, or as a result of questionnaires, surveys, observations or other interactions 
with research subjects.  
All members of the research team are responsible for the appropriate reporting to the IRB 
and other applicable parties of unanticipated problems involving risk to subjects or others. 
The Principal Investigator, however, is ultimately responsible for ensuring the prompt 
reporting of unanticipated problems involving risk to subjects or others to the IRB. The 
Principal Investigator is also responsible for ensuring that all reported unanticipated risks 
to subjects and others which they receive are reviewed to determine whether the report 
represents a change in the risks and/or benefits to study participants, and whether any 
changes in the informed consent, protocol or other study-related documents are required.  
Any unanticipated problems involving risks to subjects or others occurring at a site where 
the study has been approved by the WFUHS IRB (internal events) must be reported to 
the WFUHS IRB within 7 calendar days of the investigator or other members of the study 
team becoming aware of the event.  
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external events) 

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must be reported to the WFUHS IRB within 7 calendar days of the investigator or other 
members of the study team becoming aware of the event.  
Any event, incident, experience, or outcome that alters the risk versus potential benefit of 
the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects.  
 
9.6 Sponsor Reporting Requirements  
All serious adverse events will be reported by the investigator to Therabionic Inc. and 
Bayer within 24 h of the occurrence:  
 
Therabionic Inc. 
 Phone: 1-312-286-4703  
 
 Fax: 1-312-342-0578  
 
Bayer HealthCare Pharmaceuticals Inc, Phone: 1-888-842-2937.  
 
In the rare event that the investigator does not become aware of the occurrence of a 
serious adverse event immediately (e.g., if an outpatient study subject initially seeks 
treatment elsewhere), the investigator is to report the event within 24 hours after learning 
of it and document the time of his/her first awareness of the adverse event.  
For all serious adverse events, the investigator is obligated to pursue and provide 
information to Therabionic Inc. and Bayer in accordance with the timeframes for reporting 
specified above. In addition, an investigator may be requested by Therabionic Inc. and or 
Bayer to obtain specific additional follow-up information in an expedited fashion. This 
information may be more detailed than that captured on the adverse event case report 
form. In general, this will include a description of the adverse event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject death, 
a summary of available autopsy findings must be submitted as soon as possible to 
Therabionic Inc. or its designated representative.  
 
9.6.1.  Conflict of Interest Management Plan Summary 
Dr. Richard Zellars, Professor and Chair at the Indiana University 
Comprehensive Cancer Center, will be appointed as an independent 
member on the Cancer Center’s Safety and Toxicity Reporting Committee, 
and will provide data oversight by reviewing the adverse events and 
assessment of the relationship with study drug/device prior to data 
submission to Bayer Healthcare.  If Dr. Zellars expresses concerns about 

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the safety data he will report his concerns to Dr. Blackstock, and Dr. 
Blackstock will promptly notify the COI Office.  These concerns will be 
elevated to the I-CIRC. 
Dr. Stefan Grant, a member of the Cancer Center’s Safety and Toxicity 
Reporting Committee, has a financial interest in the investigational device 
and will recuse himself from all adverse event assessments related to this 
study. 
 
10.0 Pharmaceutical Information  
A list of the adverse events and potential risks associated with the TheraBionic device 
and the regorafenib administered in this study can be found in Section 9.0. 
 
10.1 Device Programming and treatment accountability 
A description of the adverse events and potential risks associated with the device 
administered in this study can be found in Section 9.1. 
 
10.1.1 Programming  
The generator of amplitude-modulated electromagnetic fields consists of a 
battery-driven radiofrequency (RF) electromagnetic field (EMF) generator 
connected to a 1.2 m long 50 Ohm coaxial cable with a medical grade 316 
stainless steel spoon-shaped mouthpiece connected via an impedance 
transformer. The RF source of the device corresponds to a linear amplifier 
operating at 27.12 MHz. The carrier frequency is amplitude modulated with 
a modulation depth of 85%. The resolution of the modulation frequencies is 
2-24 (59.6*10-9 in decimal). The output signal is in its entirety synthesized 
by a Field-Programmable Gate Array (FPGA). The treatment sequence is 
controlled by a microcontroller (Atmel XMega643U), i.e. duration of session, 
sequence of modulation frequencies and duration of each sequence are 
programmed individually during the manufacturing process just before 
shipment. The RF output is adjusted to 100 mW into a 50 Ohm load, which 
results in an emitting power identical to the OncoBionic P1 device and that 
of a similar device previously used for the treatment of patients with 
insomnia on several hundred patients and healthy volunteers. An activation 
card allows a defined number of therapeutic sessions, as prescribed by the 
physician. The docking station has a chip card reader for the activation card 
as well as a RS-232 interface for monitoring treatment for use by the 

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physician’s office. The power supply for the docking station is an external 
wall-cube type power supply. The device is built in compliance with 
European EN ISO 13485:2016 guidelines, and the essential requirements 
of Annex 1 of the Medical Device Directives MDD 93/42/EEC 
 
10.1.2 Accountability 
Each device monitors the number and the total duration of treatments 
administered, which will be checked by reading the device display.  The 
device is not FDA approved for the treatment of cancer in the United 
States, but deemed a low risk device [56]. 
 
10.2 AM RF EMF Device (TheraBionic® P1 Device) 
 
 
Product description:  The device consists of a battery-driven 
radiofrequency electromagnetic field generator connected to a 1.2 
meter long coaxial cable, to the other end of which a spoon-shaped 
mouth piece made of steel is connected with the inner conductor. 
 
Spoon antenna cleaning  The cable with the spoon-shaped 
electrode comes into contact with the healthy oral mucosa. As such 
the spoon-shaped electrode and its holder need to be cleaned with 
the appropriate agents. It should be cleaned with soap and rinsed 
under running water between treatments. If desired, the patient 
spoon can be wiped with an alcohol swab (70% isopropanol or 70% 
ethanol). It cannot be used in patients with mucositis, thrush or any 
alteration of the oral mucosa. The spoon-shaped electrode needs 
to be cleaned prior to the first use and regularly cleaned between 
uses. 
 
Storage requirements:  Store all components in the case provided 
between treatment sessions 
 
Route of administration:  The metal mouth spoon antenna is 
placed on the anterior part of the tongue during treatment.  
 
Disposal:  If the device malfunctions, please inform study staff 
immediately. Do not dispose of any component of the device 
 

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10.3 Pharmaceutical Accountability 
 
Regorafenib is commercially available. 
10.4 Regorafenib (STIVARGA) 
 
 
Product description:  Stivarga is a 40 mg, light pink, oval-shaped, film-
coated tablet, debossed with ‘BAYER’ on one side and ‘40’ on the other 
side. 
 
Storage requirements: Store at a controlled room temperature of 25 
degrees C (77 degrees F), with excursions permitted between 15 and 30 
degrees C (59 and 86 degrees F). Store in original bottle, do not remove 
desiccant, and keep bottle tightly closed.  
 
Stability:  Stable at room temperature. 
 
Route of administration:  Oral 
 
Disposal:  Discard any unused tablets 28 days after opening original 
bottle per local guidelines or per the Wake Forest Baptist Medical Center 
waste stream. 
11.0 Laboratory Correlative Studies  
Blood and tissue samples collected at baseline will be assessed for responders and 
matched non-responders.  
Exome-Seq of germline and hepatocellular carcinoma tissues from exceptional 
responders: Sequence variants associated with HCCMF responsiveness will be 
assessed in both germline (blood) and somatic (tumor) DNA. These experiments will be 
conducted by Drs. Lance Miller and Greg Hawkins, co-directors of the CCC Cancer 
Genomics Core. For germline analysis, 8.5 ml blood draws will be collected from each 
patient at the time of enrollment into PAXgene Blood DNA Tubes (Qiagen) that contain a 
proprietary DNA stabilizing agent and coagulation preventative. Additionally, for total RNA 
isolation, 2.5 mL blood draws will be collected into Paxgene Blood RNA tubes (BD 
biosciences) that contain proprietary reagent for RNA stabilization. Samples will 
transported by study staff to the Pasche lab, NRC, 441. Samples will be transported at 
room temperature then refrigerated within 24 hours of collection. Within 5 days of 
refrigeration, samples will be moved to -80°C storage. DNA extraction from blood sample 

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batches will be performed according to the PAXgene Blood DNA System Kit (Qiagen). 
Total RNA isolation will be performed according to Invitrogen MagMAX for stabilized 
Blood Tubes RNA isolation kit (including miRNA). Pathologist-verified tumor needle core 
biopsies (formalin- fixed and paraffin-embedded at the time of biopsy) will be extracted 
for DNA according to the QIAamp DNA FFPE Tissue Kit (Qiagen). Purified genomic DNA 
will be assessed for quantity and quality on a Qubit Fluorometer (Life Technologies). 
Purified total RNA will be assessed for quantity and quality on EPOCH2 microplate reader 
(BioTek). Indexed DNA libraries will be constructed from 50 ng genomic DNA (Illumina 
Nextera XT library kit). Enriched libraries (Nextera Rapid Capture Expanded Exome kit) 
will be sequenced using 150x150 nt paired end sequencing targeting 30X and 100X 
genomic coverage for germline and tumor DNA, respectively. Samples will be sequenced 
in a multiplex of 10 libraries on the Illumina NextSeq 500 DNA sequencer with the 
expectation of >80% of sequence reads at >Q30 Phred quality scores.  
 
Comparison of exceptional responders versus nonresponders:  
Exome-Seq data will be analyzed by FastQC (Babraham Bioinformatics) to assess 
multiple parameters related to sequence quality and reliability. The ExScalibur suite of 
scalable whole exome sequencing analysis pipelines, designed exclusively for the 
detection of germline and somatic mutations derived from Illumina exome sequence data, 
will be used to profile the spectrum of mutations present in responders and non-
responders. Importantly, the ExScalibur suite does not rely on a single sequence 
alignment or variant calling algorithm, but rather incorporates 3 aligners, 6 germline 
variant callers and 6 somatic mutation callers, then aggregates variants by outputting a 
collective estimate of concordance of all aligner-caller combinations using a simple 
multiplicative score. The average non-silent mutation rate in HCC has been estimated at 
1.3 to 2.5 per Mb of DNA sequenced equating with approximately 60 protein-altering 
mutations, on average, per whole exome sequence. Cumulative results of multiple 
independent whole exome studies indicate that at least 38 genes are significantly 
recurrently mutated (SNVs, indels) in HCC, with 15 additional genomic loci recurrently 
amplified or deleted. In our study, we will define: 1) the comprehensive mutation profile 
(silent, non-silent), and 2) the intrinsic non-silent mutation profile of each patient 
specimen, and evaluate the significance of disproportionality between responders and 
non-responders. We will use a Fisher’s exact test to compare the proportion of changes 
in the two groups. With the relatively small sample size available (n=10 per group) we will 
be able to detect large changes in the loss of driver mutations between groups. For 
instance, we compute 82% power to detect the difference between groups equal to 55% 
(10% change in one group versus 65% in the second group) using a Fisher’s exact test 
with alpha=0.05 (2-sided). In a pre-specified sub analysis intended to control for multiple 

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testing, we will limit significance testing to the previously-discovered 38 driver genes and 
15 genomic loci known to be recurrently mutated in HCC. Genes significant at q<0.05 
after false discovery correction (Benjamini-Hochberg) will be defined as candidate 
effectors of HCCMF efficacy for downstream studies. miRNA (hsa-Let-7g and hsa-miR-
1246) levels will be examined via qRT-PCR (using a Roche Lightcycler II) as potential 
biomarkers of response. miRNAs will be examined over time and compared to baseline 
measurements in both responder and non-responder groups. Significance will be 
assessed via repeated measures mixed models analysis. Group and time will be fixed 
effects and the patients are treated as random effects. A time by group interaction will be 
examined to determine if miRNA levels are different between groups. If time by group 
interaction is found to be significant, mixed models can be fit again stratified by time to 
allow for groups to be compared at individual time points to determine when the observed 
effects become statistically significant. 
12.0 Data Management  
The RED Cap system will be used to prospectively collect the following data:  
• 
Demographic data (age, sex, ethnic status, environmental exposure, habits, origin, 
etc.)  
• 
Personal and family history (association with other diseases, familial risk, etc.)  
• 
Exposure to medications or infections (risk factors related to treatment)  
• 
Tumor features (staging, pathology, evolution)  
• 
Type and duration of previous treatments  
• 
Status of tumor progression prior to study entry  
• 
Laboratory analysis including AFP and correlative studies  
• 
Imaging data analysis collected as per mRECIST.  
• 
Progression-free survival  
• 
Overall survival - REDCap is a free, secure, web-based application for building 
and managing online surveys and databases that can be used for data projects 
spanning multiple institutions. REDCap databases are HIPAA compliant, include 
audit trails, and data is backed up twice daily.  
 
Informed consent document 
EPIC 
Protocol registration form (Appendix B) 
WISER/OnCore 
Off Treatment, Off Study, Survival, and 
Withdrawal forms 
WISER/OnCore 
Best Response 
WISER/OnCore 
Baseline Pre-Toxicity 
Forte EDC 

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Oncologic History 
Forte EDC 
Current Medications 
Forte EDC 
Cycle Tracking 
Forte EDC 
Treatment Response Evaluation 
Forte EDC 
ECOG PS, body weight, and vital signs 
Forte EDC 
Adverse Events 
Forte EDC 
Patient AM RF EMF Diary 
Forte EDC 
Device Reconciliation Form 
Forte EDC 
Alpha-Fetoprotein levels 
Forte EDC 
Post Study Anti-cancer treatment 
Forte EDC 
Disease status at withdrawal 
Forte EDC 
 
This project will also utilize REDCap Clinical Data Interoperability Services. This is a 
special feature for importing data into REDCap from WakeOne. It provides an 
adjudication process whereby REDCap users can approve all incoming data from 
WakeOne before it is officially saved in their REDCap project. REDCap Clinical Data 
Interoperability Services can only be enabled by a REDCap administrator who serves 
as an honest broker to PHI. REDCap’s Clinical Data Interoperability Services can only 
be accessed by users with valid WakeOne credentials. Using the Clinical Data 
Interoperability Service requires using the Medical Record Number (MRN) as a key to 
automatically gather demographics and laboratory data and reduces data entry errors. 
13.0 Statistical Considerations  
13.1 Analysis of Primary Objective  
 
The primary objective of this study is to estimate progression free survival rate and 
compare this with the historical outcomes for patients receiving second line Regorafenib 
(alone). PFS will be estimated along with estimates of 95% confidence intervals for the 
treatment group.  In addition, we will determine the proportion of patients who are 
progression free after 12 weeks (after 2nd 6-week visit) and compare this to the 
proportion of patients that were described as progression free in the RESORCE trial 
using a Simon’s two stage design.  
 
13.2 Analysis of Secondary Objectives  
 
To examine feasibility and compliance data we will assess for each patient the proportion 
of days that they used the AM RF EMF device within recommendations.  We will estimate 
that this proportion and corresponding 95% Clopper-Pearson exact confidence 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
Page 61 of 81 
 
intervals.  Next, for overall survival we will examine Kaplan Meier curves for patients 
survival and also estimate the percent of patients who are alive at 6 months and the 
corresponding 95% Clopper Pearson exact confidence intervals will be calculated.  For 
Disease Control Rates, Objective Response Rates and Response rates we will estimate 
the proportion of patients who respond and the corresponding 95% Clopper Pearson 
exact confidence intervals.   Based on the RESORCE study, the 6-month Disease control 
rates (DCR) were 30% and the Objective Response rates (ORR) were 11%.  Using these 
values, we will compare the observed DCRs and ORRs from this study to those fixed 
values using one-sample exact binomial tests.  Patients who are removed from study 
before the 6-month time point will be considered to not have disease control at that time 
point.  
 
Descriptive statistics will be estimated for the treatment group for each of the categorical 
endpoints (see 5.2.2).  
 
Adverse events: Adverse events will be described for each CTL type for this study using 
counts/percent’s.  In addition these adverse events will be compared for each CTL type 
for the treatment group and historical control (from the RESORCE trial), using the Fisher’s 
exact test (two-sided) at level 0.05. These comparisons will be made to compare events 
of grade greater than or equal to 3 between each group.  
 
AFP levels: We will examine whether these is any association between the AFP levels 
(potential biomarker for response) and the objective response observed for each 
patient.  Average AFP levels will be examined over time, and these changes in AFP rates 
after 6 months will be examined for each Response category (CR/PR/SD/PD) and tested 
using a 1-way ANOVA to see if the change in AFP level differs by response category. 
 
13.3 Power and Sample Size  
 
The RESORCE trial reported a median PFS rate of 3.1 months by mRECIST in the 
regorafenib arm of the trial.  Using the survival distribution parameter conversion tool in 
PASS version 13 [57]. We estimated that this would correspond to expecting 54% of 
patients being free of progression at 12 weeks post treatment (46% are expected to 
have progressed).  Using this as our historical PFS rate (54% at 12 weeks), we 
designed a Simon’s two stage design [58] to examine our primary objective.  The null 
hypothesis that the true 12-week PFS rate is 54% will be tested against a one-sided 
alternative. In the first stage, 11 patients will be accrued. If there are six or fewer 
responses in these 11 patients, the study will be stopped. In other words, if there are six 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields 
and Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular 
Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
Protocol Version Date: 06/07/21 
Page 62 of 81 
 
or fewer patients who are not progression free at 12 weeks then the trial will be stopped. 
Otherwise, 14 additional patients will be accrued for a total of 25. The null hypothesis 
will be rejected if 17 or more responses (patients who do not progress after 12 weeks) 
are observed in 25 patients. This design yields a type I error rate of 9.8% and power of 
80% when the true response rate (proportion of patients who do not progress by 12 
weeks) is 75%. 
 
13.4 Interim Analysis  
 
As described above, after 11 patients are accrued an interim analysis will be performed 
to determine the proportion who have progressed within 12 weeks.  If there are 6 or 
fewer responses in these 11 patients, the study will be stopped. In other words, if there 
are six or fewer patients who are not progression free at 12 weeks then the trial will be 
stopped. 
 
13.5 Estimated Accrual Rate  
We anticipate that there will be approximately 25 patients enrolled over the course of 18 
months (1-2 patients per month). This will allow accrual to be completed within 1.5 years.  
 

A P h a s e II St u d y Of  I ntr a b u c all y A d mi ni st er e d A m plit u d e -M o d ul at e d  El e ctr o m a g n eti c Fi el d s a n d 
R e g or af e ni b a s S e c o n d -li n e T h er a p y F or P ati e nt s wit h A d v a n c e d H e p at o c ell ul ar C ar ci n o m a. 
W a k e F or e st B a pti st C o m pr e h e n si v e C a n c er C e nt er  
W F B C C C # 5 5 3 1 9  
 
Pr ot o c ol V er si o n D at e: 0 6 / 07 / 2 1 
P a g e 6 3  of 8 1  
 
 A p p e n di x A – Eli gi bilit y C h e c kli st  
I R B Pr ot o c ol N o.  
W F B C C C Pr ot o c ol N o. 5 5 3 1 9  
St u d y Titl e:  P h a s e II St u d y Of   I ntr a b u c all y A d mi ni st er e d A m plit u d e -M o d ul at e d  El e ctr o m a g n eti c Fi el d s 
a n d R e g or af e ni b a s S e c o n d -li n e T h er a p y F or P ati e nt s wit h A d v a n c e d H e p at o c ell ul ar C ar ci n o m a. 
Pri n ci p a l I n v e sti g at or:  A. Willi a m Bl a c k st o c k , M. D. 
 
I n cl u si o n Crit eri a 
( a s o utli n e d i n st u d y pr ot o c ol) 
Crit eri a 
i s m et 
Crit eri a i s 
N O T m et  
S o ur c e U s e d t o  C o nfir m *  
( Pl e a s e d o c u m e nt d at e s a n d l a b r e s ult s) 
-Bi o p s y -pr o v e n H C C t h at i s l o c all y a d v a n c e d or 
m et a st ati c .   
-P ati e nt s wit h o ut bi o p s y c o nfir m ati o n ar e al s o 
eli gi bl e if t h e y m e et t h e f oll o wi n g:  
R a di ol o gi c di a g n o si s of H C C a s p er t h e A A S L D 
g ui d eli n e s :  
– li v er cirr h o si s A N D 
– a li v er m a s s c o nfir m e d b y BI C R t h at s h o w s 
art eri al p h a s e h y p er e n h a n c e m e nt o n tri p h a si c C T 
or M RI, A N D EI T H E R:  
         I s ≥2 0 m m wit h eit h er n o n-p eri p h er al 
p ort al w a s h o ut or a n e n h a n ci n g c a p s ul e  
         O R i s 1 0 -1 9 m m wit h n o n -p eri p h er al 
p ort al v e n o u s w a s h o ut A N D a n 
e n h a n ci n g c a p s ul e   
 
□ 
□ 
 
P ati e nt s m u st h a v e b e e n tr e at e d wit h at l e a st o n e 
st a n d ar d s y st e mi c tr e at m e nt m o d alit y f or 
a d v a n c e d H C C s u c h a s s or af e ni b, l e n v ati ni b, 
at e z oli z u m a b pl u s b e v a ci z u m a b, or a n ot h er 
a p pr o v e d or e x p eri m e nt al s y st e mi c t h er a p y pri or 
t o st u d y e ntr y. 
□ 
□ 
 
M e a s ur a bl e di s e a s e a c c or di n g t o R E CI S T 1. 1 a n d 
m o difi e d R E CI S T ( m R E CI S T) f or H C C  [5 4 ] 
□ 
□ 
 
At l e a st o n e t ar g et l e si o n s h o ul d n ot h a v e 
pr e vi o u sl y r e c ei v e d a n y l o c al t h er a p y, s u c h a s 
s ur g er y, r a di ati o n t h er a p y, h e p ati c art eri al 
e m b oli z ati o n, T A C E, h e p ati c art eri al i nf u si o n, 
r a di o-fr e q u e n c y a bl ati o n, p er c ut a n e o u s et h a n ol 
i nj e cti o n or cr y o a bl ati o n, u nl e s s it h a s 
s u b s e q u e ntl y pr o gr e s s e d b y 2 0 % or m or e 
a c c or di n g t o R E CI S T 1. 1 a n d m R E CI S T  f or H C C 
□ 
□ 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
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Patients with Child’s Pugh A (at time of enrollment), 
with compensated cirrhosis, as defined by the 
parameters contained in the Child’s Pugh 
Calculator found in Appendix E  
□ 
□ 
 
Performance Status ECOG 0-2 
□ 
□ 
 
Absence of medical or psychiatric contraindication 
which, in the opinion of the treating investigator, 
would make the patient’s participation in this trial 
inappropriate.  
□ 
□ 
 
Patient must not have curative treatment options, 
including surgery and radiofrequency ablation, 
available. 
□ 
□ 
 
Any extra-hepatic metastases, including treated 
CNS metastases but patients cannot have 
leptomeningeal disease. 
□ 
□ 
 
At least 2 weeks must have elapsed since 
administration of any anti-cancer treatment.  
□ 
□ 
 
Other anti-cancer treatments are not permitted 
during this study, including alternative and herbal 
therapies.  
□ 
□ 
 
Patients must be 18+ years old and must be able 
to understand and sign an informed consent. 
□ 
□ 
 
Patient must agree to be followed up according to 
the study protocol. 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Known leptomeningeal disease. 
□ 
□ 
 
Fibro lamellar HCC 
□ 
□ 
 
Patients who had surgical resection of the 
disease and who do not have measurable 
disease. 
□ 
□ 
 
Patients with any of the following within the 12 
months prior to study drug administration: 
severe/unstable angina, myocardial infarction, 
coronary artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular 
accident, including transient ischemic attack, or 
pulmonary embolism. 
□ 
□ 
 
Pregnant or breastfeeding women  
□ 
□ 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
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Patients diagnosed with another type of cancer 
(excluding basal cell carcinoma) whose cancer 
diagnosed previously is not in remission. 
□ 
□ 
 
Patients receiving calcium channel blockers and 
any agent blocking L-type or T-type Voltage 
Gated Calcium Channels, e.g. amlodipine, 
nifedipine, ethosuximide, etc. are not allowed in 
the study unless their medical treatment is 
modified-prior to enrollment to exclude calcium 
channel blockers prior to enrollment. (Refer to 
Appendix F for a complete list of excluded 
medications and/or pathways). 
□ 
□ 
 
Patients allergic or intolerant to Sorafenib. 
 
□ 
□ 
 
 
This subject is      
 eligible / 
 ineligible     for participation in this study. 
 
OnCore Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility: _______________________  
 
Date: ___ ___ / ___ ___ / ___ ___ 
 
Signature of Treating Physician:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
Signature of Principal Investigator**:  _____________________________________  
 
Date:  ___ ___ / ___ ___ / ___ ___ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, 
specifically state which document in the medical record was used to assess eligibility. Also include the date on the 
document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 
 
 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
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Appendix B – Protocol Registration Form  
DEMOGRAPHICS 
Patient: Last Name: 
_____________________ 
First Name: 
___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ 
___ 
DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ 
___ 
ZIPCODE:  ___ ___ ___ ___ ___ 
 
 
SEX:   
  Male      Female 
Ethnicity (choose 
one):   
 Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
 
 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ______________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ _  
  Performance Status: ___  ECOG   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Registrar can be contact by calling 
 between 8:30 AM and 4:00 PM, Monday – Friday. 
 
Compete the eligibility checklist in WISER and then give the completed Eligibility Checklist and Protocol Registration Form 
must be hand delivered, faxed or e-mailed to the registrar at 
 or 
, respectively. 
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES 
  NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by OnCore): 
___ ___ ___ ___ ___ ___ ___ __ 

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WFBCCC # 55319 
 
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Appendix C - Race & Ethnicity Verification Form 
 
 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our 
information. As a brief reminder, the information you provide today will be kept confidential. 
 
1. Are you: 
Hispanic or Latino/a 
Not Hispanic or Latino/a 
 
2. What is your race? One or more categories may be selected. 
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
          
      
 
 
 
 
 
Internal use only: 
 
 
 Name: ____________________ MRN#: ____________________  
 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
 
Was a discrepancy found?       Yes         No 
         If yes, please provide what is currently indicated in the EMR:  
 
 
Ethnicity: ____________________ 
 
Race: ____________________ 
Additional comments: 
__________________________________________________________________ 
________________________________________________________________________________
________________________________________________________________________________
__________ 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
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WFBCCC # 55319 
 
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Appendix D Safety and Toxicity Review Committee Requirements 
  
Data and Safety Monitoring (DSMC) 
Serious Adverse 
Event (SAE) Notification SOP  
Date: 02/11/2021  
  
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC Investigator Initiated 
interventional trials to the Data and Safety Monitoring Committee (DSMC). A trial is considered a 
WFBCCC Investigator Initiated interventional trial if the following criteria are met: 
 
1) The Principal Investigator (PI) of the trial is a member of a department at the Wake Forest 
University Baptist Medical Center. 
2) WFBCCC is considered as the primary contributor to the design, implementation and/or 
monitoring of the trial. 
3) The trial is designated as “Interventional” using the Clinical Research Categories 
definitions provided by the NCI in the Data Table 4 documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where 
patient enrollment occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all patients are 
enrolled from one of the WFBCCC sites. These include the main outpatient Cancer Center clinics 
(located in Winston-Salem) as well as WFBCCC affiliate sites located in Bermuda Run (Davie 
Medical Center), Clemmons, Lexington, High Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials where patients 
are enrolled from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program (NCORP) that are 
conducted at multiple sites where the PI is a member of a department at the Wake Forest 
University Baptist Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the PI is a member 
of a department at the Wake Forest University Baptist Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a member 
of a department at the Wake Forest University Baptist Medical Center. 
 
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients enrolled on 
WFBCCC Investigator Initiated Interventional trials must be entered into the WISER system. The only 
exception to this requirement is for patients enrolled on NCORP trials at non- WFBCCC sites. AEs and 
SAEs for NCORP patients enrolled at WFBCCC sites must be entered into the WISER system. Once these 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
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AEs and SAEs are entered in WISER, certain actions must be taken regarding the reporting of specific 
Adverse Events to the DSMC. 
 
 
 
All Adverse Events that occur during protocol intervention (defined below) and are coded as either 1) 
unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours (regardless of grade), or grade 5 
(death) must be reported to the DSMC using the using the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event meets one of 
the above criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is responsible for 
informing a clinical member of the DSMC by phone (or in-person) about the adverse event. The 
nurse/coordinator should contact the treating physician prior to calling the DSMC clinical member to 
obtain all details of the SAE, as well as all associated toxicities to be recorded along with the SAE. In 
addition, this nurse or coordinator is responsible for entering the adverse event information into the SAE 
console in WISER.  Once the adverse event has been entered into the SAE console an email informing the 
entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC 
Institutional Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE 
identification, documentation, grading and assignment of attribution to the investigational 
agent/intervention. However, when an AE event as described above is observed, it is the responsibility 
of the person who observed the event to be sure that it is reported to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study treatment or 
during the time period within 30 days of last study treatment (even if patient begins a new (non-study) 
treatment during the 30 days). This window of 30 days should be the standard window to be used in all 
protocols unless a specific scientific rationale is presented to suggest that a shorter window can be used to 
identify events. If it is a trial sponsored by Industry and the sponsor requires a longer window for 
monitoring of SAEs, then the longer window of time specified by the sponsor should be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the protocol should be 
considered as unexpected. A grade 4 adverse event can be considered to be unexpected if it is an event that 
would not be expected based on the treatment being received or if it is unexpected based on the health of 
the patient. In either case, if there is any uncertainty about whether a grade 4 adverse event is expected or 
unexpected it should be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of the SAE 
in WISER: 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
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1. Make a phone call (or speak in person) to the appropriate clinical member of the DSMC according 
to the schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER WITHIN 
24 HOURS of first knowledge of the event. Information can be entered and saved, but the DSMC 
members will not be notified until a date is entered into the  DSMC Notification Date Field. This will 
ensure that all persons that need to be made aware of the event (i.e., PI, study team members and 
DSMC members) will be notified; remember to file a copy of the confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate the name of 
the DSMC clinician that was contacted and the date and time contacted in the Event Narrative field 
in the SAE console of the particular subject. 
4. Document whether or not the protocol should be suspended based on the discussion with the 
DSMC clinician. This is the major function of the email notification. Enter whether the protocol 
should be suspended in the Event Narrative Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments or information 
obtained during the course of the SAE investigation and reporting process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, including 
therapies believed related to event). Begin narrative with the DSMC clinician who was notified and 
Date/Time notified. In addition, state attribution by DSMC clinician as either “Unrelated”, “Unlikely”, 
“Possibly”, “Probably”, or “Definitely”.  Always include the following here: 
i. DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 
iii. Is suspension of the protocol needed? Y/N 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not Resolved, 
Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, Recovering and 
Resolving) 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 

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d. Comments 
e. Grade/Severity 
f. Unexpected Y/N 
g. DLT Y/N 
h. Attributions 
i. Action 
j. Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. If you do not 
receive an email within 5 minutes, check that you have entered the “Date Notified DSMC” and the 
“SAE Classification”. If these have been entered and the email still has not been received, take a 
screen shot of the SAE in WISER and immediately email it out to all of the DSMC members listed in 
this SOP. In the subject line, indicate that this is a manual transmission of the SAE in lieu of the auto-
generated email. It is required that a notification goes to the DSMC members immediately so that 
their assessment can be obtained within the 24 hour period requirement. Contact the Cancer Center 
Programmer/Analyst to alert that there is an issue with the auto-generated email. 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
 
  
 
 
 
 
 
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone call or page 
within 30 minutes, then initiate contact with the next DSMC clinician listed in the table above on the 
particular day the SAE is being reported. Allow up to 30 minutes for the new DSMC clinician to respond to a 
phone call or page before contacting the next member in the table. These times (30 minutes) are a general 
guideline. Best judgment as a clinical research professional should be used giving considerations of the time 
of day, severity of the SAE, and other circumstances as to when it is appropriate to contact backup 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
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WFBCCC # 55319 
 
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clinicians. If the event occurs near the end of day, then leave messages (voice or email) as appropriate and 
proceed with submitting the DSMC notification form. It is important to take reasonable steps and to 
document that some type of contact has been initiated to one or more of the clinical members of DSMC. 
 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the events as they are 
reported; and communicate a response to the Investigator, event reporter and the members of DSMC. The 
review will include but not be limited to the information reported; there may be times when additional 
information is needed in order for an assessment to be made and further communication directly with the 
investigator may be warranted. DSMC reserves the right to disagree with the Investigator's assessment. If 
DSMC does not agree with the Investigator, DSMC reserves the right to suspend the trial pending further 
investigation. If there is any immediate danger or harm that could be present for a future patient based on 
the information provided in the DSMC report then an immediate suspension of enrollment should be 
considered. 
 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional information is 
available do not submit a new report. Rather, go to the original email that was sent to the DSMC and using 
that email “reply to all”. Entitle this new email “Amendment for (list date of event and patient ID)” this will 
avoid duplications of the same event. List the additional information being reported. This information 
needs to be entered into WISER as well. To do this, go to the Subject console and click SAEs on the left 
column. Click on the appropriate SAE number that needs updating. Then click Update. This will allow 
additional  information to be added. 
 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 
Screen Shots:  
  
The following screen shots come from the SAE Console within the Subject Console in WISER.  
  
Screen Shot 1:  

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
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WFBCCC # 55319 
 
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Screen Shot 2:
  
  
Screen Shot 3:  

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
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WFBCCC # 55319 
 
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 Screen Shot 4
  
 
 
 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
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WFBCCC # 55319 
 
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Appendix E  Calculator: Child Pugh score for severity of liver disease (SI units) 
(adapted from UptoDate 2019 (2019) ) 
  
Encephalopathy 
None (1 point) 
Grade 1: Altered mood/confusion (2 points) 
Grade 2: Inappropriate behavior, impending stupor, somnolence (2 points) 
Grade 3: Markedly confused, stuporous but arousable (3 points) 
Grade 4: Comatose/unresponsive (3 points) 
Ascites 
Absent (1 point) 
Slight (2 points) 
Moderate (3 points) 
Bilirubin 
<34.2 mcmol/L (1 point) 
34.2 to 51.3 mcmol/L (2 points) 
>51.3 mcmol/L (3 points) 
Albumin 
>35 g/L (1 point) 
28 to 35 g/L (2 points) 
<28 g/L (3 points) 
Prothrombin time prolongation 
Less than 4 seconds above control/INR <1.7 (1 point) 
4 to 6 seconds above control/INR 1.7 to 2.3 (2 points) 
More than 6 seconds above control/INR >2.3 (3 points) 
  
Total criteria point count: 
 
 
Child Pugh score interpretation 
  
5 to 6 points:Child class A 
7 to 9 points:Child class B 
10 to 15 points:Child class C 
  
Notes The Child Pugh score is a modification of the Child Turcotte score.  
The terms Child Pugh classification and Child Turcotte Pugh classification are used interchangeably by some clinicians. 

A Phase II Study Of Intrabucally Administered Amplitude-Modulated Electromagnetic Fields and 
Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
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WFBCCC # 55319 
 
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Appendix F- List of items/agents/compounds that block T-type channels ( Cav 3.1/2/3)  
 
Antihypertensives 
Mibefradil 
flunarizine 
Nicardipine 
Nifedipine 
Nimodipine 
Methoxyverapamil 
Diltiazem 
Felodipine 
Amlodidpine 
Aranidipine 
Azelnidipine 
Barnidipine 
Benidipine 
Efonidipine 
 
ANTIEPILIPETICS: 
Ethosuximide 
Methyl-phenylsuccinimide….the active metabolite of the antiepileptic drug methsuximide 
Phenytoin (blocks t-type channels but is thought to work by blocking Na+ channels) 
Zonisamide 
Valproate 
Phenobarbital 
Trimethadione 
 
Anesthetics / Barbiturates: 
Isoflurane 
Halothane 
Nitrous Oxidie –selective for Cav 3.2 
Octanol 
Ketamine 
Propofol 
Etomidate 
Thiopental 
 
Antipsychotics: 
Penfluridol 
Thioridazine 
Clozapine 
Haloperidol 
fluspiriline 

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WFBCCC # 55319 
 
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pimozide 
flunarzine 
 
Vitamins/supplements 
Nickel (100uM Ni2+) 
Vitamin C 
 
Other compounds/agents: 
Amiloride 
Tetrandrine 
Lomerizine 
 
Drug Candidate Pathways Inhibited IC50 -T channel Neuroprotection 
A1048400 T-Type and N-Type 1.2-4.6μM 
KYS05044 T-Type (CaV3.1, CaV3.2) 1μM  
ML218 T-Type (CaV3.1-CaV3.3) 150-310nM  
NNC 55-0396 T-Type 7μM  
RQ-00311610 T-Type 110-170nM   
TTA-A2 T-Type (CaV3.1-3.3) 50-100nM 
TTA-P2 T-Type 22nM  
VH04 T-Type (CaV3.1) 100nM  
Z941/944 T-Type 50-160nM 
 
 
 
References by DOI 
https://doi.org/10.1152/physrev.00018.2002 - black type lettering 
https://doi.org/10.1254/jjp.85.339 - BLUE type lettering 
10.1007/s00424-014-1454-x – green type lettering 
 
 

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Regorafenib as Second-line Therapy For Patients with Advanced Hepatocellular Carcinoma. 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 55319 
 
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