Compositions, systems, and methods for treating cancer patients who have not received standard of care and / or profibrotic chemotherapy drug treatment with tumor treating electric fields and chemotherapy drugs

Abstract

Disclosed are compositions, systems, and methods for treating cancer and preventing an increase in the volume of a tumor present in a body of a living subject. The systems and methods involve selecting a subject who has not received at least one standard of care chemotherapy drug, such as but not limited to a fibrosis-inducing chemotherapy drug, and subsequently applying an alternating electric field to the selected subject. The methods can further include concurrently administering at least one chemotherapy drug to the subject.

Description

[0001] Cross-reference to related applications

[0002] Pursuant to 35 U.S.C., 119(e), this application claims the benefit of U.S. Provisional Application No. 63 / 561,607, filed March 5, 2024. The entire contents of the aforementioned patent application are hereby expressly incorporated herein by reference.

[0003] Statement on Federally Funded Research

[0004] not applicable. Background Technology

[0005] Tumor therapeutic electric fields (TTFields) are low-intensity (e.g., 1-3 V / cm) alternating electric fields in the mid-frequency range (such as, but not limited to, 100-500 kHz) that target solid tumors via mitosis. This non-invasive treatment of targeted solid tumors is described, for example, in U.S. Patents 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776. TTFields are typically delivered via two pairs of transducer arrays that generate a vertical electric field within the treated tumor; the electrode arrays constituting each pair are positioned on opposite sides of the body site being treated. More specifically, for the OPTUNE® system, one pair of electrodes is positioned to the left and right of the tumor (LR), and another pair of electrodes is positioned to the front and back of the tumor (AP). TTFields are approved for the treatment of glioblastoma multiforme (GBM) and can be delivered, for example, via the OPTUNE® system (Novocure Limited, St. Helier, Jersey), which includes a transducer array placed on the patient's laser head.

[0006] Each transducer array used to deliver TTFields in the OPTUNE® device comprises a set of ceramic disc electrodes coupled to the patient's skin (such as, but not limited to, the patient's shaved head for treating GBM) via a layer of conductive medical gel. The medical gel is designed to deform to conform to the body's contours and provide good electrical contact between the array and the skin; thus, the gel interface bridges the skin and reduces interference. The device is intended to be worn continuously by the patient for 2 to 4 days, then removed for hygiene and regrowth (if necessary), followed by reapplication of a new array. Thus, the medical gel maintains substantially continuous contact with the patient's skin area for each contact period of 2 to 4 days. Furthermore, the array can be moved a few centimeters in either direction to allow the skin to heal between treatment periods. Therefore, when the replaced electrodes are moved slightly, the portion of skin covered by the electrodes / gel for 2 to 4 days is exposed for 2 to 4 days; the device can then be reapplied to the original portion of the skin for the next 2 to 4 days.

[0007] TTFields has been studied in clinical trials in combination with standard-of-care (SOC) immunotherapy or chemotherapy regimens for the treatment of non-small cell lung cancer that has progressed after platinum-based therapy (Leal et al., (2023), Lancet Oncol, 24(9):1002–1017), and in preclinical studies in combination with immune checkpoint inhibitors (Voloshin et al., (2020), Cancer Immunol Immunother, 69(7):1191–1204; Barsheshet et al., (2022), Int J Mol Sci, 23(22):14073). Attached Figure Description

[0008] Figure 1 A study design for evaluating the safety and efficacy of TTFields therapy in combination with weekly paclitaxel versus weekly paclitaxel alone in platinum-resistant ovarian cancer (PROC) is depicted graphically. Abbreviations / acronyms used: CT, Computed Tomography; ECOG, Eastern Cooperative Oncology Group; HR, Hazard Ratio; HRQoL, Health-Related Quality of Life; MRI, Magnetic Resonance Imaging; ORR, Objective Response Rate; OS, Overall Survival; PFS, Progression-Free Survival; PROC, Platinum-Resistant Ovarian Cancer; TTFields, Tumor Treating Fields; QW, Weekly; Q4W, Every 4 Weeks; Q8W, Every 8 Weeks.

[0009] Figure 2 Include Figure 1Demographic and baseline characteristics of the study group. *PLD accounted for 93% of anthracyclines used, with the remaining 7% being unspecified doxorubicin formulations. Abbreviations / acronyms used: BRCA, Breast Cancer Gene; ECOG PS, Eastern Cooperative Oncology Performance Status Score; PLD, pegylated liposomal doxorubicin; ITT, Intention to Treat; TTFields, Tumor Treating Fields.

[0010] Figure 3 The overall survival of the ITT population in this study is depicted graphically.

[0011] Figure 4 Subgroup analyses of study participants based on stratification factors and exploratory analyses were summarized. *PLD accounted for 93% of anthracycline drugs used, with the remaining 7% being unspecified doxorubicin formulations. BRCA, breast cancer gene; PARP, poly-ADP-ribose polymerase; PLD, pegylated liposomal doxorubicin.

[0012] Figure 5 Multivariate analysis of study participants is presented. Model parameters: group, group x prior PLD* usage, prior bevacizumab, BRCA status, number of lines after platinum administration, number of prior lines, prior PARP administration, FIGO stage, grade, ascites, platinum-free interval, patient age, and ECOG. *Indicates a variable retained in the model, limited by a significance level of 0.25 for exclusion. *PLD accounted for 93% of anthracycline use, with the remaining 7% being unspecified doxorubicin formulations. †The mITT population included all patients who had received ≥1 complete 28-day study treatment cycle. BRCA, breast cancer gene; ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecologic and Obstetric Societies; mITT, modified intention-to-treat; PARP, poly-ADP-ribose polymerase; PH, proportional hazards; PLD, pegylated liposomal doxorubicin; TTFields, tumor therapeutic electric fields.

[0013] Figure 6 Demographic and baseline characteristics table including a subgroup that did not receive PLD* treatment. *PLD accounted for 93% of anthracycline use, with the remaining 7% being unspecified doxorubicin formulations. BRCA, Breast Cancer Gene; ECOG PS, Eastern Cooperative Oncology Performance Status Score; ITT, Intention to Treat; PLD, Pegylated Liposome Doxorubicin; TTFields, Tumor Therapeutic Electric Fields.

[0014] Figure 7Overall survival is graphically depicted in the subgroup that did not receive PLD treatment. *PLD accounted for 93% of anthracyclines used, with the remaining 7% being unspecified doxorubicin formulations. HR, hazard ratio; OS, overall survival; PLD, pegylated liposomal doxorubicin; TTFields, tumor therapeutic electric fields.

[0015] Figure 8 Includes a table analyzing the safety of the study in terms of adverse events (AEs). PLD, pegylated liposomal doxorubicin; SAE, serious adverse events; TTFields, tumor therapeutic electric fields.

[0016] Figure 9 Includes a table analyzing the safety of TTFields therapy-related adverse events (AEs) in this study. AE stands for Adverse Event; SAE for Serious Adverse Event; TTFields for Tumor Therapeutic Electric Fields.

[0017] Figure 10 Overall survival analyses of paclitaxel alone or TTFields plus paclitaxel treatment groups were graphically depicted, and patients who did not receive dorurubicin treatment were compared with those who received dorurubicin treatment before treatment.

[0018] Figure 11 The overall survival analysis of patients who did not receive excessive rubicin treatment was graphically depicted for those treated with paclitaxel alone or with TTFields plus paclitaxel.

[0019] Figure 12 Showing Figure 10-11 Multivariate analysis of the study. Detailed Implementation

[0020] Before explaining in detail at least one embodiment of the inventive concept through exemplary language and results, it should be understood that the application of the inventive concept is not limited to the details of the construction and arrangement of the components set forth in the following description. The inventive concept can be implemented in other ways or practiced or performed in various manner. Therefore, the language used herein is intended to give the broadest possible scope and meaning; and these embodiments are intended to be exemplary rather than exhaustive. Furthermore, it should be understood that the wording and terminology used herein are for descriptive purposes and should not be considered limiting.

[0021] Unless otherwise defined herein, scientific and technical terms used in conjunction with the inventive concepts disclosed herein shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms, and plural terms shall include singular terms. The foregoing techniques and procedures are generally performed according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed throughout this specification. The terminology, laboratory procedures, and techniques related to analytical chemistry, synthetic organic chemistry, medical chemistry, and medicinal chemistry described herein are well known and commonly used in the art. Standard techniques are used for chemical synthesis and chemical analysis.

[0022] All patents, published patent applications, and non-patent publications mentioned in this specification represent the skill level of a person skilled in the art to which the inventive concept of this disclosure pertains. All patents, published patent applications, and non-patent publications cited in any part of this application are expressly incorporated herein by reference in their entirety, to the extent that each individual patent or publication is specifically and individually indicated by reference.

[0023] All compositions, components, systems, kits, and / or methods disclosed herein can be prepared and performed without excessive experimentation based on this disclosure. While the compositions, components, systems, kits, and methods of the inventive concept have been described according to specific embodiments, those skilled in the art will appreciate that variations may be made to the compositions and / or methods and steps or sequences of steps described herein without departing from the concept, spirit, and scope of the inventive concept. All such similar substitutions and modifications that are apparent to those skilled in the art are considered to be within the spirit, scope, and concept of the inventive concept as defined by the appended claims.

[0024] As used in accordance with this disclosure, unless otherwise specified, the following terms shall be understood to have the following meanings:

[0025] When used in conjunction with the term "comprising" in the claims and / or description, the use of the terms "a" or "an" can mean "one," but also aligns with the meanings of "one or more," "at least one," and "one or more." Therefore, unless the context clearly indicates otherwise, the terms "a," "an," and "the" include plural indicators. Thus, for example, reference to "a compound" can refer to one or more compounds, two or more compounds, three or more compounds, four or more compounds, or more quantities of compounds. The term "a plurality" means "two or more."

[0026] The term "at least one" should be understood to include any quantity including one and more than one, including but not limited to 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term "at least one" can be extended to 100 or 1000 or more, depending on the terms it is connected to; furthermore, quantities of 100 / 1000 are not considered limiting, as higher limits can also produce satisfactory results. Furthermore, the term "at least one of X, Y, and Z" should be understood to include individual X, individual Y, and individual Z, as well as any combination of X, Y, and Z. The use of ordinal terms (e.g., "first," "second," "third," "fourth," etc.) is solely for the purpose of distinguishing two or more items and does not imply any order or sequence of importance or any order of addition of one item relative to another.

[0027] The term "or" used in the claims is used to indicate inclusion ("and / or"), unless explicitly stated to refer only to alternatives, or unless the alternatives are mutually exclusive. For example, the condition "A or B" can be satisfied by any of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0028] As used herein, any reference to “an embodiment,” “an embodiment,” “some embodiments,” “an example,” “for example,” or “example” means that a particular element, feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. For example, the phrase “some embodiments” or “an example” appearing in different places in the specification does not necessarily refer to the same embodiment. Furthermore, all references to one or more embodiments or examples should be construed as non-limiting to the claims.

[0029] Throughout this application, the term “about” is used to indicate values ​​including inherent error variations in the composition / device / apparatus, variations in the method used to determine the value, or variations present in research subjects. For example, but not as a limitation, when using the term “about,” the specified value may vary from the specified value by adding or subtracting 20 percent, or 15 percent, or 12 percent, or 11 percent, or 10 percent, or 9 percent, or 8 percent, or 7 percent, or 6 percent, or 5 percent, or 4 percent, or 3 percent, or 2 percent, or 1 percent, as such variations are suitable for performing the disclosed methods and as understood by one of ordinary skill in the art.

[0030] As used in this specification and claims, the terms “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unreferenced elements or method steps.

[0031] As used herein, the term "or a combination thereof" refers to all permutations and combinations of the items preceding the term. For example, "A, B, C, or a combination thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and, if the order is important in the particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, explicitly included are combinations containing repetitions of one or more items or terms, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, etc. Those skilled in the art will understand that there is generally no limit to the number of items or terms in any combination unless it is obvious from the context.

[0032] As used herein, the term "substantially" means that the subsequently described event or situation occurs completely or substantially. For example, when relating to a particular event or situation, the term "substantially" means that the subsequently described event or situation occurs for at least 80% of the time, or at least 85% of the time, or at least 90% of the time, or at least 95% of the time. For example, the term "substantially adjacent" can mean that two items are 100% adjacent to each other, or that two items are very close to each other but not 100% adjacent, or that a portion of one of two items is not 100% adjacent to another item but is very close to another item.

[0033] The term “pharmaceutically acceptable” means a compound or composition that is suitable for administration to humans and / or animals without excessive adverse side effects (such as, but not limited to, toxicity, irritation and / or allergic reactions) and in a manner that is commensurate with a reasonable benefit / risk ratio.

[0034] As used herein, the terms “patient” or “subject” include both human and veterinary subjects. “Mammalian” for therapeutic purposes means any animal classified as a mammal, including (but not limited to) humans, livestock and farm animals, non-human primates, and any other animal with mammary tissue.

[0035] The term "treatment" refers to therapeutic procedures as well as preventative or preventative measures. Individuals requiring treatment include, but are not limited to, individuals who already have a specific condition / disease / infection and individuals at risk of acquiring a specific condition / disease / infection (e.g., individuals requiring preventative / preventative measures). The term "treatment" also refers to the administration of a drug / element / method to a patient for therapeutic and / or preventative / preventative purposes.

[0036] As used herein, the terms “therapeutic composition” or “pharmaceutical composition” refer to a pharmaceutical agent that can be administered in vivo to produce therapeutic and / or preventive / protective effects.

[0037] Administering a therapeutically effective or prophylactically effective dose is intended to provide therapeutic benefit in the treatment, prevention, and / or management of a disease, condition, and / or infection. The specific therapeutically effective dose can be readily determined by a physician of general practice and can vary based on factors known in the art, such as (but not limited to) the type of condition / disease / infection, the patient's medical history and age, the stage of the condition / disease / infection, and the combined administration of other agents.

[0038] The term "effective amount" refers to the amount of a bioactive molecule or its conjugates or derivatives, or the amount of a therapeutic agent (e.g., an alternating electric field), sufficient to produce a detectable therapeutic effect without excessive adverse side effects (such as, but not limited to, toxicity, irritation, and allergic reactions), and is comparable to a reasonable benefit / risk ratio when used in the manner conceived in this invention. Therapeutic effects may include, for example, but not as a limitation, the prevention, inhibition, or reduction of the occurrence of at least one condition, disease, and / or infection. The effective amount for a subject will depend on the type of subject, the subject's body size and health status, the nature and severity of the condition / disease / infection to be treated, the method of administration, the duration of treatment, the nature of concurrent therapies (if any), the specific formulation used, etc. Therefore, it is impossible to predefine an exact effective amount. However, the effective amount for a given situation can be determined by a person skilled in the art using conventional experiments based on the information provided herein.

[0039] As used herein, the term "concurrent therapy" may be used interchangeably with the terms "combined therapy" and "adjunctive therapy," and should be understood to mean that a patient requiring treatment is treated in combination with the treatment of this disclosure, using or receiving another drug targeting the condition / disease / infection. Such concurrent therapy can be sequential therapy, wherein the patient is first treated with one treatment regimen / drug composition, then treated with another treatment regimen / drug composition, or two treatment regimens / drug compositions are administered simultaneously.

[0040] As used herein, the terms “administration” and “administering” should be understood to include all routes of administration known in the art, including but not limited to oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intravitreal, intratumoral, intertumoral, and / or intravenous routes, and include both local and systemic administration. Furthermore, the compositions of this disclosure (and / or their methods of administration) may be engineered to provide delayed, controlled, or sustained release using formulation techniques well known in the art.

[0041] Turning now to the inventive concept, research has found that the use of standard treatments and / or pro-fibrotic chemotherapy drugs (or other pro-fibrotic antitumor therapies) prior to initiating alternating electric field (e.g., TTFields) treatment leads to tumor fibrosis, which reduces the conductivity of the tumor, thereby decreasing the effectiveness of alternating electric field treatment. Therefore, in this disclosure, TTFields cancer treatment is targeted at subjects who have not received standard treatments and / or pro-fibrotic chemotherapy (in some non-limiting embodiments, when receiving pro-fibrotic chemotherapy, other pro-fibrotic antitumor therapies are also included). In some non-limiting embodiments, the cancer treatment may include a concurrent therapy comprising the use of an alternating electric field (e.g., TTFields) and at least one chemotherapy drug. In other non-limiting embodiments, the cancer treatment may include a concurrent therapy comprising the combined use of an alternating electric field (e.g., TTFields) with at least one chemotherapy drug and at least one antifibrotic agent. This disclosure demonstrates that, compared with TTFields-treated subjects who had previously received standard chemotherapy and / or pro-fibrotic chemotherapy / pro-fibrotic antitumor therapy, the survival rate of subjects who had not received standard chemotherapy and / or pro-fibrotic chemotherapy / pro-fibrotic antitumor therapy treated with TTFields therapy was statistically significantly improved. Furthermore, a statistically improved survival rate was observed when TTFields was administered concurrently with chemotherapy drugs (including pro-fibrotic drugs) to patients who had not received standard chemotherapy and / or pro-fibrotic chemotherapy / pro-fibrotic antitumor therapy.

[0042] Table 1 lists various cancers and their current first-line standard chemotherapy regimens.

[0043] Table 1

[0044] cancer First-line standard treatment drugs Glioblastoma Temozolomide (TMZ), bevacizumab, carmustine Mesothelioma Bevacizumab, Carboplatin, Cisplatin, Cyclophosphamide, Doxorubicin, Gemcitabine, Ipilimumab, Nivolumab, Oxaliplatin, Pembrolizumab, Pemetrexed, Raltitrexed, Vinorelbine Ovarian cancer Docetaxel, gemcitabine, paclitaxel, PARP inhibitors pancreatic cancer Capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, pemetrexed Non-small cell lung cancer Carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, vinorelbine

[0045] Certain additional non-limiting embodiments of this disclosure relate to a method for treating cancer in a subject. The method includes the steps of: (1) selecting a subject who has not received (a) standard therapeutic chemotherapy and / or (b) pro-fibrotic chemotherapy and pro-fibrotic antitumor therapy; (2) applying an alternating electric field to a target area of ​​the subject for a period of time; and (3) administering to the subject at least one composition, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0046] Certain additional non-limiting embodiments of this disclosure relate to a method for reducing the volume of a tumor present in the body of a living subject, wherein the tumor comprises multiple cancer cells. The method comprises the steps of: (1) selecting a subject who has not received (a) standard therapeutic chemotherapy and / or (b) pro-fibrotic chemotherapy and pro-fibrotic antitumor therapy; (2) applying an alternating electric field to a target area of ​​the subject for a period of time; and (3) administering to the subject at least one composition, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0047] Certain additional non-limiting embodiments of this disclosure relate to a method for preventing the growth of a tumor, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells. The method comprises the steps of: (1) selecting a subject who has not received (a) standard therapeutic chemotherapy and / or (b) pro-fibrotic chemotherapy and pro-fibrotic antitumor therapy (such as, but not limited to, radiotherapy); (2) applying an alternating electric field to a target area of ​​the subject for a period of time; and (3) administering to the subject at least one composition, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0048] In any of the above methods, the subject may have glioblastoma and has not received standard chemotherapy selected from temozolomide (TMZ), bevacizumab, carmustine, and combinations thereof. In one specific (but not limiting) implementation, the subject has not received TMZ treatment. In another specific (but not limiting) implementation, the subject has not received at least two or all of temozolomide (TMZ), carmustine, and bevacizumab treatment.

[0049] In any of the methods described above, the subject may have mesothelioma and has not received standard chemotherapy selected from bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, vinorelbine, or combinations thereof. In another specific (but not limiting) implementation scheme, the subject has not received at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or all of the following treatments: bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, or vinorelbine.

[0050] In any of the above methods, the subject may have ovarian cancer and has not received standard chemotherapy selected from docetaxel, gemcitabine, paclitaxel, PARP inhibitors, and combinations thereof. In another specific (but not limiting) embodiment, the subject has not received at least two, at least three, or all of docetaxel, gemcitabine, paclitaxel, and PARP inhibitors.

[0051] In any of the methods described above, the subject may have pancreatic cancer and has not received standard chemotherapy selected from capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, pemetrexed, or combinations thereof. In another specific (but not limiting) embodiment, the subject has not received at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following treatments: capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, and pemetrexed.

[0052] In any of the methods described above, the subject may have non-small cell lung cancer and has not received standard chemotherapy selected from carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, vinorelbine, or combinations thereof. In another specific (but not limiting) implementation scheme, the subject has not received at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following treatments: carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, and vinorelbine.

[0053] Certain additional non-limiting embodiments of this disclosure relate to a method for treating cancer in a subject. The method includes the steps of: (1) selecting a subject who has not received excessive rubella treatment; (2) applying an alternating electric field to a target area of ​​the subject for a period of time; and (3) administering to the subject at least one composition, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0054] Certain additional non-limiting embodiments of this disclosure relate to a method for reducing the volume of a tumor present in the body of a living subject, wherein the tumor comprises multiple cancer cells. The method includes the steps of: (1) selecting a subject who has not received excessive rubella treatment; (2) applying an alternating electric field to a target area of ​​the subject for a period of time; and (3) administering to the subject at least one composition, wherein the at least one composition comprises at least one chemotherapeutic agent.

[0055] Certain additional non-limiting embodiments of this disclosure relate to a method for preventing the growth of a tumor, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells. The method includes the steps of: (1) selecting a subject who has not received excessive rubella treatment; (2) applying an alternating electric field to a target area of ​​the subject for a period of time; and (3) administering to the subject at least one composition, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0056] The steps of any method in this disclosure may be performed in combination or sequentially, and in particular substantially simultaneously or wholly or partially sequentially.

[0057] The methods disclosed herein can be used to treat any type of cancer cells / cancers / tumors that respond to alternating electric fields (e.g., TTFields) therapy. Non-limiting examples of cancer cells / cancers / tumors that can be treated according to this disclosure include hepatocellular carcinoma / hepatocellular carcinoma cells, glioblastoma / glioblastoma cells, pleural mesothelioma / pleural mesothelioma cells, differentiated thyroid cancer / differentiated thyroid carcinoma cells, advanced renal cell carcinoma / advanced renal cell carcinoma cells, ovarian cancer / ovarian carcinoma cells, pancreatic cancer / pancreatic carcinoma cells, lung cancer / lung cancer cells, breast cancer / breast cancer cells, colorectal cancer cells, and any combination thereof.

[0058] In a particular (but not limiting) implementation, cancer may be in the form of a solid tumor.

[0059] According to the method of this disclosure, an alternating electric field can be generated using any type of conductive or non-conductive electrode and / or transducer array known in the art or otherwise contemplated herein for the purpose of generating an alternating electric field. According to this disclosure, non-limiting examples of electrode and transducer arrays that can be used to generate alternating electric fields include those that function as part of a TTFields system, such as, but not limited to, the electrode and transducer arrays described in the following patent applications: U.S. Patents Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776; and U.S. Patent Applications Nos. 2018 / 0160933, 2019 / 0117956, 2019 / 0307781, and 2019 / 0308016.

[0060] According to this disclosure, the alternating electric field can be generated at any frequency. For example (but not as a limitation), the frequency of the alternating electric field can be approximately 50 kHz, approximately 75 kHz, approximately 100 kHz, approximately 125 kHz, approximately 150 kHz, approximately 175 kHz, approximately 200 kHz, approximately 225 kHz, approximately 250 kHz, approximately 275 kHz, approximately 300 kHz, approximately 325 kHz, approximately 350 kHz, approximately 375 kHz, approximately 400 kHz, approximately 425 kHz, approximately 450 kHz, approximately 475 kHz, approximately 500 kHz, approximately 550 kHz, approximately 600 kHz, approximately 650 kHz, approximately 700 kHz, approximately 750 kHz, approximately 800 kHz, approximately 850 kHz, approximately 900 kHz, approximately 950 kHz, approximately 1 MHz, approximately 2 MHz, approximately 3 MHz, approximately 4 MHz, approximately 5 MHz, approximately 6 MHz, approximately 7 MHz, approximately 8 MHz, approximately 9 ...1 MHz, approximately 2 MHz, approximately 3 MHz, approximately 4 MHz, approximately 5 MHz, approximately 6 MHz, approximately 7 MHz, approximately 8 MHz, approximately 9 MHz, approximately 1 MHz, approximately 2 MHz, approximately 3 MHz, approximately 4 MHz, approximately 5 MHz, approximately 6 MHz, approximately 7 MHz MHz, approximately 10 MHz, etc., and ranges formed by any of the above values ​​(e.g., a range of approximately 50 kHz to approximately 10 MHz, a range of approximately 50 kHz to approximately 1 MHz, a range of approximately 50 kHz to approximately 500 kHz, a range of approximately 100 kHz to approximately 500 kHz, a range of approximately 150 kHz to approximately 300 kHz, etc.), and ranges of two integers that combine two values ​​falling between the above values ​​(e.g., a range of approximately 122 kHz to approximately 313 kHz, a range of approximately 78 kHz to approximately 298 kHz, etc.).

[0061] In certain specific (but not limiting) embodiments, an alternating electric field may be applied at two or more different frequencies. When two or more frequencies are present, each frequency is selected from any of the values ​​described above, or a range formed by any of the values ​​described above, or a range of two integers falling between two of the values ​​described above.

[0062] The alternating electric field can have any field strength in the subject / cancer cell, as long as the alternating electric field can function according to this disclosure. For example (but not as a limitation), the electric field strength of the alternating electric field can be at least about 1 V / cm, about 1.5 V / cm, about 2 V / cm, about 2.5 V / cm, about 3 V / cm, about 3.5 V / cm, about 4 V / cm, about 4.5 V / cm, about 5 V / cm, about 5.5 V / cm, about 6 V / cm, about 6.5 V / cm, about 7 V / cm, about 7.5 V / cm, about 8 V / cm, about 9 V / cm, about 9.5 V / cm, about 10 V / cm, about 10.5 V / cm, about 11 V / cm, about 11.5 V / cm, about 12 V / cm, about 12.5 V / cm, about 13 V / cm, about 13.5 V / cm, about 14 V / cm, about 14.5 V / cm, about 15 V / cm, about 15.5 V / cm, about 16 V / cm, and about 16.5 V / cm. V / cm, approximately 17 V / cm, approximately 17.5 V / cm, approximately 18 V / cm, approximately 18.5 V / cm, approximately 19 V / cm, approximately 19.5 V / cm, approximately 20 V / cm, etc., and ranges formed by any of the above values ​​(e.g., a range from approximately 1 V / cm to approximately 20 V / cm, a range from approximately 1 V / cm to approximately 10 V / cm, a range from approximately 1 V / cm to approximately 4 V / cm, etc.), and ranges of two integers that combine two values ​​falling between the above values ​​(e.g., a range from approximately 1.1 V / cm to approximately 18.6 V / cm, a range from approximately 1.2 V / cm to approximately 9.8 V / cm, a range from approximately 1.3 V / cm to approximately 4.7 V / cm, etc.).

[0063] An alternating electric field can be applied in a single direction between a pair of arrays, or it can alternate in two or more directions / channels (e.g., front-to-back and left-to-right) between two or more pairs of arrays. For example, certain TTFields devices (such as, but not limited to, the OPTUNE® system (Novocure Limited, St. Helier, Jersey)) operate in both directions to increase the chance that dividing cells will align with the electric field, allowing the field to have the desired anti-mitotic effect. However, it should be understood that the scope of this disclosure also includes applying an alternating electric field in a single direction. As used herein, the term "alternating electric field" should be understood to include application in a single direction / channel as well as application in two or more directions / channels; furthermore, as used herein, the term "alternating electric field" should be understood to include both the application of a single alternating electric field and the continuous application of multiple alternating electric fields over a time duration.

[0064] An alternating electric field can be applied for any continuous or cumulative period of time sufficient to reduce cancer cell viability and / or tumor size (and / or prevent tumor size increase). This period of application of the alternating electric field includes both continuous and cumulative periods. That is, this period of application includes a single treatment session (i.e., continuous application) and multiple treatment sessions with slight rest between sessions (i.e., continuous application within a cumulative period). For example, subjects may be allowed to rest during treatment with the alternating electric field device, and it is anticipated that the device will only be placed on the body and operated for at least approximately 50%, at least approximately 60%, at least approximately 70%, or at least approximately 80% of the total treatment period (e.g., over a day, a week, two weeks, a month, two months, three months, four months, five months, etc.).

[0065] For example, but not as a limitation, the alternating electric field may be applied for a continuous or cumulative period of at least approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, approximately 11 hours, approximately 12 hours, approximately 15 hours, approximately 18 hours, approximately 21 hours, approximately 24 hours, approximately 27 hours, approximately 30 hours, approximately 33 hours, approximately 36 hours, approximately 39 hours, approximately 42 hours, approximately 45 hours, approximately 48 hours, approximately 51 hours, approximately 54 hours, approximately 57 hours, approximately 60 hours, approximately 63 hours, approximately 66 hours, approximately 69 hours, approximately 72 hours, or approximately 75 hours. The ranges are approximately 78 hours, 81 hours, 84 hours, 87 hours, 90 hours, 93 hours, 96 hours, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 21 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc., as well as the ranges formed by any of the above values ​​(e.g., the range from approximately 1 hour to approximately 6 months, the range from approximately 24 hours to approximately 72 hours, etc.), and the ranges of two integers that combine two values ​​falling between the above values ​​(e.g., the range from approximately 14 hours to approximately 68 hours, etc.).

[0066] In one particular (but not limiting) implementation, the period during which the alternating electric field is applied is at least about 24 cumulative hours within a continuous 48-hour period.

[0067] According to this disclosure, any composition known in the art or otherwise contemplated herein as a chemotherapeutic agent may be used, provided that the composition is capable of functioning as described herein. Non-limiting examples include anti-fibrotic (or possibly anti-fibrotic) chemotherapeutic agents, such as (but not limited to) taxanes (such as, but not limited to, paclitaxel, docetaxel, cabazitaxel, and albumin-bound paclitaxel), nimustine, gefitinib, pazopanib, nintedanib, sorafenib, sunitinib, imatinib, everolimus, and combinations thereof. Furthermore, according to this disclosure, chemotherapeutic agents that induce (or may induce) fibrosis may also be used. Non-limiting examples of chemotherapeutic (or potentially fibrotic) drugs include anthracyclines (such as, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, penoxorubicin), bleomycin, carmustine, cisplatin, oxaliplatin, gemcitabine, cyclophosphamide, fluorouracil, leucovorin, capecitabine, mitoxantrone, bevacizumab, carboplatin, olaparib, dacomitinib, raltitrexed, and combinations thereof. Furthermore, chemotherapy drugs that have not previously been shown to have pro-fibrotic effects may also be used; non-limiting examples include temozolomide, docetaxel, lomustine, pemetrexed, vinorelbine, irinotecan, etoposide, afatinib, osimertinib, erlotinib, pazopanib, sotoprazib, ramucirumab, mitusimizumab, nexituzumab, niraparib, durvalumab, atezolizumab, cimiprimab, avelumab, and combinations thereof. Additionally, according to this disclosure, compositions comprising one or more anti-fibrotic (or possibly anti-fibrotic) chemotherapy drugs, one or more pro-fibrotic (or possibly pro-fibrotic) chemotherapy drugs, and / or one or more chemotherapy drugs that have not yet been shown to have any effect on fibrosis may also be used.

[0068] In one particular (but not limiting) implementation, the patient has ovarian cancer, and at least one chemotherapy drug administered to the patient includes paclitaxel.

[0069] As disclosed above, certain chemotherapeutic agents are known in the art to be both antitumor and antifibrotic. Therefore, a chemotherapeutic composition administered to a subject may include a combination of two or more chemotherapeutic agents, wherein at least one chemotherapeutic agent is antifibrotic (or possibly antifibrotic), while another chemotherapeutic agent may be profibrotic (or possibly profibrotic).

[0070] Alternatively (and / or in addition), in some non-limiting embodiments, an antifibrotic agent may also be administered to the subject. The use of an antifibrotic agent may be particularly useful when the chemotherapeutic agent used is profibrotic (or possibly profibrotic), and / or when the chemotherapeutic agent is not antifibrotic (or its ability to induce or reduce fibrosis is unknown); however, an antifibrotic agent may also be used in combination with an antifibrotic (or possibly antifibrotic) chemotherapeutic agent. According to this disclosure, any composition known in the art or otherwise contemplated herein as an antifibrotic agent may be used, provided that the composition is capable of functioning as described herein.

[0071] According to this disclosure, compounds of various classes known to have antifibrotic effects can be used as antifibrotic agents. Non-limiting examples of such compounds include calcium channel blockers, angiotensin II receptor blockers (ARBs), IL11 inhibitors (e.g., IL11 antagonists or IL11 neutralizing antibodies), IL13 inhibitors (e.g., IL13 antagonists or IL13 neutralizing antibodies), receptor tyrosine kinase inhibitors (RTKIs), renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, antihypertensive drugs, and any combination thereof.

[0072] Specific (but not limiting) examples of antifibrotic agents used in this disclosure include losartan, fasudil, pirfenidone, pindananib, nintedanib, hyaluronidase, tranilast, vemodil, felodipine, verapamil, diltiazem, nifedipine, and any combination thereof.

[0073] The compositions disclosed herein may be provided in any formulation known in the art or otherwise contemplated herein. In certain specific (but not limiting) embodiments, the composition comprises one or more pharmaceutically acceptable carriers (and therefore, the composition may also be referred to as a “pharmaceutical composition”). Non-limiting examples of suitable pharmaceutically acceptable carriers include: water; saline; dextran solution; fructose or mannitol; calcium carbonate; cellulose; ethanol; oils of animal, plant, or synthetic origin; carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; detergents; liposome carriers; nanocarriers; scaffold materials for achieving sustained drug release (such as, but not limited to, hydrogels); buffer solutions such as sodium chloride, saline, phosphate-buffered saline, and / or other physiologically acceptable and / or safe substances; diluents; excipients such as polyethylene glycol (PEG); or any combination thereof. Suitable pharmaceutically acceptable carriers for pharmaceutical formulations are described, for example, in Remington: Science and Practice of Pharmacy, 23rd edition (2020).

[0074] In certain specific (but not limiting) embodiments, the compositions disclosed herein may further comprise one or more additional active agents. A variety of active agents that can be used concurrently with alternating electric fields and / or immunomodulatory cytokine inhibitors are known in the art, and certain combination therapies have been FDA approved or are currently being tested in clinical trials.

[0075] Furthermore, any composition disclosed herein may contain other pharmaceutical agents that allow the composition to be administered via a particular route of administration. For example, but not as a limitation, the composition may be formulated for administration via oral, topical, transdermal, parenteral, subcutaneous, intranasal, mucosal, intramuscular, intraperitoneal, intravitreal, intratumoral, and / or intravenous routes. Depending on the route of administration, the composition may contain one or more additional components in addition to the active agent (e.g., an immunomodulatory cytokine inhibitor and / or an adjunct therapeutic agent). Examples of possible adjunctive compounds include, but are not limited to, fillers, salts, buffers, preservatives, stabilizers, solubilizers, wetting agents, emulsifiers, dispersants, gels, binders, and other materials well known in the art.

[0076] In one particular (but not limiting) embodiment, any of the compositions disclosed herein are administered to a subject via injection or implantation. For example (but not as a limitation), in some cases it may be desirable to administer the composition at a local / regional level to ensure that the composition targets a specific location in the subject's body and inhibits non-specific interactions in other parts of the body; in other cases, more systematic administration may be required.

[0077] Any composition disclosed herein (i.e., containing an immune checkpoint inhibitor and / or an MHC class I activator) may be administered before or after the application of an alternating electric field. In certain specific (but not limiting) embodiments, at least one composition may be administered before the application of an alternating electric field. In other specific (but not limiting) embodiments, at least one composition may be administered after the application of an alternating electric field. In particular (but not as a limitation), the composition may be administered during the application of the alternating electric field (e.g., before the end of that period of application of the alternating electric field) and / or after the end of the application of the alternating electric field.

[0078] For example (but not as a limitation), any of the compositions disclosed herein may be applied at least after the application of an alternating electric field for the following periods: about 3 hours, about 6 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, etc., and ranges formed by any of the above values ​​(e.g., a range from about 24 hours to about 96 hours, etc.), and ranges of two integers that combine two values ​​falling between the above values ​​(e.g., a range from about 14 hours to about 94 hours, etc.). In one particular (but not limiting) embodiment, at least one composition is applied at least 24 hours after the alternating electric field is started.

[0079] In other non-limiting examples, any of the compositions disclosed herein may be applied after the end of the period in which the alternating electric field is applied, wherein the one or more compositions are applied for the following time periods after the end of the period: about 3 hours, about 6 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 39 hours, about 42 hours, about 45 hours, about 48 hours, about 51 hours, about 54 hours, about 57 hours, about 60 hours, about 63 hours, about 66 hours, about 69 hours, about 72 hours, about 75 hours, about 78 hours, about 81 hours, about 84 hours, about 87 hours, about 90 hours, about 93 hours, about 96 hours, about 5 days, about 6 days, about 7 days, etc.

[0080] In one particular (but not limiting) embodiment, one or more of the compositions disclosed herein are applied within approximately 96 hours after the end of that period.

[0081] The compositions disclosed herein can be administered to cancer cells / subjects at any concentration of the active agent (i.e., chemotherapeutic agents and / or antifibrotic agents) that provides a therapeutically effective concentration. In some non-limiting embodiments, applying an alternating electric field reduces the amount of active agent required to make the treatment effective compared to a normal therapeutically effective amount of the active agent administered in the absence of an alternating electric field. For example, but not as a limitation, the therapeutically effective concentration of the composition may be reduced by at least about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% or more relative to doses of compositions known to be therapeutically effective without the application of an alternating electric field. In one particular (but non-limiting) embodiment, the therapeutically effective concentration of the composition is reduced by at least about 50% compared to doses of compositions known to be therapeutically effective in the absence of an alternating electric field.

[0082] The therapeutically effective concentration of each active agent used according to this disclosure may be, for example (but not limited to): about 1 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, about 100 nM, about 125 nM, about 150 nM, about 175 nM, about 200 nM, about 250 nM, about 300 nM, about 350 nM, about 400 nM, about 450 nM, about 500 nM, about 550 nM, about 600 nM, about 650 nM, about 700 nM, about 750 nM, about 800 nM, about 850 nM, about 900 nM, about 950 nM, about 1 mM, about 2 mM, about 3 mM, about 4 mM, about 5 mM, about 6 mM, approximately 7 mM, approximately 8 mM, approximately 9 mM, approximately 10 mM, approximately 11 mM, approximately 12 mM, approximately 13 mM, approximately 14 mM, approximately 15 mM, approximately 16 mM, approximately 17 mM, approximately 18 mM, approximately 19 mM, approximately 20 mM, approximately 25 mM, approximately 30 mM, approximately 35 mM, approximately 40 mM, approximately 45 mM, approximately 50 mM, etc., and ranges formed by any of the above values ​​(e.g., a range from approximately 12.5 nM to approximately 100 nM, a range from approximately 1 nM to approximately 20 nM, etc.), and ranges of two integers that combine two values ​​falling between the above values ​​(e.g., a range from approximately 17 nM to approximately 83 nM, etc.).

[0083] In one particular (but not limiting) embodiment, the therapeutically effective concentration of each active agent is from about 10 nM to about 100 nM.

[0084] In certain (but not limiting) embodiments, the therapeutically effective concentration of each active agent used according to this disclosure may be, for example (but not as a limitation): about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 3 ... mg / kg, approximately 34 mg / kg, approximately 35 mg / kg, approximately 36 mg / kg, approximately 37 mg / kg, approximately 38 mg / kg, approximately 39 mg / kg, approximately 40 mg / kg, approximately 41 mg / kg, approximately 42 mg / kg, approximately 43 mg / kg, approximately 44 mg / kg, approximately 45 mg / kg, approximately 46 mg / kg, approximately 47 mg / kg, approximately 48 mg / kg, approximately 49 mg / kg, approximately 50 mg / kg, approximately 51 mg / kg, approximately 52 mg / kg, approximately 53 mg / kg, approximately 54 mg / kg, approximately 55 mg / kg, approximately 56 mg / kg, approximately 57 mg / kg, approximately 58 mg / kg, approximately 59 mg / kg, approximately 60 mg / kg, approximately 65 mg / kg, approximately 70 mg / kg, approximately 75 mg / kg, approximately 80 mg / kg, approximately 85 mg / kg, approximately 90 mg / kg, approximately 95 mg / kg, approximately 100 mg / kg, etc., and ranges formed by any of the above values ​​(e.g., a range of about 10 mg / kg to about 50 mg / kg, a range of about 1 mg / kg to about 40 mg / kg, a range of about 1 mg / kg to about 30 mg / kg, a range of about 1 mg / kg to about 25 mg / kg, a range of about 1 mg / kg to about 20 mg / kg, a range of about 1 mg / kg to about 10 mg / kg, etc.).

[0085] In certain specific (but not limiting) embodiments, the method includes one or more additional steps. For example (but not as a limitation), the method may further include the step of stopping the application of the alternating electric field (such as, but not limited to, allowing cell / tissue recovery). Furthermore, any of these steps may be repeated once or multiple times.

[0086] In certain specific (but not limiting) embodiments, any of the compositions disclosed herein may be administered using any dosing regimen known in the art. For example, but not as a limitation, each composition may be administered in a single dose or multiple doses over a defined period of treatment. For example (but not as a limitation), one or more compositions may be administered at therapeutically effective concentrations at the following frequencies: approximately every 4 hours, approximately every 8 hours, approximately every 12 hours, approximately once daily, approximately every other day, approximately every three days, approximately once weekly, approximately twice weekly, approximately three times weekly, approximately once every two weeks, approximately once every three weeks, approximately once monthly, etc., and ranges formed by any of the above values ​​(ranges from approximately every 4 hours to approximately every 8 hours, from approximately once weekly to approximately once monthly, etc.).

[0087] Furthermore, when multiple compositions are administered (i.e., two or more chemotherapeutic agents, two or more antifibrotic agents, and / or at least one chemotherapeutic agent and at least one antifibrotic agent, wherein at least two agents are present in different compositions), the two or more compositions may be administered via the same route (e.g., both administered intravenously), or the two or more compositions may be administered via different routes (e.g., one composition is administered orally and the other is administered intravenously).

[0088] In certain specific (but not limiting) embodiments, the method involves concurrent therapy using additional supplementary compositions. Therefore, the method may include the additional step of administering at least one additional therapeutic composition to cancer cells / the subject.

[0089] When present, the application of at least one additional therapeutic composition may be performed substantially simultaneously with or wholly or partially sequentially with the application of any composition containing an immunomodulatory cytokine inhibitor, such that individual compositions may be applied simultaneously or wholly or partially sequentially. Furthermore, when the method includes the application of the additional composition, the optional application steps may be performed in the same manner and time range as described above for the other compositions, before or after the application of the alternating electric field, during the application of the alternating electric field, and / or after the application of the alternating electric field has ended.

[0090] In certain specific (but non-limiting) embodiments, the method may further include the step of administering at least one additional therapy to the cells / subject. Any therapy known in the art or otherwise contemplated herein for use with alternating electric fields (e.g., TTFields), chemotherapeutic agents, and / or antifibrotic agents may be used according to the methods of this disclosure. Non-limiting examples of possible additional therapies include radiotherapy, photodynamic therapy, transarterial chemoembolization (TACE), or combinations thereof.

[0091] Any step in the procedure may be repeated once or multiple times. Each step within the procedure may be repeated multiple times as needed. When repeating the step of applying the alternating electric field, the transducer array may be placed on the subject in a slightly different location from its original placement; repositioning the array in this way can further aid in the treatment of tumors / cancer. Furthermore, any step in the procedure of administering any composition / additional therapy may be repeated a different number of times and at different intervals to follow any known and / or generally accepted dosage / treatment regimen of the composition / therapy.

[0092] Certain non-limiting embodiments of this disclosure relate to kits that include any components of an alternating electric field (e.g., TTFields) generating system disclosed herein or otherwise contemplated (such as, but not limited to, one or more transducer arrays and / or one or more hydrogel compositions, as disclosed in: U.S. Patent Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776; and U.S. Patent Application Nos. US 2018 / 0160933, US 2019 / 0117956, US 2019 / 0307781, and US 2019 ...60933, US 2019 / 011 (No. 2019 / 0308016), any component thereof is combined with at least one of the compositions disclosed herein or otherwise contemplated. The kit may optionally further include one or more of the optional compositions disclosed herein or otherwise contemplated (such as, but not limited to, one or more optional compositions comprising at least one additional active agent). The kit may optionally further include one or more devices (or one or more components of a device) used in one or more additional therapeutic steps.

[0093] In one particular (but not limiting) embodiment, the kit may further include instructions for performing any of the methods disclosed herein or otherwise contemplated. For example (but not as a limitation), the kit may include instructions for applying one or more components of an alternating electric field (e.g., TTFields) generating device to a patient's skin, instructions for applying an alternating electric field to a patient, instructions for formulating one or more compositions in the composition, instructions for when and how to apply one or more compositions, and / or instructions for when to activate and deactivate the alternating electric field relative to the application of the composition and / or optional therapeutic steps.

[0094] In addition to the components described in detail above, the kit may further contain other components / reagents for performing any specific method of the particular method described herein or otherwise contemplated. For example (but not as a limitation), the kit may additionally include: (i) components for preparing the skin prior to treatment of the hydrogel composition and / or the transducer array thereon (e.g., razor, cleaning composition, or wipe / towel, etc.); (ii) components for removing the gel / transducer array; (iii) components for cleaning the skin after removing the gel / transducer array; and / or (iv) other components for use with the system (e.g., conductive materials, non-conductive materials, emollient gels or creams, bandages, etc.). The nature of these additional components / reagents will depend on the specific form of treatment, and their identification is entirely within the skill of a person skilled in the art; therefore, further description of them is not considered necessary. Moreover, the components / reagents present in the kit may each be located in a separate container / compartment, or various components / reagents may be combined and located in one or more containers / compartments, depending on the sterility, cross-reactivity, and stability of the components / reagents.

[0095] The kit can be placed in any packaging that allows the components present therein to function according to this disclosure. In some non-limiting embodiments, the kit also includes a sealed package in which the components are placed. In some specific (but non-limiting) embodiments, the sealed package is substantially airtight and / or substantially lighttight.

[0096] Furthermore, the kit may include a set of written instructions explaining how to use one or more components of the kit. Kits of this nature can be used in any of the methods described herein or otherwise conceived.

[0097] In some non-limiting embodiments, the kit has a shelf life of at least about 6 months, such as (but not limited to) at least about 9 months or at least about 12 months.

[0098] Certain non-limiting embodiments of this disclosure relate to systems comprising any components of an alternating electric field generating system disclosed herein or otherwise contemplated (such as, but not limited to, one or more transducer arrays and / or one or more hydrogel compositions, as disclosed in: U.S. Patent Nos. 7,016,725, 7,089,054, 7,333,852, 7,565,205, 8,244,345, 8,715,203, 8,764,675, 10,188,851, and 10,441,776; and U.S. Patent Application Nos. US 2018 / 0160933, US 2019 / 0117956, US 2019 / 0307781, and US 2019 / 0160933). (No. 2019 / 0308016), any component thereof is combined with at least one of the compositions disclosed herein or otherwise contemplated. The system may optionally further include one or more of the compositions disclosed herein or otherwise contemplated. The system may optionally further include one or more devices (or one or more components of devices) used in one or more additional therapeutic steps.

[0099] Example

[0100] Examples are provided below. However, this disclosure should be understood to be limited in its application to the specific experiments, results, and laboratory procedures disclosed below. Rather, the examples are provided only as one of various implementations and are exemplary, not exhaustive.

[0101] Example 1

[0102] Ovarian cancer is one of the top ten deadliest cancers among women worldwide, with an age-standardized mortality rate of 4.0 per 100,000 people in 2022. Approximately 20-30% of patients with high-grade serous ovarian cancer develop primary resistance to platinum-based drugs; patients who are sensitive to platinum-based drugs are likely to relapse and develop progressive resistance over time.

[0103] Treatment options for platinum-resistant ovarian cancer (PROC) include systemic chemotherapy alone (i.e., paclitaxel, gemcitabine, doxorubicin, and topotecan) or in combination with bevacizumab, as well as mituximab-solavtansin-gynx. However, despite these available options, the prognosis for PROC remains poor (median overall survival (OS) is approximately 10–12 months). Therefore, there is still an urgent need for further innovative, well-tolerated, and effective treatments.

[0104] TTFields therapy works by applying an electric field to disrupt cellular processes crucial for cancer cell viability and tumor progression. TTFields exerts an antimitotic effect by disrupting microtubules and enhances the effects of taxanes, which target tubulin and induce cell cycle arrest. Furthermore, TTFields, when used in combination with paclitaxel, has shown efficacy in preclinical ovarian models (Voloshin et al., (2016) Int J Cancer, 139(12):2850-2858). TTFields therapy has received multiple regulatory approvals worldwide for the treatment of glioblastoma and pleural mesothelioma, and has also demonstrated efficacy and a good safety profile in metastatic non-small cell lung cancer. TTFields is a non-invasive, localized treatment delivered to the abdomen via a portable medical device and two pairs of arrays. It is recommended to use the system substantially continuously (≥18 hours / day).

[0105] The INNOVATE pilot study (NCT02244502) demonstrated that weekly paclitaxel-based TTFields therapy is safe and feasible in 31 patients with recurrent ovarian cancer (Vergote et al., (2018) Gynecol Oncol, 150(3):471-477). The median progression-free survival (PFS) was 8.9 months, and the median overall survival (OS) has not yet been reached; the 1-year survival rate was 61%.

[0106] The antimitotic effect of TTFields is dose-dependent and may be affected by changes in tissue conductivity. Preclinical data (unpublished) show that doxorubicin can induce tumor fibrosis and alter tissue conductivity.

[0107] This randomized phase 3 study investigated the efficacy of TTFields therapy in combination with paclitaxel (TTFields+PTX) versus paclitaxel (PTX) in patients with platinum-resistant ovarian cancer (PROC).

[0108] To evaluate the safety and efficacy of TTFields therapy combined with weekly paclitaxel treatment compared with weekly paclitaxel treatment alone in the PROC, the following methods were used. Figure 1 The phase 3 study design is shown. ENGOT-ov50 / GOG-3029 / INNOVATE-3 (NCT03940196) enrolled adults with PROC (prolapsed cerebral arteriosclerosis) who had ≤5 prior lines of therapy (LOT), ≤2 prior LOT after platinum resistance, and an ECOG of 0–1. Patients received TTFields (200 kHz; ≥18 hours / day) + PTX (80 mg / m²). 2) Once a week or PTX. The primary endpoint was overall survival (OS). From March 2019 to November 2021, 558 patients were randomized to receive TTFields+PTX (n=280) or PTX (n=278).

[0109] like Figure 2 As shown, the baseline characteristics of the two study groups were well-balanced (median age, 62 [22–91] years; serous histology, 88.7%; ECOG 0, 60.2%; BRCA+, 15.6%). Patients in the ITT population had received extensive pretreatment, with 24.4% having received four or more lines of prior therapy (LOT) and 65.9% having received prior bevacizumab therapy. In the overall intention-to-treat population, the median duration of TTFields therapy was 15.9 (0.1–159.7) weeks.

[0110] like Figure 3 As shown, the median overall survival (OS) for TTFields plus paclitaxel (TTFields+PTX) was 12.2 months, while the median OS for paclitaxel alone (PTX) was 11.9 months (HR, 1.01; 95% CI, 0.83–1.24; p = 0.89). Therefore, when examined across the entire cohort, TTFields plus paclitaxel did not significantly prolong survival compared to paclitaxel alone.

[0111] Therefore, subgroup analysis and exploratory analysis were conducted. Figure 4 Subgroup analyses based on stratification factors and exploratory analysis were summarized. No differences were observed in subgroup analyses based on stratification factors. However, multivariate Cox regression analysis to exclude other covariates showed that TTFields and previous PLD* status were statistically significant covariates after stepwise narrowing.

[0112] In addition, multivariate analysis was performed, such as Figure 5 As shown. The model parameters assessed included group, group × prior PLD* use, prior bevacizumab use, BRCA status, number of post-platinum lines, number of prior lines, prior PARP, FIGO stage, grade, ascites, platinum-free interval, patient age, and ECOG. ε indicates variables retained in the model, limited by a significance level of 0.25 for exclusion. The inclusion of the interaction between treatment group and prior PLD* use produced significant results for the treatment group.

[0113] Based on these analyses, a subgroup that had not received PLD* treatment was analyzed. Figure 6The demographic and baseline characteristics of the subgroup that did not receive PLD* treatment compared to the overall ITT population are listed. The subgroup that did not receive PLD* treatment comprised 36% of the ITT population.

[0114] Figure 7 Overall survival was depicted in the PLD*-naïve subgroup. A post-hoc analysis of patients who had not received pegylated liposomal doxorubicin (PLD) showed that TTFields + PTX (n=113) was associated with prolonged survival compared to PTX (n=88) (16 months vs 11.7 months; HR, 0.67; 95% CI, 0.49–0.94; p=0.03). Therefore, a significantly improved survival was observed in the PLD*-naïve subgroup compared to the overall cohort (12.2 months with TTFields plus paclitaxel (TTFields + PTX) vs 11.9 months with paclitaxel alone (PTX)). Figure 3 ).

[0115] In addition, a safety analysis was performed on adverse events (AEs), such as Figure 8 As shown. The incidence of ≥ grade 3 adverse events (AEs) was similar between the two treatment groups. 60% of patients experienced ≥ grade 3 adverse events (AEs), and no increase in serious systemic toxicity associated with TTFields was observed; device-related skin AEs (all grade 1 / 2) occurred in 83.6% of patients treated with TTFields. The most common ≥ grade 3 AE was leukopenia, which was similar between the two groups. TTFields did not increase systemic AEs compared with paclitaxel alone. No new safety signals were identified in the PLD*-naïve subgroup (data not shown).

[0116] In addition, a safety analysis was conducted on adverse events (AEs) particularly associated with TTFields therapy, such as... Figure 9 As shown, 83.6% of patients receiving TTFields therapy experienced Grade 1 / 2 device-related skin adverse events (AEs). TTFields therapy did not result in Grade 4 AEs or death. Furthermore, no new safety signals were identified in the subgroup that had not received PLD* treatment (data not shown).

[0117] in conclusion

[0118] In the overall cohort, TTFields+PTX did not improve overall survival compared to PTX. However, post-hoc analysis showed that TTFields therapy significantly improved survival both clinically and statistically in PROC patients who had not received PLD* treatment (representing one-third of the ITT population). TTFields therapy was well-tolerated in PROC patients, with no additional systemic toxicity and no new safety signals. These results demonstrate the therapeutic value of TTFields therapy in PROC patients who have not received PLD treatment.

[0119] Example 2

[0120] The Innovate-3 study excluded patients who had received doxorubicin treatment prior to TTFields + paclitaxel or paclitaxel treatment.

[0121] This embodiment includes further data related to the study in Embodiment 1. Figure 10-11 Data included patients with PROC who had received or not received doxorubicin / PLD prior to treatment and received TTFields plus paclitaxel or paclitaxel alone. In the case of prior doxorubicin treatment, overall survival with TTFields was 10.97 months, and overall survival without TTFields was 13.21 months. In contrast, in the group that had not previously received doxorubicin / PLD, overall survival with TTFields was 18 months, and overall survival without TTFields was 11.93 months. Furthermore, the hazard ratio for TTFields in the case of no prior doxorubicin / PLD treatment was 0.593 (p=0.005).

[0122] Figure 12 The multivariate analysis of this embodiment is illustrated. As shown in the figure, compared with paclitaxel alone, patients who had not received PLD treatment had a 36% lower risk of death when receiving TTFields + paclitaxel. Furthermore, when treated with TTFields, patients who had not received PLD treatment had a 44% lower risk of death compared with patients who had previously received PLD treatment.

[0123] Non-limiting exemplary embodiments of the present invention

[0124] Exemplary Implementation 1: A method for treating cancer in a subject, the method comprising the steps of: (1) selecting a subject who has not received treatment with at least one standard chemotherapy drug for the cancer to be treated; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0125] Exemplary Implementation 2: A method for reducing the volume of a tumor present in the body of a living subject, wherein the tumor comprises multiple cancer cells, the method comprising the steps of: (1) selecting a subject who has not received treatment with at least one standard therapeutic chemotherapy drug for the cancer to be treated; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0126] Exemplary Implementation 3: A method for preventing tumor growth, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells, the method comprising the steps of: (1) selecting a subject who has not received treatment with at least one standard chemotherapy drug for the cancer to be treated; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0127] Exemplary Implementation 3A: The method according to any one of Exemplary Implementations 1-3, wherein at least one standard therapeutic chemotherapy drug that the subject has not received is further defined as at least one profibrotic chemotherapy drug.

[0128] Exemplary Implementation 3B: The method according to any one of Exemplary Implementations 1-3, wherein at least one standard treatment chemotherapy drug that the subject has not received is further defined as at least one antifibrotic chemotherapy drug.

[0129] Exemplary Implementation 3C: The method according to any one of Exemplary Implementations 1-3, wherein at least one standard treatment chemotherapy drug that the subject has not received is further defined as at least one non-fibrotic chemotherapy drug or at least one chemotherapy drug with an unknown fibrotic status.

[0130] Exemplary Implementation 3D: The method according to any one of Exemplary Implementations 1-3, wherein the subject has not received any of the current standard treatment chemotherapy drugs for the cancer to be treated.

[0131] Exemplary Implementation 4: A method for treating cancer in a subject, the method comprising the steps of: (1) selecting a subject who has not received profibrotic chemotherapy and profibrotic antitumor therapy for the cancer to be treated; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0132] Exemplary Implementation 5: A method for reducing the volume of a tumor present in the body of a living subject, wherein the tumor comprises multiple cancer cells, the method comprising the steps of: (1) selecting a subject who has not received profibrotic chemotherapy and profibrotic antitumor therapy for the cancer to be treated; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0133] Exemplary Implementation 6: A method for preventing tumor growth, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells, the method comprising the steps of: (1) selecting a subject who has not received profibrotic chemotherapy and profibrotic antitumor therapy for the cancer to be treated; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0134] Exemplary Implementation 7: The method according to any one of Exemplary Implementations 1-6 further includes the step of: (3) administering at least one composition to the subject, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0135] Exemplary Implementation 7A: The method according to Exemplary Implementation 7, wherein at least one composition administered to the subject in step (3) comprises at least one antifibrotic chemotherapy drug.

[0136] Exemplary Implementation 7B: The method according to Exemplary Implementation 7, wherein at least one composition administered to the subject in step (3) comprises at least one non-fibrotic chemotherapy drug.

[0137] Exemplary Implementation 7C: The method according to Exemplary Implementation 7, wherein at least one composition administered to the subject in step (3) comprises at least one profibrotic chemotherapeutic drug.

[0138] Exemplary Implementation 8: The method according to any one of Exemplary Implementations 1-7C, wherein the subject has glioblastoma and wherein the subject has not received treatment with at least one standard therapeutic chemotherapy drug selected from temozolomide (TMZ), bevacizumab, carmustine, and combinations thereof.

[0139] Exemplary Implementation 8A: The method according to Exemplary Implementation 8, wherein the subject has not received at least two of the following treatments: temozolomide (TMZ), bevacizumab, and carmustine.

[0140] Exemplary Implementation 8B: The method according to Exemplary Implementation 8, wherein the subject has not received treatment with temozolomide (TMZ), bevacizumab, and carmustine.

[0141] Exemplary Implementation 9: The method according to any one of Exemplary Implementations 1-8B, wherein the subject has mesothelioma and wherein the subject has not received standard treatment chemotherapy drugs selected from bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, vinorelbine, and combinations thereof.

[0142] Exemplary Implementation 9A: The method according to Exemplary Implementation 9, wherein the subject has not received at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve treatments from the following: bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, and vinorelbine.

[0143] Exemplary Implementation 9B: The method according to Exemplary Implementation 9, wherein the subject has not received all of the following treatments: bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, and vinorelbine.

[0144] Exemplary Implementation 10: The method according to any one of Exemplary Implementations 1-9B, wherein the subject has ovarian cancer and wherein the subject has not received treatment with at least one standard therapeutic chemotherapy drug selected from docetaxel, gemcitabine, paclitaxel, PARP inhibitors and combinations thereof.

[0145] Exemplary Implementation 10A: The method according to Exemplary Implementation 10, wherein the subject has not received at least two or at least three of docetaxel, gemcitabine, paclitaxel and PARP inhibitors.

[0146] Exemplary Implementation 10B: The method according to Exemplary Implementation 10, wherein the subject has not received all of the treatments among docetaxel, gemcitabine, paclitaxel and PARP inhibitors.

[0147] Exemplary Implementation 11: The method according to any one of Exemplary Implementations 1-10B, wherein the subject has pancreatic cancer and wherein the subject has not received treatment with at least one standard chemotherapy drug selected from capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, pemetrexed, and combinations thereof.

[0148] Exemplary Implementation 11A: The method according to Exemplary Implementation 11, wherein the subject has not received at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine treatments from capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, and pemetrexed.

[0149] Exemplary Implementation 11B: The method according to Exemplary Implementation 11, wherein the subject has not received all of the following treatments: capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, and pemetrexed.

[0150] Exemplary Implementation 12: The method according to any one of Exemplary Implementations 1-11B, wherein the subject has non-small cell lung cancer and wherein the subject has not received treatment with at least one standard chemotherapy drug selected from carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, vinorelbine and combinations thereof.

[0151] Exemplary Implementation 12A: The method according to Exemplary Implementation 12, wherein the subject has not received at least two, at least three, at least four, at least five, at least six, or at least seven treatments from carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, and vinorelbine.

[0152] Exemplary Implementation 12B: The method according to Exemplary Implementation 12, wherein the subject has not received all of the treatments in carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, and vinorelbine.

[0153] Exemplary Implementation 13: A method for treating cancer in a subject, the method comprising the steps of: (1) selecting a subject who has not received excessive rubicin treatment; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0154] Exemplary Implementation 14: A method for reducing the volume of a tumor present in the body of a living subject, wherein the tumor comprises multiple cancer cells, the method comprising the steps of: (1) selecting a subject who has not received excessive rubicin treatment; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0155] Exemplary Implementation 15: A method for preventing tumor growth, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells, the method comprising the steps of: (1) selecting a subject who has not received excessive rubicin treatment; and (2) applying an alternating electric field to a target area of ​​the subject for a period of time.

[0156] Exemplary Implementation 16: The method according to any one of Exemplary Implementations 13-15 further includes the step of: (3) administering at least one composition to the subject, wherein the at least one composition comprises at least one chemotherapeutic drug.

[0157] Exemplary Implementation 17: The method according to any one of Exemplary Implementations 1-16, wherein at least one of the following is true: the frequency of the applied alternating electric field is in the range of about 50 kHz to about 1 MHz; the alternating electric field has an electric field strength of at least about 1 V / cm in at least a portion of the cancer cells / target region of the subject; and the time during which the alternating electric field is applied is at least about 50% of a continuous 24-hour time period (i.e., at least about 12 cumulative hours in the 24-hour time period).

[0158] Exemplary Implementation 18: The method according to any one of Exemplary Implementations 1-17, wherein the application of at least one composition is performed completely or partially simultaneously with the initiation of the application of an alternating electric field.

[0159] Exemplary Implementation 19: The method according to any one of Exemplary Implementations 1-18, wherein at least one composition is applied after the alternating electric field is started.

[0160] Exemplary Implementation 20: The method according to Exemplary Implementation 19, wherein at least one composition is applied before the end of the time period during which the alternating electric field is applied.

[0161] Exemplary Implementation 21: The method according to Exemplary Implementation 19, wherein at least one composition is applied after the end of the time period.

[0162] Exemplary Implementation 22: The method according to any one of Exemplary Implementations 1-21, wherein any of these steps is repeated once or multiple times.

[0163] Exemplary Implementation 23: The method according to any one of Exemplary Implementations 1-22, wherein the cancer is at least one form of solid tumor.

[0164] Exemplary Implementation 24: The method according to any one of Exemplary Implementations 1-23, wherein at least one chemotherapeutic agent is selected from paclitaxel, nimustine, gefitinib, pazopanib, nintedanib, sorafenib, sunitinib, imatinib, everolimus, temozolomide, docetaxel, lomustine, pemetrexed, vinorelbine, irinotecan, etoposide, afatinib, osimertinib, erlotinib, pazopanib, sotorasib, ramucirumab, mitoxiximab, nexituzumab, niraparib, durvalumab, atezolizumab, cimiprimab, avelumab, and combinations thereof.

[0165] Exemplary Implementation 25: The method according to any one of Exemplary Implementations 1-24, optionally wherein the composition applied in step (3) (when present) further comprises at least one anti-fibrotic agent.

[0166] Exemplary Implementation 26: The method according to any one of Exemplary Implementations 1-25, wherein the method further comprises the step of: (4) administering at least one additional composition to the subject, wherein the at least one additional composition comprises at least one antifibrotic agent.

[0167] Exemplary implementation 27: The method according to exemplary implementation 26, wherein steps (3) and (4) are performed simultaneously.

[0168] Exemplary Implementation 28: The method according to Exemplary Implementation 26, wherein steps (3) and (4) are performed in whole or in part sequentially.

[0169] Exemplary Implementation 29: The method according to any one of Exemplary Implementations 25-28, wherein at least one antifibrotic agent is selected from calcium channel blockers, angiotensin II receptor blockers (ARBs), IL11 inhibitors, IL13 inhibitors, receptor tyrosine kinase inhibitors (RTKIs), renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, antihypertensive drugs, and combinations thereof.

[0170] Exemplary Implementation 30: The method according to any one of Exemplary Implementations 25-29, wherein at least one antifibrotic agent is selected from losartan, fasudil, pirfenidone, pindananib, nintedanib, hyaluronidase, tranilast, vemodigine, felodipine, verapamil, diltiazem, nifedipine, and combinations thereof.

[0171] Exemplary Implementation 31: The method according to any one of Exemplary Implementations 25-30, optionally wherein at least one chemotherapeutic agent (when present) applied in step (3) comprises at least one anthracycline.

[0172] Exemplary Implementation 32: The method according to any one of Exemplary Implementations 25-31, optionally wherein at least one chemotherapeutic agent (when present) administered in step (3) is selected from paclitaxel, nimustine, gefitinib, pazopanib, nintedanib, sorafenib, sunitinib, imatinib, everolimus, temozolomide, docetaxel, lomustine, pemetrexed, raltitrexed, vinorelbine, irinotecan, etoposide, afatinib, osimertinib, erlotinib, and pazopanib. Zopanib, sotorazib, ramucirumab, mituximab, nexituzumab, niraparib, durvalumab, atezolizumab, cimiprimab, averumab, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, penoxorubicin, bleomycin, carmustine, doxorubicin, cisplatin, oxaliplatin, gemcitabine, cyclophosphamide, fluorouracil, leucovorin, capecitabine, mitoxantrone, bevacizumab, carboplatin, olaparib, dacomitinib, and combinations thereof.

[0173] Exemplary Implementation 33: The method according to any one of Exemplary Implementations 1-32, wherein at least one of steps (2) and (3) (and step (4, if present)) is repeated once or more.

[0174] Exemplary Implementation 34: The method according to any one of Exemplary Implementations 1-33, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, pleural mesothelioma, differentiated thyroid carcinoma, advanced renal cell carcinoma, ovarian cancer, pancreatic cancer, lung cancer, breast cancer, colorectal cancer, and combinations thereof.

[0175] Exemplary Implementation 35: The method according to Exemplary Implementation 34, wherein the cancer is ovarian cancer, and optionally wherein at least one chemotherapy drug (if present) administered in step (3) includes paclitaxel.

[0176] Exemplary Implementation 36: The method according to any one of Exemplary Implementations 1-35, wherein the cancer to be treated is selected from soft tissue cancer, bone cancer, breast cancer, ovarian cancer, bladder cancer, thyroid cancer and small cell lung cancer; wherein at least one standard treatment chemotherapy drug not previously received by the subject includes doxorubicin, and optionally wherein at least one chemotherapy drug administered in step (3) (when present) includes paclitaxel.

[0177] Exemplary Implementation 37: The method according to any one of Exemplary Implementations 1-36, wherein the cancer to be treated is ovarian cancer, wherein at least one standard treatment chemotherapy drug that the subject has not received includes doxorubicin, and optionally wherein at least one chemotherapy drug administered in step (3) (when present) includes paclitaxel.

[0178] Exemplary Implementation 38: The method according to any one of Exemplary Implementations 1-37 is further defined as a method for reducing the volume of a tumor, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells.

[0179] Exemplary Implementation 39: The method according to any one of Exemplary Implementations 1-38 is further defined as a method for preventing the increase in volume of a tumor, wherein the tumor is present in the body of a living subject and comprises multiple cancer cells.

[0180] Exemplary implementation 40: The method according to any one of exemplary implementations 1-39, wherein the method is performed without step (3) (i.e., alternating electric field single therapy method).

[0181] Exemplary embodiment 41: A composition comprising at least one chemotherapeutic agent for use in any one of exemplary embodiments 1-40.

[0182] Exemplary Embodiment 41A: The composition according to Exemplary Embodiment 41, wherein at least one chemotherapeutic agent is further defined as at least one antifibrotic chemotherapeutic agent.

[0183] Exemplary Implementation 41B: The composition according to Exemplary Implementation 41, wherein at least one chemotherapeutic agent is further defined as at least one profibrotic (or possibly profibrotic) chemotherapeutic agent.

[0184] Exemplary embodiment 41C: The composition according to exemplary embodiment 41, wherein at least one chemotherapeutic agent is further defined as at least one non-fibrotic chemotherapeutic agent or a chemotherapeutic agent with an unknown fibrotic state.

[0185] Exemplary embodiment 42: The composition according to any one of exemplary embodiments 41-41C further includes at least one anti-fibrotic agent.

[0186] Exemplary embodiment 43: A combination therapy comprising an alternating electric field and at least one composition including at least one chemotherapeutic drug, for use in any one of exemplary embodiments 1-40.

[0187] Exemplary Implementation 43A: The combination therapy according to Exemplary Implementation 43, wherein at least one chemotherapy drug is further defined as at least one antifibrotic chemotherapy drug.

[0188] Exemplary Implementation 43B: The combination therapy according to Exemplary Implementation 43, wherein at least one chemotherapy drug is further defined as at least one profibrotic (or possibly profibrotic) chemotherapy drug.

[0189] Exemplary Implementation 43C: The combination therapy according to Exemplary Implementation 43, wherein at least one chemotherapy drug is further defined as at least one non-fibrotic chemotherapy drug or a chemotherapy drug with an unknown fibrotic state.

[0190] Exemplary embodiment 44: The combination therapy according to any one of exemplary embodiments 43-43C further includes at least one additional composition, wherein the at least one additional composition includes at least one antifibrotic agent.

[0191] Exemplary Embodiment 45: A kit for the method according to any one of Exemplary Embodiments 1-40, the kit comprising: an alternating electric field generating device; and at least one composition comprising at least one chemotherapeutic drug.

[0192] Exemplary Implementation 45A: The kit according to Exemplary Implementation 45, wherein at least one chemotherapeutic drug is further defined as at least one antifibrotic chemotherapeutic drug.

[0193] Exemplary Implementation 45B: The kit according to Exemplary Implementation 45, wherein at least one chemotherapeutic drug is further defined as at least one profibrotic (or possibly profibrotic) chemotherapeutic drug.

[0194] Exemplary Implementation 45C: The kit according to Exemplary Implementation 45, wherein at least one chemotherapy drug is further defined as at least one non-fibrotic chemotherapy drug or a chemotherapy drug with an unknown fibrotic state.

[0195] Exemplary Embodiment 46: The kit according to any one of Exemplary Embodiments 45-45C further comprises at least one additional composition, wherein the at least one additional composition comprises at least one anti-fibrotic agent.

[0196] Exemplary Implementation 47: A system for the method according to any one of Exemplary Implementations 1-40, the system comprising: an alternating electric field generating device; and at least one composition comprising at least one chemotherapeutic drug.

[0197] Exemplary Implementation 47A: The system according to Exemplary Implementation 47, wherein at least one chemotherapeutic drug is further defined as at least one antifibrotic chemotherapeutic drug.

[0198] Exemplary Implementation 47B: The system according to Exemplary Implementation 47, wherein at least one chemotherapeutic agent is further defined as at least one profibrotic (or possibly profibrotic) chemotherapeutic agent.

[0199] Exemplary Implementation 47C: The system according to Exemplary Implementation 47, wherein at least one chemotherapeutic agent is further defined as at least one non-fibrotic chemotherapeutic agent or a chemotherapeutic agent with an unknown fibrotic state.

[0200] Exemplary embodiment 48: The system according to any one of exemplary embodiments 47-47C further includes at least one additional composition, wherein the at least one additional composition includes at least one anti-fibrotic agent.

[0201] Exemplary Implementation 49: A composition / combination therapy / kit / system according to any one of Exemplary Implementations 42, 44, 46 or 48, wherein at least one antifibrotic agent is selected from calcium channel blockers, angiotensin II receptor blockers (ARBs), IL11 inhibitors, IL13 inhibitors, receptor tyrosine kinase inhibitors (RTKIs), renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, antihypertensive drugs, and combinations thereof.

[0202] Exemplary Implementation 50: A composition / combination therapy / kit / system according to any one of Exemplary Implementations 41A, 43A, 45A or 47A, wherein the antifibrotic chemotherapy drug is selected from taxanes, paclitaxel, docetaxel, cabazitaxel, albumin-bound paclitaxel, nimustine, gefitinib, pazopanib, nintedanib, sorafenib, sunitinib, imatinib, everolimus and combinations thereof.

[0203] Exemplary Implementation 51: A composition / combination therapy / kit / system according to any one of Exemplary Implementations 41B, 43B, 45B or 47B, wherein the profibrotic (or possibly profibrotic) chemotherapeutic agent is selected from anthracyclines, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, penoxorubicin, bleomycin, carmustine, cisplatin, oxaliplatin, gemcitabine, cyclophosphamide, fluorouracil, leucovorin, capecitabine, mitoxantrone, bevacizumab, carboplatin, olaparib, dacomitinib, raltitrexed and combinations thereof.

[0204] Exemplary Implementation 52: A composition / combination therapy / kit / system according to any one of Exemplary Implementations 41C, 43C, 45C or 47C, wherein the chemotherapeutic agent is selected from temozolomide, docetaxel, lomustine, pemetrexed, vinorelbine, irinotecan, etoposide, afatinib, osimertinib, erlotinib, pazopanib, sotorazib, ramucirumab, mitoxiximab, nexituzumab, niraparib, durvalumab, atezolizumab, cimiprimab, avelumab, and combinations thereof.

[0205] While the appended disclosure describes the inventive concept in conjunction with the specific experiments, results, and language set forth below, many alternatives, modifications, and variations will be apparent to those skilled in the art. Therefore, this disclosure is intended to cover all such alternatives, modifications, and variations that fall within the spirit and broad scope of this disclosure.

Claims

1. A combination therapy for treating cancer in a subject, the subject having not received at least one standard chemotherapy drug for the cancer to be treated, wherein the cancer is at least one form of solid tumor, the combination therapy comprising: Alternating electric field; as well as At least one composition comprising at least one chemotherapeutic drug.

2. The combined treatment according to claim 1, wherein at least one of the following: (i) The cancer to be treated is selected from soft tissue cancer, bone cancer, breast cancer, ovarian cancer, bladder cancer, thyroid cancer and small cell lung cancer, and wherein the at least one standard chemotherapy drug that the subject has not received includes doxorubicin; (ii) wherein the cancer to be treated is glioblastoma, and wherein the subject has not received at least one standard chemotherapy drug selected from temozolomide (TMZ), bevacizumab, carmustine, and combinations thereof; (iii) wherein the cancer to be treated is mesothelioma, and wherein the subject has not received at least one standard chemotherapy drug selected from bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, vinorelbine, or combinations thereof. (iv) wherein the cancer to be treated is ovarian cancer, and wherein the subject has not received at least one standard chemotherapy drug selected from docetaxel, gemcitabine, paclitaxel, PARP inhibitors and combinations thereof; (v) wherein the cancer to be treated is pancreatic cancer, and wherein the subject has not received standard chemotherapy treatment with at least one of capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, pemetrexed, or combinations thereof; or (vi) wherein the cancer to be treated is non-small cell lung cancer, and wherein the subject has not received at least one standard chemotherapy drug selected from carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, vinorelbine and combinations thereof.

3. The combination therapy according to claim 1 or 2, wherein the cancer to be treated is ovarian cancer, wherein the subject has not received the at least one standard chemotherapy drug including doxorubicin, and wherein the at least one composition includes paclitaxel.

4. The combination therapy according to any one of claims 1-3, wherein the at least one chemotherapeutic agent in the at least one composition is selected from paclitaxel, nimustine, gefitinib, pazopanib, nintedanib, sorafenib, sunitinib, imatinib, everolimus, temozolomide, docetaxel, and combinations thereof.

5. The combination therapy according to any one of claims 1-4, wherein the at least one composition further comprises at least one antifibrotic agent.

6. The combination therapy according to any one of claims 1-5, further comprising at least one additional composition, wherein the at least one additional composition comprises at least one antifibrotic agent.

7. The combination therapy according to claim 5 or 6, wherein the at least one antifibrotic agent is selected from calcium channel blockers, angiotensin II receptor blockers (ARBs), IL11 inhibitors, IL13 inhibitors, receptor tyrosine kinase inhibitors (RTKIs), renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, antihypertensive drugs, and combinations thereof.

8. The combination therapy according to any one of claims 1-7, wherein the subject has not received pro-fibrotic chemotherapy and pro-fibrotic antitumor therapy for the cancer to be treated.

9. A kit comprising the combination therapy according to any one of claims 1-8.

10. A method for treating cancer in a subject, the method comprising the following steps: (1) Subjects who have not received at least one standard chemotherapy drug for the cancer to be treated, wherein the cancer is at least one form of solid tumor; (2) Apply an alternating electric field to the target area of ​​the subject for a period of time; as well as (3) Administering at least one composition to the subject, wherein the at least one composition comprises at least one chemotherapeutic drug.

11. The method of claim 10, wherein at least one of the following: (i) The cancer to be treated is selected from soft tissue cancer, bone cancer, breast cancer, ovarian cancer, bladder cancer, thyroid cancer and small cell lung cancer, wherein the subject has not received at least one standard treatment chemotherapy drug including doxorubicin; (ii) wherein the cancer to be treated is glioblastoma, and wherein the subject has not received at least one standard chemotherapy drug selected from temozolomide (TMZ), bevacizumab, carmustine, and combinations thereof; (iii) wherein the cancer to be treated is mesothelioma, and wherein the subject has not received at least one standard chemotherapy drug selected from bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, ipilimumab, nivolumab, oxaliplatin, pembrolizumab, pemetrexed, raltitrexed, vinorelbine, or combinations thereof. (iv) wherein the cancer to be treated is ovarian cancer, and wherein the subject has not received at least one standard chemotherapy drug selected from docetaxel, gemcitabine, paclitaxel, PARP inhibitors and combinations thereof; (v) wherein the cancer to be treated is pancreatic cancer, and wherein the subject has not received standard chemotherapy treatment with at least one of capecitabine, fluorouracil, FOLFIRINOX, gemcitabine, irinotecan, leucovorin, NALIRIFOX, oxaliplatin, paclitaxel, pemetrexed, or combinations thereof; or (vi) wherein the cancer to be treated is non-small cell lung cancer, and wherein the subject has not received at least one standard chemotherapy drug selected from carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, paclitaxel, pemetrexed, vinorelbine and combinations thereof.

12. The method according to claim 10 or 11, wherein the cancer to be treated is ovarian cancer, wherein the at least one standard chemotherapy drug that the subject has not received includes doxorubicin, and wherein the at least one chemotherapy drug administered in step (3) includes paclitaxel.

13. The method according to any one of claims 10-12, wherein at least one of the following: The frequency at which the alternating electric field is applied is in the range of approximately 50 kHz to approximately 1 MHz; The alternating electric field has an electric field strength of at least about 1 V / cm in at least a portion of the target region of the subject; The period during which the alternating electric field is applied is at least about 50% of a continuous 24-hour time period; and The at least one chemotherapy drug applied in step (3) is selected from paclitaxel, nimustine, gefitinib, pazopanib, nintedanib, sorafenib, sunitinib, imatinib, everolimus, temozolomide, docetaxel, and combinations thereof.

14. The method according to any one of claims 10-13, wherein the composition of (3) further comprises at least one anti-fibrotic agent, or wherein the method further comprises the following steps: (4) Administer at least one additional composition to the subject, wherein the at least one additional composition comprises at least one antifibrotic agent.

15. The method according to claim 14, wherein the at least one antifibrotic agent is selected from calcium channel blockers, angiotensin II receptor blockers (ARBs), IL11 inhibitors, IL13 inhibitors, receptor tyrosine kinase inhibitors (RTKIs), renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme (ACE) inhibitors, antihypertensive drugs, and combinations thereof.

16. The method according to any one of claims 10-15, wherein the subject has not received profibrotic chemotherapy or profibrotic antitumor therapy for the cancer to be treated.

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