Electric Field Therapy (AM RF EMF) in Combination with Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer

Inclusion Criteria

• Participant must have histologically or cytologically confirmed metastatic colorectal adenocarcinoma. There must be previous documentation of RAS, BRAF, microsatellite instability(MSI)/mismatch repair (MMR), and HER2 status
• Participant must have progressed on or been intolerant to the following previous treatments (if not contraindicated): * Fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy * Anti-VEGF biological therapy, such as bevacizumab, aflibercept, or ramucirumab * If RAS is wild type, an anti-EGFR therapy like cetuximab or panitumumab ** Participants are considered intolerant if they have received at least one dose of agent and were discontinued from therapy for reasons other than disease progression
• Participants with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors (ICIs) unless the participant is ineligible for ICI therapy
• Participants with BRAF-mutant tumors must have been treated with a BRAF inhibitor unless the participant is ineligible for treatment with a BRAF inhibitor
• Participants with HER2 overexpression/amplified metastatic colorectal carcinoma (mCRC) must have been treated with anti-HER2 agent
• Participants are allowed to have previous TAS-102 and/or regorafenib exposure
• Participants who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within six months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting
• Participants who developed metastatic disease more than six months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible unless they have persistent neuropathy from or allergy to oxaliplatin
• Participant must have evaluable disease as defined by the investigator using CT, MRI, or PET scan
• Participant must have a body weight ≥ 40 kg
• Participant must be aged 22 years or older
• Participant must be able to understand a written informed consent document and be willing to sign it
• Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min (within 14 days prior to the initiation of treatment) * Creatinine clearance is calculated as described by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation
• Total bilirubin ≤ 1.5 x ULN (within 14 days prior to the initiation of treatment) * Participants with previously documented Gilbert syndrome and bilirubin < 2 x ULN are eligible
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x ULN for participants without hepatic metastases (within 14 days prior to the initiation of treatment) * ALT or AST ≤ 5 x ULN for participants with hepatic metastases
• Hemoglobin ≥ 8.0 g/dL (transfusion permitted) (within 14 days prior to the initiation of treatment)
• Platelet count ≥ 100 x 10^3/mm^3 (within 14 days prior to the initiation of treatment)
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^3/mm^3 (within 14 days prior to the initiation of treatment) * For patients with the Duffy null phenotype, ANC ≥ 1.0 x 10^3/mm^3
• International normalized ratio (INR) ≤ 1.5 x ULN OR activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN, unless the subject is currently receiving or intended to receive anticoagulants for prophylactic purposes (within 14 days prior to the initiation of treatment)
• Urinalysis with protein < 2+ OR 24-hour urine protein with protein < 1.0 g (over the course of the full 24 hours) (within 14 days prior to the initiation of treatment) * Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level
• Participant should have an expected lifespan of > 12 weeks as determined by the investigator
• Fruquintinib is suspected to cause loss of human pregnancy and impaired development of the embryo or fetus. Therefore, women of child-bearing potential must agree to avoid becoming pregnant and male participants should avoid impregnating a female partner starting at initiation of treatment up until at least 14 days after the last fruquintinib dose. * Female participants must meet one of the following: ** Surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) ** Post-menopausal, defined as no menses for at least 12 months prior to the screening visit without alternative medical causation ** Agree to practice true abstinence from sexual intercourse when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence methods such as calendar, ovulation, symptothermal, or post ovulation tracking are not acceptable ** Not in a sexual relationship in which they may become pregnant (i.e. same-sex relationship) ** If they are of childbearing potential, agree to use at least one highly effective AND at least one additional method of contraception. Withdrawal is not an acceptable contraceptive method * Male participants must meet one of the following: ** In a sexual relationship with a post-menopausal or surgically sterile female (see above definitions) ** Agree to practice true abstinence from sexual intercourse with a female of child-bearing potential starting at initiation of therapy up until at 30 days after the last fruquintinib dose/TheraBionic session ** Not in a sexual relationship in which their partner may become pregnant (i.e. same-sex relationship) ** In a sexual relationship with a woman of child-bearing potential and agree to use at least one highly effective AND at least one additional method of contraception. Withdrawal is not an acceptable contraceptive method *** Highly Effective Methods **** Intrauterine device (IUD) **** Hormonal therapy (birth control pills, injection, implants) **** Tubal ligation **** Vasectomy *** Additional Methods of Contraception **** Male OR female condoms (should not be used together) used with a spermicide **** Diaphragm **** Cervical cap

Exclusion Criteria

• Participants with uncontrolled hypertension per investigator discretion
• Participants with a history or presence of gastric/duodenal ulcer or ulcerative colitis, hemorrhage of an unresected gastrointestinal tumor, perforation, fistulas, or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation
• Participants with a history or presence of hemorrhage from any other site (i.e., lower gastrointestinal [GI] bleed, hemoptysis or hematemesis) within two months prior to screening
• Participants with a history of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within three months prior to screening unless they are on a stable dose of anticoagulant and no further evidence of active thromboses are seen on CT scan or venous Doppler imaging. Participants with saddle (massive) pulmonary embolism that require thrombectomy/thrombolysis within 12 months of screening are excluded from the trial
• Participants with a history of stroke and/or transient ischemic attack within 12 months prior to screening
• Participants with clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within six months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or previous left ventricular ejection fraction (LVEF) < 50% by echocardiogram
• Participants with corrected QT interval using the Fridericia method (QTcF) > 480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative
• Participants taking concomitant medications with a known risk of causing QT prolongation and/or torsades de pointes. (Source list is continuously updated online at www.crediblemeds.org.)
• Participants taking systemic anti-neoplastic therapies four weeks prior to the first dose of study drug, including chemotherapy, biotherapy, or immunotherapy. Palliative radiation is allowed if it does not cover all evaluable disease
• Participants taking systemic small molecule targeted therapies (e.g., tyrosine kinase inhibitors) within five half-lives or four weeks, whichever is shorter, prior to the first dose of study drug
• Participants who have undergone major surgery within 30 days prior to the first dose of study drug or if they still have unhealed surgical incision from previous surgery
• Participants with any unresolved toxicities from a previous antitumor treatment greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade 2
• Participants that have current drug or alcohol abuse
• Participants with known human immunodeficiency virus (HIV) infection are not eligible if their viral load and/or CD4 count are considered poorly controlled with anti-HIV therapy
• Participants with a known history of active viral hepatitis. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants that test positive for hepatitis C virus (HCV) but are currently being treated are eligible if they have an undetectable HCV viral load
• Participants with clinically uncontrolled active infections requiring intravenous antibiotics
• Participants with tumor invasion of a large vascular structure (e.g., pulmonary artery, superior or inferior vena cava)
• Participants with brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy and without clinical imaging evidence of stable disease for 14 days or longer
• Participants with known active secondary malignancy, unless, in the opinion of the investigator, it is unlikely to interfere with the safety and efficacy of the endpoints
• Participants that are unable to take medication orally including those with dysphagia or an active gastric ulcer resulting from previous surgery (e.g., gastric bypass) or severe gastrointestinal disease, or any other condition that the investigator believes may affect absorption of fruquintinib
• Participants with metabolic disorder that the investigator suspects may prohibit fruquintinib action, affect interpretation of study results, or put the participant at undue risk of harm based on the investigator’s assessment
• Participants that have received prior fruquintinib treatment
• Participants with a known hypersensitivity to fruquintinib or any of its inactive ingredients including the azo dyes tartrazine, Federal Food, Drug, and Cosmetic Act (FD&C) yellow 5, and sunset yellow FCF
• Participants taking strong inducers or inhibitors of CYP3A4 within five half-lives or four weeks, whichever is longer, before the first dose of study drug
• Participants that are taking any other investigational drugs
• Participants with active oral mucosal inflammation, ulceration, or other pathology that could interfere with the use of TheraBionic P1 device (for example: mucositis, thrush, bleeding mucosal lesions, oral herpes, aphthous stomatitis, mouth ulcers, chancre sores, gingivostomatitis, herpangina, aphthae)
• Participants receiving calcium channel blockers and any agent blocking L-type or T-type voltage gated calcium channels (for example: amlodipine, nifedipine, ethosuximide, ascorbic acid/vitamin C, etc.) unless these drugs are discontinued at least 7 days prior to starting TheraBionic P1 device treatment. Participant must agree to abstain from using calcium channel blockers for the duration of treatment on study
• Participants that are pregnant or breastfeeding are ineligible for this study. If a breastfeeding participant would like to be part of this study, breastfeeding must be discontinued
• Participants who have received a live vaccine ≤ 28 days before the first dose of fruquintinib. (Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.)
• Participants that do not agree to be followed according to the study protocol or have cognitive or physical inability to use the device