Electromagnetic Fields Versus Placebo as Third-line Therapy For Patients With Advanced Hepatocellular Carcinoma

• ClinicalTrials.gov Identifier: NCT04797884
• Recruitment Status: Recruiting
• First Posted: March 15, 2021
• Last Update Posted: November 29, 2021
• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI); Therabionics
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

Brief Summary:

The primary goal of this study is to gather efficacy data concerning overall survival with electromagnetic fields when compared to a placebo amplitude-modulated radiofrequency electromagnetic field device in subjects who have failed or are intolerant to at least two previous systemic therapies.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Cancer	Device: TheraBionic Device; Device: Placebo Device	Phase 2

Detailed Description:

Primary Objective: To estimate overall survival and quality of life.

Secondary Objectives

• To estimate progression-free survival
• To evaluate safety and tolerability in this patient population.
• To evaluate the effect on levels of alpha-fetoprotein.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 166 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study Of Intrabucally Administered Electromagnetic Fields Versus Placebo as Third-line Therapy For Patients With Advanced Hepatocellular Carcinoma
• Estimated Study Start Date: February 2022
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: June 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: TheraBionic Arm - Active Arm; For subjects who are randomized to the active arm, the device will be programmed with hepatocellular carcinoma-specific modulation frequencies and will be activated for >200 one-hour treatment sessions.	Device: TheraBionic Device; Each treatment day consists of three courses of 60-minute treatments to be administered in the morning, at noon, and in the evening. Each 6-week treatment period will be considered a cycle of treatment. With the exception of the first 60-minute treatment, which will be delivered at one of the Comprehensive Cancer Centers, all other treatments will be self-administered at the patient's home.
Placebo Comparator: Placebo Arm; For subjects randomized to the placebo arm, the device will not emit any hepatocellular carcinoma-specific modulation frequencies and will be activated for >200 one-hour treatment sessions.	Device: Placebo Device; Each treatment day consists of three courses of 60-minute treatments to be administered in the morning, at noon, and in the evening. Each 6-week treatment period will be considered a cycle of treatment. With the exception of the first 60-minute treatment, which will be delivered at one of the Comprehensive Cancer Centers, all other treatments will be self-administered at the patient's home.

Outcome Measures

Primary Outcome Measures :

1. Overall Survival [ Time Frame: Baseline to 6 months ]
   The co-primary objectives of this study are to compare overall survival (OS) and quality of life between patients receiving active vs. placebo treatment with the TheraBionic device. Overall survival will be assessed on an intention to treat basis using a 2-sided log rank test to compare hazard rates between groups. Kaplan-Meier survival curves will also be generated and median survival and corresponding 95% confidence intervals will be estimated for each group.
2. Quality of Life Survey - EQ-5D-5L [ Time Frame: Baseline to 6 months ]
   The primary fixed effects of interest are treatment (TheraBionic device vs Placebo) and time (baseline and every 6 week) and the time by treatment interaction. The five dimensions of the survey include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The answers given to ED-5D permit to find 243 unique health states or can be converted into EQ-5D index an utility scores anchored at 0 for death and 1 for perfect health. The EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst possible health status) to 100 (the best possible health status).

Secondary Outcome Measures :

1. Progression-Free Survival [ Time Frame: Up to 2 years ]
   Progression free survival (PFS) will be compared between groups using a 2-sided log rank test. Kaplan-Meier survival curves for PFS will also be generated and median progression free survival and corresponding 95% confidence intervals will be estimated for each group
2. Proportion of Patients With Disease Control [ Time Frame: At 4 months and 6 months and up to 2 years ]
   Proportion of patients who respond and the corresponding 95% Clopper Pearson exact confidence intervals. Patients who are removed from study before the 6-month time point will be considered to not have disease control at that time point.
3. Proportion of Participants That Are Progression Free [ Time Frame: At 12 weeks, 4 months and 6 months and up to 2 years ]
   we will determine the proportion of patients who are progression free after 12 weeks (after 2nd 6-week visit) and compare this between groups using a Fisher's exact test. In addition, the corresponding 95% Clopper Pearson exact confidence intervals will be calculated for the 4 month and 6 month progression free survival rates.
4. Number of Adverse Events [ Time Frame: Up to 28 days after study treatment administration or until death ]
   Using Common Terminology Criteria for Adverse Events [CTCAE], version 5.0, timing, seriousness, and relatedness of adverse events and laboratory abnormalities. These adverse events will be compared for each cytotoxic T Lymphocyte type between the two groups 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.
5. Changes in Alfa-Fetoprotein Levels [ Time Frame: 6 months ]
   Investigators will examine whether these is any association between the AFP levels (potential biomarker for response) and the objective response observed for each participant. Average alfa-fetoprotein levels will be examined over time, and these changes in alfa-fetoprotein rates after 6 months will be examined for each Response category (complete response/ partial response/ stable disease/ progressive disease) and tested using a 1-way ANOVA to see if the change in AFP level differs by response category.
6. Quality of Life Survey - FACT Hepatobiliary [ Time Frame: At baseline and every 6 weeks up to 6 months ]
   The primary fixed effects of interest are treatment (TheraBionic device vs Placebo) and time (baseline and every 6 week) and the time by treatment interaction. Self-administered 45-item questionnaire on a 5 point Likert-type scale (0 not at all to 4 very much). Scoring range 0-180. Some items are reverse scored. Subscales are physical, social/family, emotional and functional well-being and hepatobiliary cancer subscale. Higher score indicates better quality of life.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Biopsy-proven hepatocellular carcinoma that is locally advanced or metastatic
• Patients must have measurable disease.
• Failure or intolerance to prior treatments with at least two different approved or experimental systemic therapies including atezolizumab and bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab, nivolumab, nivolumab plus ipilumab, pembrolizumab or any approved or experimental first line and/or second line therapy that did not include the TheraBionic device (defined as documented radiological progression according to the radiology charter). Randomization needs to be performed within 10 weeks after the last systemic treatment
• Measurable disease according to RECIST v 1.1 50 and mRECIST for HCC 51.
• 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 v 1.1 50 and mRECIST for HCC51.
• Patients with Child's Pugh A or B (at time of enrollment) as defined by the p parameters contained in the Child Pugh Calculator found in Appendix E 52.-Subjects with Child's Pugh score of B8-B9 may be included if they have
• Albumin > 2.8 mg/l AND
• Total Bilirubin < 3.0mg/l.
• Performance status ECOG 0-2
• Patient must not have curative treatment options, including surgery or radiofrequeny ablation, available as assessed by their physician.
• Any extra-hepatic metastases, including treated CNS metastases but patients cannot have leptomeningeal disease.
• At least 4 weeks must have elapsed since administration of any anti-cancer treatment.
• Other anti-cancer treatments are not permitted during this study
• Patients must be more than 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.
• Any patient who is not eligible for systemic treatment as per NCCN guidelines version 5.2020, August 4, 2020 and fulfills the other inclusion criteria related to liver function, i.e., Child-Pugh A or B with total bilirubin ≥ 2.8 mg/L and total bilirubin ≤ 3.0 mg/L

Exclusion Criteria:

• Known leptomeningeal disease.
• Fibro lamellar hepatocellular carcinoma.
• 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
• Has received treatment for other carcinomas within the last three years except for cured non-melanoma skin cancer, low-risk prostate cancer, T1/T2 glottic cancer, stage 0 or stage I breast cancer, non-invasive bladder cancer, or treated in-situ cervical cancer).
• Patients receiving calcium channel blockers and any agent blocking L-type of T-type Voltage Gated Calcium Channels, e.g. amlodipine, nifedipine, ethosuximide, ascorbic acid (vitamin C), etc. are not allowed in the study unless their medical treatment is modified to exclude calcium channel blockers prior to enrollment. (Refer to Appendix G for a comprehensive list of excluded medications)

Contacts and Locations

Contacts

Contact: Study Nurse; 336-713-7646; snmoore@wakehealth.edu

Locations

United States, Arizona

Mayo Clinic College of Medicine and Science of Arizona; Not yet recruiting

Phoenix, Arizona, United States, 85054

Contact: Tanios Bekaii-Saab, MD Bekaii-Saab.Tanios@mayo.edu

Principal Investigator: Tanios Bekaii-Saab, MD

United States, Illinois

Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Not yet recruiting

Chicago, Illinois, United States, 60611

Contact: Al B Benson, MD albenson@nm.org

Principal Investigator: Al Benson, MD

United States, North Carolina

Wake Forest Baptist Comprehensive Cancer Center; Recruiting

Winston-Salem, North Carolina, United States, 27157

Contact: Study Nurse snmoore@wakehealth.edu

Principal Investigator: William Black, MD

Sponsors and Collaborators

Wake Forest University Health Sciences

National Cancer Institute (NCI)

Therabionics

Investigators

• Principal Investigator: William Blackstock, MD; Wake Forest University Health Sciences

More Information

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT04797884
• Other Study ID Numbers: IRB00072592; WFBCCC 55121 ( Other Identifier: Wake Forest Baptist Comprehensive Cancer Center ); P30CA012197 ( U.S. NIH Grant/Contract )
• First Posted: March 15, 2021
• Last Update Posted: November 29, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Carcinoma, Hepatocellular; Liver Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases