Triple therapy for the treatment of cancer

Abstract

A method of treating cancer with triple therapy is disclosed. The method includes a cancer treatment regimen with two or three different antitumor drugs including tamoxifen, gefitinib, and vinorelbine (TGV). The cancer treatment regimen may include sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine. The cancer treatment regimen may include sequential and / or simultaneous administration of tamoxifen and gefitinib as an adjuvant to the prescribed treatment. The cancer treatment regimen may be cyclical or may be continuous metronomic treatment with metronomic dosing. The cancer treatment regimen may be cyclical followed by continuous metronomic treatment with metronomic dosing.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 244,412, filed September 15, 2021, which is incorporated by reference herein in its entirety.

[0002] FIELD OF THEINVENTION This disclosure relates to triple therapy for the systemic treatment of cancer, and in particular to the combination of tamoxifen, gefitinib, and vinorelbine (TGV) in the treatment of a wide range of cancers. [Background technology]

[0003] Many types of cancer treatments have been developed to fight cancer. Treatments may vary from patient to patient and may include biomarker testing to establish which cancer treatment will be most helpful to the patient. Available cancer treatments include systemic therapies such as chemotherapy, targeted therapy, hormonal therapy, immunotherapy, stem cell transplantation, and chimeric antigen receptor (CAR) T-cell therapy. They also include localized therapies such as radiation therapy, and regional therapies such as surgery.

[0004] The type of treatment a cancer patient receives typically depends on the cancer itself and how advanced it is. Some people with cancer receive only one treatment, such as surgery for localized cancer, or localized therapy for localized cancer. However, most people receive a combination of treatments, such as surgery and chemotherapy and / or radiation therapy.

[0005] Even with the most precise determination of the type of treatment to use, a patient's cancer may develop resistance to the selected treatment. Improved cancer treatments with broad activity against multiple types of cancer are needed, and therapies that are active against cancers that have been resistant to standard systemic therapies are needed. Summary of the Invention

[0006] The present disclosure relates to a method of treating cancer in a human subject, comprising administering to the subject a regimen comprising sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine.

[0007] The present disclosure also relates to a method of treating cancer in a subject, comprising administering to the subject a regimen of sequential and / or simultaneous administration of tamoxifen, gefitinib, and a prescribed chemotherapeutic agent.

[0008] The present disclosure also relates to a method of treating cancer in a human subject, comprising administering to the subject a regimen comprising sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine at metronomic dosing.

[0009] The present disclosure also relates to a kit comprising tamoxifen and gefitinib, optionally in blister packs, each blister pack containing a dose of tamoxifen and gefitinib for daily use. Other kits of the present disclosure include those comprising tamoxifen, gefitinib, and vinorelbine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present disclosure may be understood more readily by reference to the following detailed description of the preferred embodiments and the examples included therein.

[0011] Throughout this specification, the description refers to methods of using anti-cancer therapeutics.

[0012] It should be understood that certain features of the disclosed methods that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0013] Various terms relating to aspects of this description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein.

[0014] "Substantial" refers to a degree of similarity, difference, increase, or decrease in comparison to a known value. Substantial can include at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% similarity, difference, increase, or decrease in comparison to a known value.

[0015] The term "treat" or "treatment" refers to any success or indication of success in attenuating or ameliorating cancer, or making an injury, disease state, or condition more tolerable to a subject, improving the physical health of a subject, or prolonging survival, including any objective or subjective parameter, such as reduction, remission, or shrinkage of one or more symptoms of cancer. The treatment or amelioration of one or more symptoms can be based on objective or subjective parameters, including the results of a physical exam, clinical test, non-invasive imaging, and / or self-reported by the subject.

[0016] The terms "remission," "remission from cancer," and "complete remission" refer to a state of improvement in the course of disease in which no signs of disease are identified by physical, laboratory, imaging, and / or clinical evaluation.

[0017] The term "partial remission" refers to a state of improvement in the course of disease where residual signs of disease are identified by physical, laboratory, imaging, and / or clinical assessment.

[0018] The terms "effective amount" and "therapeutically effective amount" are used interchangeably herein and refer to an amount of a drug that is effective to achieve a particular biological or therapeutic result, such as, but not limited to, the amelioration of one or more symptoms of cancer. The therapeutically effective amount of a drug may vary according to factors such as the disease state, age, sex, body surface area, and weight of an individual, and the ability of the drug to produce a desired response in an individual. Such results may include, but are not limited to, the treatment of cancer, as determined by any means suitable in the art.

[0019] The term "subject" as used herein is intended to mean any animal, particularly a mammal. The methods described herein are applicable to humans and non-human animals, but are preferably used on pets and humans, most preferably humans. "Subject" and "patient" are used interchangeably herein. In some embodiments, the subject is a human.

[0020] The term "metronomic administration" or "metronomic dosing" refers to a treatment in which relatively low doses of an anticancer drug are given on a continuous or frequent regular schedule (such as daily or weekly), usually over a long period of time. Without wishing to be bound by any particular theory, chemotherapy with metronomic dosing according to the present disclosure is effective and safe for the treatment of cancer.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, the present specification, including definitions, will prevail. Preferred methods and materials are described below, but methods and materials similar or equivalent to those described herein may be used in practice or testing. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0022] It is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, to reflect tolerances, conversion factors, rounding, measurement errors, and the like, and other factors known to those skilled in the art. In general, amounts, sizes, formulations, parameters, or other quantities or characteristics are "about" or "approximately" whether or not they are explicitly stated as such. When "about" is used before a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless otherwise specified. As used herein, the term "about" when referring to a measurable value, such as an amount, a temporal period, and the like, is meant to encompass a variation of ±10%, ±5%, ±1%, or ±0.1% from the stated value, where such variation is appropriate for carrying out the disclosed method.

[0023] As used herein, approximation words may be applied to modify any quantitative expression that may vary without resulting in a change in the relevant basic function. Thus, a value modified by "about" may not be limited to the exact value specified in some cases. In at least some instances, approximation words may correspond to the precision of an instrument for measuring the value. The modifier "about" should also be considered as disclosing a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4". The term "about" may refer to plus or minus 10% of the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" may mean 0.9 to 1.1. Other meanings of "about" may be apparent from the context, such as rounding, so for example, "about 1" may also mean 0.5 to 1.4.

[0024] Unless indicated to the contrary, numerical values ​​should be understood to include numerical values ​​that are the same when converted to the same number of significant figures, and numerical values ​​that differ from the stated value by less than experimental error using conventional measuring techniques of the type described in this application to determine the value.

[0025] All ranges disclosed herein are inclusive of the recited endpoints, and independent of the endpoints (e.g., "from 2 grams to 10 grams, including all intermediate values, including 2 grams, 10 grams, and all intermediate values"). The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact ranges or values. They are sufficiently imprecise to include values ​​that are approximations of these ranges and / or values. All ranges are combinable.

[0026] Furthermore, the term "comprising" should be understood to have the open-ended meaning of "including," but it also includes the closed-ended meaning of the term "consisting of. For example, a composition containing components A and B may be a composition that contains A, B, and other components, but it may also be a composition made up of only A and B.

[0027] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0028] Triple therapy for treating cancer A method of treating cancer in a subject, preferably a human subject, is disclosed comprising administering to the subject a regimen of sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine.

[0029] In some embodiments of the present disclosure, tamoxifen, gefitinib, and vinorelbine are administered consecutively.When administered consecutively, each dose of tamoxifen, gefitinib, and vinorelbine is administered at a discrete time interval from each dose, such as 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or more.In other embodiments, tamoxifen, gefitinib, and vinorelbine are administered simultaneously, for example, without a discrete time interval from each dose.In still other embodiments, one or more of tamoxifen, gefitinib, and vinorelbine are administered consecutively or simultaneously with other of tamoxifen, gefitinib, and vinorelbine.

[0030] In some embodiments, the method includes a regimen of administering tamoxifen and gefitinib simultaneously twice daily and vinorelbine once daily for three days. The method can include a regimen of administering tamoxifen and gefitinib simultaneously twice daily for three consecutive days and vinorelbine once daily on the second day of three consecutive days.

[0031] In some embodiments, the regimen is a 3-day regimen repeated about every week, about every 2 weeks, about every 3 weeks, about every 4 weeks, or less frequently.

[0032] The regimen can be a daily regimen that is carried out for one day, two consecutive days, three consecutive days, four consecutive days, five consecutive days, six consecutive days, seven consecutive days, eight consecutive days, nine consecutive days, or ten consecutive days.For example, the regimen can be a daily regimen.The regimen can also be continued for a period of several months or years.

[0033] In some embodiments, gefitinib is administered at a dose of about 10-500 mg / m 2 For example, gefitinib is administered at a dose of about 10 to 500 mg / m 2 at a dose of approximately 50-400 mg / m 2 at a dose of approximately 100-300 mg / m per administration. 2 or about 100-200 mg / m per dose. 2 In another example, gefitinib can be administered at a dose of about 10 to 300 mg / m per administration. 2 at a dose of approximately 10-200 mg / m per administration. 2 at a dose of approximately 10-190 mg / m 2 or about 10-180 mg / m per dose 2 In another example, gefitinib can be administered at a dose of about 10 mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 187.5mg / m 2 , about 200mg / m 2 , about 225mg / m2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , or about 500 mg / m 2 can be administered at a dose of

[0034] In some embodiments, tamoxifen is administered at about 10-500 mg / m 2 For example, tamoxifen is administered at a dose of about 10 to 500 mg / m 2 at a dose of approximately 10-400 mg / m per administration. 2 at a dose of approximately 10-300 mg / m per administration. 2 at a dose of approximately 10-200 mg / m per administration. 2 or about 10-100 mg / m per dose. 2 In another example, tamoxifen can be administered at a dose of about 10-90 mg / m per administration. 2 at a dose of approximately 10-80 mg / m 2 at a dose of approximately 10-70 mg / m 2 at a dose of approximately 10-60 mg / m 2 at a dose of approximately 10-50 mg / m 2 at a dose of approximately 10-40 mg / m 2 at a dose of approximately 10-30 mg / m 2 or about 10-20 mg / m per dose. 2 In another example, tamoxifen can be administered at a dose of about 10 mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , or about 500 mg / m 2 can be administered at a dose of

[0035] In some embodiments, vinorelbine is administered at a dose of about 5-250 mg / m 2 For example, vinorelbine is administered at a dose of about 50 to 250 mg / m 2 at a dose of approximately 50-200 mg / m 2 at a dose of approximately 50-150 mg / m per administration. 2 at a dose of approximately 50-100 mg / m 2 or about 50-90 mg / m per dose. 2 In another embodiment, vinorelbine can be administered at a dose of about 5 to 100 mg / m per administration. 2 at a dose of approximately 5-90 mg / m 2 at a dose of approximately 5-80 mg / m 2 at a dose of approximately 5-70 mg / m 2 at a dose of approximately 5-60 mg / m 2at a dose of approximately 5-50 mg / m 2 at a dose of approximately 5-40 mg / m 2 at a dose of approximately 5-30 mg / m 2 or about 5-20 mg / m per dose. 2 In another example, vinorelbine can be administered at a dose of about 5 mg / m 2 , about 10mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , or about 250 mg / m 2 can be administered at a dose of

[0036] In one embodiment, the regimen comprises 150 to 225 mg / m 2 of gefitinib orally administered twice daily on days 1, 2, and 3 of the regimen to subjects, and 2 orally administering to the subject twice daily on days 1, 2, and 3 of the regimen, and orally or intravenously administering to the subject an effective amount of vinorelbine on day 2 of the regimen.

[0037] In one embodiment, the regimen comprises 150 to 225 mg / m 2 of gefitinib orally administered twice daily on days 1, 2, and 3 of the regimen to subjects, and 2of tamoxifen orally administered twice daily to the subject on days 1, 2, and 3 of the regimen, and vinorelbine administered intravenously to the subject on day 2 of the regimen. In another embodiment, the regimen comprises 150-225 mg / m 2 of gefitinib orally administered twice daily on days 1, 2, and 3 of the regimen to subjects, and 2 tamoxifen orally administered to the subject twice daily on days 1, 2, and 3 of the regimen, and vinorelbine orally administered to the subject on day 2 of the regimen.

[0038] The disclosed method provides a single dose of about 10 mg / m 2 ~about 96mg / m 2 of vinorelbine to the subject on day two of the regimen.

[0039] The method provides a 2 The regimen can further include administering gefitinib orally twice daily on days 1, 2, and 3 of the regimen.

[0040] The method comprises administering a concentration of about 80 mg / m 2 Tamoxifen administered orally twice daily on days 1, 2, and 3 of the regimen.

[0041] In some embodiments of the method, the concentration is about 80 mg / m 2 of vinorelbine is administered orally or intravenously on day 2 of the regimen. In some embodiments of the method, about 30 mg / m 2 of vinorelbine is administered orally or intravenously on day 2 of the regimen.

[0042] Exemplary regimens using oral or intravenous vinorelbine are listed in Tables 1 and 2.

[0043] [Table 1]

[0044] [Table 2]

[0045] Subjects treated according to the present disclosure may have a body mass of approximately 0.5 mm 2 ~about 3.6m 2 In some embodiments, the subject may have a body surface area of ​​about 0.243 m 2 , about 0.563m 2 , about 0.787m 2 , about 1.236m 2 , about 1.603m 2 , about 1.92m 2 , approx. 1.98m 2 , about 2.06m 2 , about 2.5m 2 , about 3m 2 , or about 3.6m 2 has a surface area of

[0046] In some embodiments of the method, the doses of gefitinib, tamoxifen, and vinorelbine can be adjusted for each subject based on the subject's body surface area. 2 Tamoxifen is administered orally at approximately 80 mg / m 2 Vinorelbine is administered orally at approximately 80 mg / m 2 In certain embodiments of the method, the dose per administration of each of tamoxifen, gefitinib, and vinorelbine can be adjusted for each subject based on the subject's body surface area, as shown in Table 3.

[0047] [Table 3]

[0048] Two-drug combinations as adjuvants Also disclosed are methods of treating cancer in a subject, preferably a human subject, comprising administering to the subject a regimen of sequential and / or simultaneous administration of tamoxifen, gefitinib, and a prescribed treatment to which the patient has become resistant. In these methods, a combination of two drugs (a combination of tamoxifen and gefitinib (TG)) is used as an adjuvant. The combination of TG enhances the effect of the prescribed treatment. The prescribed treatment may be a prescribed chemotherapy drug or a combination of prescribed chemotherapy drugs to which the patient has developed resistance. By adding TG to the prescribed treatment, the patient can continue the prescribed treatment even if the cancer has become non-responsive to the prescribed treatment.

[0049] In methods that include administering to a subject a regimen of sequential and / or simultaneous administration of tamoxifen, gefitinib, and any prescribed treatment to which the patient has become resistant, the administration of TG is at a dose of about 10-500 mg / m per administration. 2 and a daily regimen of tamoxifen administered at a dose of about 10 to 500 mg / m 2 The regimen may include a daily regimen of gefitinib administered at a dose of:

[0050] For example, the administration of tamoxifen, gefitinib, and the prescribed treatment to which the patient has become resistant may be at about 10-500 mg / m per administration of tamoxifen. 2 at a dose of approximately 10-400 mg / m per administration. 2 at a dose of approximately 10-300 mg / m per administration. 2 at a dose of approximately 10-200 mg / m per administration. 2 or about 10-100 mg / m per dose. 2 In another embodiment, tamoxifen can be administered at a dose of about 10-90 mg / m per administration. 2 at a dose of approximately 10-80 mg / m 2 at a dose of approximately 10-70 mg / m2 at a dose of approximately 10-60 mg / m 2 at a dose of approximately 10-50 mg / m 2 at a dose of approximately 10-40 mg / m 2 at a dose of approximately 10-30 mg / m 2 or about 10-20 mg / m per dose. 2 In another example, tamoxifen can be administered at a dose of about 10 mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , or about 500 mg / m 2 can be administered at a dose of

[0051] The dosing of tamoxifen, gefitinib, and the prescribed treatment to which the patient has become resistant is approximately 10-500 mg / m per dose of gefitinib. 2 at a dose of approximately 50-400 mg / m 2 at a dose of approximately 100-300 mg / m per administration. 2or about 100-200 mg / m per dose. 2 In another example, gefitinib can be administered at a dose of about 10 to 300 mg / m per administration. 2 at a dose of approximately 10-200 mg / m per administration. 2 at a dose of approximately 10-190 mg / m 2 or about 10-180 mg / m per dose 2 In another example, gefitinib can be administered at a dose of about 10 mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 187.5mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , or about 500 mg / m 2 can be administered at a dose of

[0052] The disclosed methods may include the combination of TG, which is a two-drug combination, with vinorelbine and / or with prescribed treatments, such as chemotherapy drugs abiraterone acetate, albumin-bound (nab) paclitaxel, alemtuzumab, altretamine, belinostat, bendamustine, bevacizumab, blinatumomab, bleomycin, bortezomib, brentuximab vedotin, busulfan, cabazitaxel, capecitabine, carboplatin, carmustine, ceritinib, cetuximab, chlorambucil, cisplatin, cladribine, crizotinib, cyclophosphamide, cytarabine (Ara-C), dabrafenib, ... cerebrospinal fluid, dacarbazine, dactinomycin, dasatinib, daunorubicin, DaunoXome (liposomal daunorubicin), DepoCyt (liposomal cytarabine), Doxil (liposomal doxorubicin), doxorubicin, epirubicin, eribulin mesylate, erlotinib, estramustine, etoposide, everolimus, floxuridine, fludarabine, gemcitabine, gliadel wafer, hydroxyurea, ibritumomab, ibrutinib, idarubicin, idelalisib, ifosfamidis , imatinib, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, lenvatinib, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, nilotinib, nivolumab, ofatumumab, olaparib, oxaliplatin, paclitaxel, palbociclib, panitumumab, pazopanib, panobinostat, PEG-asparaginase, peginterferon alfa-2b, pembrolizumab, pemetidine, This may include treatment with any one or combination of: Rexed, pentostatin, pralatrexate, procarbazine, ramucirumab, rituximab, romidepsin, sipuleucel-T, sorafenib, streptozocin, sunitinib, temozolomide, temsirolimus, teniposide, thalidomide, thioguanine, thiotepa, topotecan, tositumomab, trametinib, trastuzumab, valrubicin, vandetanib, vemurafenib, vinblastine, vincristine, and vinorelbine.

[0053] The disclosed methods can include the combination of TG, which is a two drug combination, for use with a prescribed treatment, where the chemotherapy drug of the prescribed treatment is administered according to a prescribed treatment regimen.

[0054] Cancer being treated The method may include repeating the regimen about once a week, about every two weeks, about every three weeks, about every four weeks, or less frequently. The method may include repeating the regimen in a subject with cancer or in remission from cancer. The cancer may be a solid cancer or a hematological cancer. The cancer may be stage I cancer, stage II cancer, stage III cancer, or stage IV cancer. Suitable cancers include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma of the skin, biliary tract cancer, bladder cancer, bone cancer (including Ewing's sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumor, breast cancer, bronchial tumor. , Burkitt's lymphoma, carcinoid tumors, cancer of unknown primary, cardiac tumors, medulloblastoma and other CNS embryonal tumors, germ cell tumors, primary CNS lymphoma, cervical cancer, childhood cancer, bile duct cancer, chordoma, childhood bone cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, mycosis fungoides and Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, nasal Cavity neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer, stomach (abdominal) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, pediatric central nervous system germ cell tumor, ovarian germ cell tumor, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, cardiac tumor, childhood, hepatocellular (liver) cancer, Langerhans cell histiocytosis, Hodgkin's lymphoma, hypopharynx (head and neck cancer), intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma (soft tissue sarcoma), kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), leukemia, lip and oral cavity cancer (head and neck cancer), liver cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, and tracheobronchial tumors), lymphoma, male breast cancer, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma (skin cancer), malignant mesothelioma, metastatic cancer,Metastatic squamous cell carcinoma of the neck with unknown primary site (head and neck cancer), midline carcinoma with NUT gene alteration, oral cavity cancer (head and neck cancer), multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides (lymphoma), myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, myeloid leukemia, chronic (CML), myeloid leukemia, acute (AML), chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer (head and neck cancer), nasopharyngeal carcinoma (head and neck cancer), neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung Cancer, oral cavity cancer, lip and oral cavity cancer and oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated pleomorphic sarcoma of bone treatment, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (insulin cell tumor), paraganglioma, paranasal sinus and nasal cancer (head and neck cancer), parathyroid cancer, penile cancer, pharyngeal cancer (head and neck cancer), pheochromocytoma, pituitary tumor, plasmacytoma / multiple myeloma, pleuropulmonary blastoma (lung cancer), pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rare childhood Cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma (pediatric soft tissue sarcoma), salivary gland cancer (head and neck cancer), sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumor (soft tissue sarcoma), Ewing's sarcoma (bone cancer), Kaposi's sarcoma (soft tissue sarcoma), osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma, Sézary syndrome (lymphoma), skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the cervix of unknown primary These include: metastatic (head and neck cancer), abdominal (stomach) cancer, cutaneous T-cell lymphoma, testicular cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, tracheobronchial tumors (lung cancer), transitional cell carcinoma of the renal pelvis and ureter (kidney (renal cell) cancer), cancer of unknown primary site, ureter and renal pelvis, transitional cell carcinoma (kidney (renal cell) cancer, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor and other childhood kidney tumors.

[0055] In some embodiments, the cancer is breast cancer, intestinal (colon) cancer, pancreatic cancer, esophageal cancer, skin (melanoma and squamous cell) cancer, prostate cancer, neuroendocrine cancer, lung (small cell and large cell) cancer, brain (GBM) cancer, acute myeloid leukemia, non-Hodgkin's lymphoma, or meningeal cancer.

[0056] The disclosed methods can result in a reduction in the size of a cancer tumor compared to the size of the cancer tumor before the method is applied in the same subject. The reduction in size of a cancer tumor can be a substantial reduction, such as a reduction of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% compared to the size of the cancer tumor before the disclosed methods are applied to the subject.

[0057] In some embodiments, the disclosed method can result in a reduction in the level of circulating cancer markers compared to the level of circulating cancer markers before the method. The reduction in the level of circulating cancer markers can be a substantial reduction, such as at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% reduction, compared to the level of circulating cancer markers before the disclosed method is applied to the subject. The method can result in an improvement in the subject's Anamnestic Comparative Self Assessment (ACSA) compared to the subject's ACSA before the method.

[0058] Also disclosed is a method for testing a drug combination in vitro on a cancer cell of a subject for cancer cell survival, the drug combination comprising tamoxifen, gefitinib, and vinorelbine. The in vitro test can include administering tamoxifen and gefitinib before, together with, and / or after administration of vinorelbine. The in vitro test can include measuring cancer cell survival. Suitable in vitro tests and methods for measuring cancer cell survival include Differential Staining Cytotoxicity Assay (DiSC), MTT assay, ATP assay, and fluorescein diacetate assay (FDA). MTT assay is a colorimetric assay for evaluating cell metabolic activity. Cellular enzymes can reduce the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to its insoluble formazan, which has a purple color. The ATP assay is a procedure that can measure cell viability based on the detection of ATP. All living cells, including bacteria, can be detected with the ATP assay. Several detection methods can be used, such as colorimetric, fluorescent and bioluminescent. FDA uses the cell-permeable esterase substrate fluorescein diacetate, which can function as a viability probe and measures both the enzyme activity required to activate its fluorescence and the cell membrane integrity required for the intracellular retention of its fluorescent product.

[0059] In vitro testing can provide a substantial reduction in cancer cell viability of cells obtained from a subject due to the drug combination. The substantial reduction in cancer cell viability due to the drug combination can be a reduction of about 50% to about 100% compared to cancer cell viability in the absence of the drug combination. The substantial reduction in cancer cell viability can be a reduction of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% compared to cancer cell viability in the absence of the drug combination.

[0060] Also disclosed is a method of treating cancer in a subject, comprising first testing a drug combination including tamoxifen, gefitinib, and vinorelbine in vitro on the subject's cancer cells for cancer cell survival, and then administering to the subject any of the disclosed treatment regimens.

[0061] Use of a three-drug tamoxifen, gefitinib, and vinorelbine (TGV) regimen Tamoxifen is used and approved for the temporary, non-curative management of breast cancer. Gefitinib is used for the temporary, non-curative treatment of EGFR-positive non-small cell lung cancer. Vinorelbine is used for the palliative (temporary, non-curative treatment) of two types of human cancer, non-small cell lung cancer and breast cancer.

[0062] A therapeutic regimen is disclosed that combines all three of these drugs, tamoxifen, gefitinib, and vinorelbine. The therapeutic regimen has demonstrated remission in a wide range of human cancers. The TGV combination of the three drugs shows remission in cancers that have spread to the blood-brain barrier or that originate inside the blood-brain barrier. This is an extremely rare observation in cancer treatment. TGV has applications far beyond the limited cancers for which each of these drugs is approved individually. Neither tamoxifen, gefitinib, nor vinorelbine have demonstrated therapeutic efficacy inside the blood-brain barrier, where surgery or radiation are the only means of therapeutic intervention.

[0063] The disclosed treatment regimens use combinations of tamoxifen, gefitinib, and / or vinorelbine at a wide range of doses per treatment administration (from subtherapeutic to several times greater than the Food and Drug Administration approved therapeutic doses). Tamoxifen can be used at therapeutic doses nearly eight times its standard dose, and gefitinib can be used at twice the standard dose.

[0064] The three drugs can be used at or above their respective approved therapeutic doses. Their use according to the disclosed regimen does not result in toxicity greater than that expected at their respective approved therapeutic doses. The worst toxicity of chemotherapy at the approved therapeutic doses includes nausea, vomiting, hair loss, loss of nail bed, rash, life-threatening neutropenia, thrombocytopenia, anemia, and neuropathy. The disclosed regimen has substantially reduced toxicity compared to the worst toxicity of chemotherapy at the approved therapeutic doses. The described regimen has low toxicity characterized by substantially no nausea, substantially no vomiting, substantially no hair loss, substantially no loss of nail bed, substantially no rash, substantially no life-threatening neutropenia, substantially no thrombocytopenia, minimal anemia, and / or minimal neuropathy compared to the worst toxicity of chemotherapy at the approved therapeutic doses.

[0065] Without wishing to be bound by any particular theory, it is believed that two drugs, tamoxifen and gefitinib, used at relatively high concentrations, may almost exclusively accelerate the transport of a third drug (e.g., vinorelbine) into cancer cells and / or prevent the release of the third drug (e.g., vinorelbine). Due to this cancer-specific transport of vinorelbine and / or cancer-specific retention of vinorelbine, treatment toxicity from the combination of all three drugs is mild, e.g., mild bone marrow suppression, diarrhea that may usually be followed by mild constipation, both of which are easily managed with over-the-counter antidiarrheal and laxatives.

[0066] The described concentrations of two of the three generic drugs affect the unique synergistic effect of the three together. This allows the regimen to apply this combination of three generic drugs broadly in many cancers that have been observed to respond to the disclosed triple therapy. As the examples show, remissions have been seen in metastatic squamous cell carcinoma of the skin, metastatic breast cancer, metastatic prostate cancer, glioblastoma multiforme (GBM) and leptomeningeal carcinoma of the breast inside the blood-brain barrier, metastatic pancreatic cancer, non-small cell lung cancer, small cell lung cancer, and many other cancers.

[0067] The three drugs may be administered orally. The three drugs may be provided in a blister pack of pills given over three days. The doses of the three drugs may be adjusted for the body surface area of ​​the patient who administers the medication to himself. The frequency of administering the regimen may be once, once per week, once per two weeks, once per three weeks, once per four weeks, or less frequently.

[0068] In one embodiment, tamoxifen and gefitinib may be given at a specific concentration in six pills, which may be given twice daily the day before oral vinorelbine administration, twice daily on the day of oral vinorelbine administration, and twice daily the day after oral vinorelbine administration. In some aspects, vinorelbine may be the seventh pill given during the day of the second day of a three-day treatment. In one embodiment, a patient with a body surface area of ​​1.5 square meters may be given a blister pack of five pills, which may be taken twice daily the day before administration of five pills of vinorelbine, twice daily on the day of administration of five pills of vinorelbine, and twice daily the day after administration of five pills of vinorelbine, the latter given in the middle of the second day. In one embodiment, a patient with a body surface area of ​​1.75 square meters may take a combination of six pills twice daily the day before taking six pills of vinorelbine, twice daily on the day of taking six pills of vinorelbine, and twice daily the day after taking six pills of vinorelbine. Thus, as body surface area increases, the number of pills increases proportionately.

[0069] Metronome Therapy According to conventional chemotherapy regimens, anticancer drugs are administered in cycles at near or maximum tolerated doses (MDT), alternating with long drug-free periods to allow patients to recover from adverse drug reactions. This strategy has been successful in controlling the disease process in a significant number of patients, both adults and children.

[0070] In contrast to conventional chemotherapy regimens, the main features of metronomic chemotherapy (reviewed in Mross et al., J Cancer Ther Res. 2012;1:32; Maiiti, J Pharmacol Pharmacother. 2014 Jul-Sep;5(3):186-192) are: Frequent (dose-dense) administration of chemotherapy without significant interruptions; Use of biologically optimized doses instead of the MTD; - No application of hematopoietic growth factors; Prefer oral medications, - a low incidence of treatment-related side effects; and The development of resistance may be delayed.

[0071] Disclosed are methods of treating cancer in a subject, comprising administering to the subject a regimen comprising sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine in a metronomic dosing regimen. The metronomic dosing regimen comprises 5-500 mg / m per administration. 2 Tamoxifen at a dose of 5–500 mg / m 2 and gefitinib at a dose of 5–500 mg / m per dose. 2 The method may include administering vinorelbine at a dose of

[0072] Metronomic therapy is approximately 5-500 mg / m per dose. 2 For example, metronomic treatment can include administering tamoxifen at a dose of about 5 to 500 mg / m per administration. 2 at a dose of approximately 5-400 mg / m 2 at a dose of approximately 5-300 mg / m 2 at a dose of approximately 5-200 mg / m 2 at a dose of approximately 5-175 mg / m 2 at a dose of approximately 5-150 mg / m 2 at a dose of approximately 5-125 mg / m 2 or about 5 to 100 mg / m per dose. 2 In another example, metronomic treatment can include administering tamoxifen at a dose of about 5-100 mg / m per administration. 2 at a dose of approximately 5-90 mg / m 2 at a dose of approximately 5-80 mg / m 2 at a dose of approximately 5-70 mg / m 2at a dose of approximately 5-60 mg / m 2 or about 5-50 mg / m per dose. 2 In another example, metronomic therapy can include administering tamoxifen at a dose of about 5 mg / m per administration. 2 , about 10mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , or about 500 mg / m 2 The present invention can include administering the compound in a dose of

[0073] Metronomic therapy is approximately 5-500 mg / m per dose. 2 For example, metronomic therapy can include administering gefitinib at a dose of about 5 to 500 mg / m per administration. 2 at a dose of approximately 5-400 mg / m 2 at a dose of approximately 5-300 mg / m 2 at a dose of about 5-200 per dose, and at a dose of about 5-175 mg / m per dose 2 at a dose of approximately 5-150 mg / m 2 at a dose of approximately 5-125 mg / m 2 or about 5 to 100 mg / m per dose. 2 In another example, metronomic therapy can include administering gefitinib at a dose of about 5-100 mg / m per administration. 2at a dose of approximately 5-90 mg / m 2 at a dose of approximately 5-80 mg / m 2 at a dose of approximately 5-70 mg / m 2 at a dose of approximately 5-60 mg / m 2 or about 5-50 mg / m per dose. 2 In another example, metronomic therapy can include administering gefitinib at a dose of about 5 mg / m per administration. 2 , about 10mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , or about 500 mg / m 2 The present invention can include administering the compound in a dose of

[0074] Metronomic therapy is approximately 5-500 mg / m per dose. 2 For example, metronomic therapy can include administering vinorelbine at a dose of about 5 to 500 mg / m per administration. 2 at a dose of approximately 5-400 mg / m 2 at a dose of approximately 5-300 mg / m 2 at a dose of approximately 5-200 mg / m 2 at a dose of approximately 5-175 mg / m 2 at a dose of approximately 5-150 mg / m 2 at a dose of approximately 5-125 mg / m2 or about 5 to 100 mg / m per dose. 2 In another example, metronomic therapy can include administering vinorelbine at a dose of about 5-100 mg / m per administration. 2 at a dose of approximately 5-90 mg / m 2 at a dose of approximately 5-80 mg / m 2 at a dose of approximately 5-70 mg / m 2 at a dose of approximately 5-60 mg / m 2 or about 5-50 mg / m per dose. 2 In another example, metronomic therapy can include administering vinorelbine at a dose of about 5 mg / m per administration. 2 , about 10mg / m 2 , about 20mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 300mg / m 2 , about 400mg / m 2 , or about 500 mg / m 2 The present invention can include administering the compound in a dose of

[0075] A metronomic dosing regimen can include sequential and / or simultaneous administration of drugs for a period of 1, 2, 3, 4, 5, 6, or 7 days, and can be repeated weekly, biweekly, 3, 4 weeks, or less frequently. A metronomic dosing regimen can include sequential and / or simultaneous administration of drugs for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, or 10 consecutive days for a period of months or years.

[0076] Triple therapy may precede metronomic treatment with a metronomic dosing regimen.

[0077] kit Also disclosed is a kit comprising tamoxifen, gefitinib, and vinorelbine. The kit can optionally comprise tamoxifen and gefitinib in blister packs, each blister pack comprising a dose of tamoxifen and gefitinib for daily use. The kit can optionally comprise tamoxifen, gefitinib, and vinorelbine in blister packs, each blister pack comprising a dose of tamoxifen, gefitinib, and vinorelbine for daily use.

[0078] The kit may include gefitinib in a solid unit dosage form of about 10-100 mg. The kit may include gefitinib in a solid unit dosage form of about 37.5 mg. The kit may include tamoxifen in a solid unit dosage form of about 10-30 mg. The kit may include tamoxifen in a solid unit dosage form of about 20 mg. The kit may include tamoxifen and gefitinib in a single dosage form. The kit may include tamoxifen and gefitinib in a single dosage form comprising about 20 mg tamoxifen and about 37.5 mg gefitinib. The kit may also include vinorelbine in a liquid unit dosage form of about 5-60 mg. The kit may also include vinorelbine in a solid unit dosage form of about 5-60 mg. The kit may be provided with instructions for use. Exemplary dosage units provided in the kit may include the dosage units listed in Table 4.

[0079] [Table 4]

[0080] The kit components may provide the patient with the ability to self-administer the prescribed doses by providing several tamoxifen and gefitinib tablets as needed for each prescribed dose. Kits for oral administration of vinorelbine may provide vinorelbine in 20 mg or 30 mg capsules. Kits for intravenous administration of vinorelbine may provide 1 mg of vinorelbine intravenously. 2A 30 mg / ml vinorelbine capsule can be provided at 10 mg / ml, which can be administered at the clinic. For example, a blister pack for an exemplary treatment regimen as shown in Table 1 or Table 2 may contain a series of tamoxifen dosage units, a series of gefitinib dosage units, or a series of tamoxifen / gefitinib combination dosage units for days 1, 2, and 3 of the treatment regimen. The blister pack may also contain one or more series of vinorelbine dosage units for day 2 of the treatment regimen. Twice daily on days 1, 2, and 3 of the regimen, the patient can take several tamoxifen and gefitinib dosage units as needed per prescribed dose. At noon on day 2, the patient can take several vinorelbine capsules as needed per dose.

[0081] It is to be understood that the embodiments described herein are not limited to particular methods, reagents, compounds, compositions, or biological systems, which can, of course, vary, and that the terminology used herein is intended to be descriptive of antibodies and antigen-binding fragments thereof, and methods of detection and / or diagnosis and / or treatment, and is not intended to be limiting.

[0082] Exemplary embodiments Embodiment 1. A method of treating cancer in a human subject, comprising administering to the subject a regimen comprising sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine.

[0083] Embodiment 2. The method of embodiment 1, wherein the regimen comprises administering tamoxifen and gefitinib simultaneously twice daily, and vinorelbine once daily for three days.

[0084] Embodiment 3. The method of embodiment 1, wherein the regimen comprises administering tamoxifen and gefitinib simultaneously twice daily for three consecutive days, and vinorelbine once daily on the second day of three consecutive days.

[0085] Embodiment 4. The method of any one of the preceding embodiments, wherein the regimen is repeated every week, every two weeks, every three weeks, every four weeks, or less frequently.

[0086] Embodiment 5. Gefitinib is administered at a dose of 10 to 500 mg / m 2 The method of any one of the preceding embodiments, wherein the dose is

[0087] Embodiment 6. Tamoxifen is administered in a dose of 10 to 500 mg / m 2 The method of any one of the preceding embodiments, wherein the dose is

[0088] Embodiment 7. Vinorelbine is administered in a dose of 5 to 250 mg / m 2 The method of any one of the preceding embodiments, wherein the dose is

[0089] Embodiment 8. The method of any one of the preceding embodiments, wherein the regimen is administered for 1 day, for 2 consecutive days, for 3 consecutive days, for 4 consecutive days, for 5 consecutive days, for 6 consecutive days, for 7 consecutive days, for 8 consecutive days, for 9 consecutive days, or for 10 consecutive days.

[0090] Embodiment 9. The regimen comprises: 150-225mg / m 2 administering to the subject orally twice daily on days 1, 2, and 3 of the regimen; 64-96 mg / m 2 administering to the subject orally twice daily on days 1, 2, and 3 of the regimen; Administering an effective amount of vinorelbine orally or intravenously to the subject on day 2 of the regimen.

[0091] Embodiment 10 The method of any one of the preceding embodiments, wherein vinorelbine is administered intravenously to the subject on day 2 of the regimen.

[0092] Embodiment 11 The method of any one of the preceding embodiments, wherein vinorelbine is orally administered to the subject on day 2 of the regimen.

[0093] Embodiment 12. 10 to 96 mg / m 2 The method of any one of the preceding embodiments, wherein said vinorelbine is administered to said subject on day 2 of the regimen.

[0094] 13.187.5 mg / m 2 The method of any one of the preceding embodiments, wherein the gefitinib is administered orally twice daily on days 1, 2, and 3 of the regimen.

[0095] 14.80 mg / m 2 The method of any one of the preceding embodiments, wherein tamoxifen is administered orally twice daily on days 1, 2, and 3 of the regimen.

[0096] 15.80 mg / m 2 The method of any one of the preceding embodiments, wherein the vinorelbine is administered orally or intravenously on day 2 of the regimen.

[0097] 16.30 mg / m 2 The method of any one of the preceding embodiments, wherein the vinorelbine is administered orally or intravenously on day 2 of the regimen.

[0098] Embodiment 17. A method of treating cancer in a subject, comprising administering to the subject a regimen of sequential and / or simultaneous administration of tamoxifen, gefitinib, and a prescribed chemotherapeutic agent.

[0099] Embodiment 18. Tamoxifen is administered in a dose of 10 to 500 mg / m 2 and gefitinib is administered at a dose of 10-500 mg / m 2and the prescribed chemotherapy agent is administered at the prescribed dose.

[0100] Embodiment 19. The method of embodiment 17 or 18, wherein the prescribed chemotherapeutic agent is a chemotherapeutic agent to which the patient has become resistant.

[0101] 20. The target is 0.5 to 3.6 m 2 2. The method of any one of the preceding embodiments, wherein the subject has a body surface area of

[0102] Embodiment 21 The method of any one of the preceding embodiments, wherein the regimen is repeated about every two weeks.

[0103] Embodiment 22 The method of any one of the preceding embodiments, wherein the regimen is repeated about every 3 weeks.

[0104] Embodiment 23 The method of any one of the preceding embodiments, wherein the cancer is a solid cancer or a hematological cancer.

[0105] Embodiment 24 The method of any one of the preceding embodiments, wherein the cancer is stage I cancer, stage II cancer, stage III cancer, or stage IV cancer.

[0106] Embodiment 25. The cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenal cortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma of the skin, biliary tract cancer, bladder cancer, bone cancer (including Ewing's sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary, cardiac tumor, medulloblastoma and other CNS embryonal tumors, germ cell tumor, primary CNS lymphoma, cervical cancer, childhood cancer, bile duct cancer, chordoma, childhood bone cancer. , chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, mycosis fungoides and Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer, stomach (abdominal) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, germ cell tumors, childhood central nervous system germ cell tumors, ovarian embryo Cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumors, childhood, hepatocellular (liver) cancer, Langerhans cell histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer (head and neck cancer), intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma (soft tissue sarcoma), kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), leukemia, lip and oral cavity cancer (head and neck cancer), liver cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, and tracheobronchial tumor), lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eyeball) melanoma, Merkel cell carcinoma (skin cancer), malignant mesothelioma, metastatic carcinoma, metastatic squamous cell carcinoma of unknown primary (head and neck cancer), midline carcinoma with NUT gene alterations, oral cancer (head and neck cancer), multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides (lymphoma), myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, myeloid leukemia, chronic (CML), myeloid leukemia, acute (AML), chronic myeloproliferative neoplasm, nasal and paranasal sinus cancer (head and neck cancer), nasopharyngeal carcinoma (head and neck cancer), neuroblastoma,Non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer, and oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated pleomorphic sarcoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (insulin cell tumor), paraganglioma, paranasal sinus and nasal cavity cancer (head and neck cancer), parathyroid cancer, penile cancer, pharyngeal cancer (head and neck cancer), pheochromocytoma, pituitary tumor, plasmacytoma / multiple myeloma, Pleuropulmonary blastoma (lung cancer), pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rare cancers of childhood, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma (pediatric soft tissue sarcoma), salivary gland cancer (head and neck cancer), sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumor (soft tissue sarcoma), Ewing's sarcoma (bone cancer), The method of any one of the preceding embodiments, wherein the cancer is selected from the group consisting of Posi's sarcoma (soft tissue sarcoma), osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma, Sezary syndrome (lymphoma), skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the neck of unknown primary, metastatic (head and neck cancer), abdominal (gastric) cancer, cutaneous T-cell lymphoma, testicular cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, tracheobronchial tumors (lung cancer), transitional cell carcinoma of the renal pelvis and ureter (kidney (renal cell) cancer), carcinoma of unknown primary, ureter and renal pelvis, transitional cell carcinoma (kidney (renal cell) cancer, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor and other childhood kidney tumors.

[0107] Embodiment 26. The method of any one of the preceding embodiments, wherein the cancer is selected from the group consisting of breast cancer, intestinal (colon) cancer, pancreatic cancer, esophageal cancer, skin (melanoma and squamous cell) cancer, prostate cancer, neuroendocrine cancer, lung (small cell and large cell) cancer, brain (GBM) cancer, acute myeloid leukemia, non-Hodgkin's lymphoma, and meningeal cancer.

[0108] Embodiment 27 The method of any one of the preceding embodiments, wherein the method results in a decrease in the size of the cancer tumor compared to the size of the cancer tumor prior to the method.

[0109] Embodiment 28 The method of any one of the preceding embodiments, wherein the method results in a decrease in the level of the circulating cancer marker compared to the level of the circulating cancer marker prior to the method.

[0110] Embodiment 29. The method of any one of the preceding embodiments, wherein the method results in an improvement in the subject's all-time comparative self-assessment (ACSA) as compared to the subject's ACSA prior to the method.

[0111] Embodiment 30. A method of treating cancer in a human subject, comprising administering to the subject a regimen comprising sequential and / or simultaneous administration of tamoxifen, gefitinib, and vinorelbine at metronomic dosing.

[0112] Embodiment 31. The regimen comprises 5 to 500 mg / m per dose. 2 Tamoxifen at a dose of 5 to 500 mg / m 2 and gefitinib administered at a dose of 5 to 500 mg / m 2 31. The method of embodiment 30, comprising administering vinorelbine administered at a dose of

[0113] Embodiment 32. The method according to embodiment 30 or 31, wherein the regimen is optionally given for a period of months or years following the method of treating cancer according to any one of embodiments 1 to 31.

[0114] Embodiment 33. A kit comprising tamoxifen and gefitinib, optionally in blister packs, each blister pack containing a dose of tamoxifen and gefitinib for daily use.

[0115] Embodiment 34. A kit comprising tamoxifen, gefitinib, and vinorelbine.

[0116] Embodiment 35. The kit of embodiment 33 or 34, wherein gefitinib is provided in a solid unit dosage form of about 5 to 500 mg.

[0117] Embodiment 36. The kit of any one of embodiments 33 to 35, wherein gefitinib is provided in a solid unit dosage form of about 37.5 mg.

[0118] Embodiment 37. The kit according to any one of embodiments 33 to 36, wherein tamoxifen is provided in a solid unit dosage form of about 5 to 500 mg.

[0119] Embodiment 38. A kit according to any one of embodiments 33 to 37, wherein tamoxifen is provided in a solid unit dosage form of about 20 mg.

[0120] Embodiment 39. A kit according to any one of embodiments 33 to 36, wherein tamoxifen and gefitinib are provided in a single dosage form.

[0121] Embodiment 40. The kit of any one of embodiments 33-39, wherein the tamoxifen and gefitinib are provided in a single dosage form comprising about 20 mg of tamoxifen and about 37.5 mg of gefitinib.

[0122] Embodiment 41. The kit of any one of embodiments 33-40, wherein the vinorelbine is provided in a liquid unit dosage form of about 5-500 mg.

[0123] Embodiment 42. The kit of any one of embodiments 33-41, wherein the vinorelbine is provided in a solid unit dosage form of about 5-500 mg.

[0124] Embodiment 43. A method comprising testing a drug combination in vitro on cancer cells of a subject for cancer cell survival, the drug combination comprising tamoxifen, gefitinib, and vinorelbine.

[0125] Embodiment 44. The method of embodiment 43, wherein the in vitro testing comprises administering tamoxifen and gefitinib prior to, together with, and / or after administration of vinorelbine.

[0126] Embodiment 45 The method of embodiment 43 or 44, wherein the in vitro test comprises measuring cancer cell survival.

[0127] Embodiment 46. The method of any one of embodiments 43-45, further comprising treating cancer in the subject according to any one of embodiments 1-16 and 20-32 if the in vitro testing provides a substantial reduction in cancer cell survival of cells obtained from the subject.

[0128] Embodiment 47. The method of embodiment 46, wherein the substantial reduction in cancer cell survival comprises a 50% to 100% reduction in cancer cell survival.

[0129] Embodiment 48. A method of treating cancer in a subject, comprising testing a drug combination comprising tamoxifen, gefitinib, and vinorelbine on the subject's cancer cells for cancer cell survival, and subjecting the subject to a method according to any one of embodiments 1-16 and 20-32. EXAMPLES

[0130] An exemplary embodiment of a TGV treatment regimen includes 80 milligrams of tamoxifen per square meter taken orally twice daily for three days, 187.5 mg of gefitinib per square meter taken orally twice daily for three days, and 80 mg of vinorelbine per square meter taken orally at noon on the second day of a three-day cycle.

[0131] Gefitinib at a dose of 37.5 mg and tamoxifen at a dose of 20 mg can be combined into a pill or capsule so that patients of various body surface areas can take, for example, if their size is 1.2-1.3 square meters, 5 pills twice a day for 3 days, if they are 1.4-1.6 square meters, 6 pills twice a day, if they are 1.7-1.8 square meters, 7 pills a day, if they are 1.9-2.1 square meters, 8 pills, etc.

[0132] The blister pack may be formulated to allow the patient to easily measure out the appropriate dose for each three-day cycle, and the medications are ordered on the blister pack to allow the patient to easily self-administer the appropriate dose.

[0133] The use of high-dose tamoxifen, 80 milligrams per square meter (the typical dose in conventional cancer treatment is 20 mg per day) and high-dose gefitinib, 187 milligrams per square meter twice daily for three days (the typical dose in conventional cancer treatment is 250 mg per day), was found in cytometry studies using live cancer cell cultures to have an extraordinary synergistic effect in delivering vinorelbine to the cancer cells and inducing programmed apoptosis (programmed cancer cell death) in the cancer cells, while sparing much of the normal tissue, resulting in dramatic clinical outcomes.

[0134] Treatment regimens with TGV have been found to cross the blood-brain barrier and thus appear to have good clinical activity in primary brain cancer as third- or fourth-line chemotherapy, and against brain metastases from breast cancer, including lung and leptomeningeal breast cancer.

[0135] There is a broad spectrum of activity extending from the more common breast, intestinal, and lung cancers to pancreatic cancer, gastric cancer, metastatic squamous cell carcinoma of the skin, melanoma, neuroblastoma, urachal carcinoma, and many others. A very high percentage of all these cancers responded to this regimen, indicating the broad applicability of triple therapy regimens in cancer treatment. Approximately 48% of all cancer cases are breast, lung, colon, pancreatic, and prostate cancer. Approximately 89% of these cases are adenocarcinomas. Experimental studies have found that approximately 36% of all adenocarcinomas from any primary site are responsive in vitro, and approximately 33% of all adenocarcinomas are responsive in vivo. However, triple-negative breast cancer stands out. Eighty percent of all cases of this well-known intractable disease responded in vivo.

[0136] When tested in vitro, 94% of cancers predicted to respond to TGV by in vitro testing actually responded in vivo.

[0137] Below are 17 case studies of 17 cancer patients who benefited from TGV therapy. The treatment regimens of TGV therapy are listed in Tables 1 and 2. The 17 case studies represent patients with metastatic esophageal cancer, metastatic skin cancer, metastatic breast cancer, leptomeningeal breast cancer, metastatic prostate cancer, glioblastoma multiforme, lung cancer, intestinal cancer, acute myeloid leukemia, nasal neuroblastoma, and urothelial carcinoma. The case studies demonstrate that TGV therapy had a wide range of applications in various cancers with remarkable efficacy. TGV therapy also had remarkable efficacy when given to patients who had previously been heavily pretreated for cancer. TGV therapy had extremely low toxicity and was remarkably tolerable to patients.

[0138] Example 18 shows the use of a combination of two drugs (tamoxifen and gefitinib) as an adjuvant. The combination of TG enhanced the effect of the chemotherapy drug combination to which the patient had developed resistance. By adding TG to the prescribed treatment, the patient was able to continue the prescribed treatment, the chemotherapy drug combination, and responded to this treatment.

[0139] Example 1. TGV therapy for metastatic esophageal cancer The patient, a 66-year-old woman, became unable to swallow solid food. After an upper endoscopy showed adenocarcinoma of the esophagus, the patient was referred to a cancer treatment center, where extensive liver, bone, lung, and other metastases were found, as well as liver failure. She was told she was not a candidate for any treatment. After a PET-CT scan, she was also told she was not a candidate for any treatment. She later received the same response from a second treatment center. Devastated by this, the patient was admitted to undergo TGV therapy. A stent was placed in her esophagus. Tumor samples were taken from her liver for analysis.

[0140] The patient underwent intrahepatic arterial chemotherapy for his liver disease. After two weeks, his liver function returned to normal, but the remaining disease continued to grow. The patient then underwent a TGV regimen, which resulted in a complete remission. The patient is alive and disease free six years after TGV treatment.

[0141] Example 2. TGV therapy for skin cancer (squamous cell carcinoma) The patient, a 71-year-old man, developed skin cancer (squamous cell carcinoma). The cancer was removed, but subsequently recurred on the patient's scalp, measuring 850 cm 3 The tumor rapidly developed into a large mass that metastasized to the retroperitoneal and thoracic lymph nodes.

[0142] Tissue biopsy was performed and sent for cytometry testing. Testing showed that only TGV therapy was active in his disease. The patient started TGV, went into complete remission, and is alive and completely disease-free four years after TGV treatment according to the present disclosure.

[0143] Example 3. TGV therapy for breast cancer metastasizing to the brain The patient was a 65-year-old woman who had been successfully treated for breast cancer but developed headaches 12 years later.

[0144] An MRI showed 31 metastases to her brain and extensive metastatic disease in the lungs, bones, and liver. A neurosurgeon removed 3 of the 31 lesions in the cerebellum and sent them for cytometry testing. Tests showed that the TGV therapy was active. The TGV therapy was administered for over 6 months. She went into complete remission. She is alive and disease free 4 years after TGV treatment according to the present disclosure. Radiation, the standard treatment for this disease, was not used during treatment.

[0145] Example 4. TGV therapy for glioblastoma multiforme The patient is a 53-year-old female with a multi-year history of resection of recurrent glioblastoma multiforme (GBM). She was treated with radiation and Temodar® (Schering Corporation, Kenilworth, NJ), the standard therapy for GBM, but the disease progressed and she failed the experimental regimen, becoming wheelchair bound and paralyzed in her left arm. She was sent to the neurosurgery unit for TGV therapy. She began the TGV regimen and is now free of any symptoms of her disease (she is no longer wheelchair bound, has regained use of her left arm, and is in near complete remission after TGV treatment according to the methods disclosed herein).

[0146] Example 5. TGV therapy for metastatic prostate cancer The patient is a 71-year-old man who has been treated with all standard hormone therapy and chemotherapy for the treatment of metastatic prostate cancer and was referred to TGV therapy after one experimental therapy failed. The patient received the TGV regimen and his PSA went from 600 to 16 and all bone pain completely disappeared. Treatment is given every 2 weeks and the patient continues TGV treatment according to the methods disclosed herein.

[0147] Example 6. TGV therapy for leptomeningeal breast cancer The patient was a 51-year-old woman with mucinous adenocarcinoma of the left breast. It had metastasized to her bones, brain, and leptomeninges. The survival rate for leptomeningeal breast cancer is about 31 days. The patient underwent TGV and after only 4 months she was in complete remission, which lasted for 3.5 years before she died of metastatic cancer in the liver.

[0148] Example 7. TGV therapy for glioblastoma multiforme The patient was a 61-year-old woman with glioblastoma multiforme. She was approached for TGV therapy after undergoing primary resection of the bulk of her tumor approximately 2 years ago. She received radiation therapy and temozolomide, which put her in remission for 2 years. Upon recurrence, she underwent another resection. Her tumor was tested for TGV therapy and it demonstrated sensitivity to TGV. She received the TGV regimen. She went into complete remission, which lasted 3 years.

[0149] Example 8. TGV therapy for widespread metastatic breast cancer The patient is a 41-year-old woman with untreated breast cancer and widespread metastatic disease in the bones, brain, spinal cord, lungs, and liver. She eventually consented to undergo cytometric testing of her 14 cm fungus-like breast mass immediately prior to receiving regional chemotherapy to the left breast to control odor and infection. Cytometric testing showed that TGV was the most active agent, which was administered. The patient went into remission of disease with nearly equal response both inside and outside the blood-brain barrier. Remission lasted 2.5 years.

[0150] Example 9. TGV therapy for lung cancer The patient is a 71-year-old male with adenocarcinoma of the right lower lobe of the lung with multiple effusions and multiple brain metastases. The patient has been treated with TGV for 4 months and is in near complete remission, and continues to receive TGV treatment according to the methods disclosed herein, with comparable responses both inside and outside the blood-brain barrier. Approximately 90% of all signs of pleural effusion and cancer have been treated, and the patient has had few side effects.

[0151] Example 10. TGV therapy for recurrent metastatic intestinal cancer The patient is a 75 year old male with metastatic recurrent colon cancer. He was treated with 5-fluorouracil and oxaliplatin approximately 10 years ago. He had a recurrence in the lower pelvis. The tumor was resected but there was evident residual disease in the peritoneal cavity. The patient was treated with TGV and went into 2 years of remission with 6 months of TGV treatment according to the present disclosure.

[0152] Example 11. TGV therapy for triple-negative squamous cell carcinoma of the breast A 44-year-old woman presented with squamous cell carcinoma of the breast that was refractory to cytoxan, adriamycin, and taxotere. Cytometry studies indicate that the most active agent was TGV. The patient was treated with 6 cycles of TGV. Her tumor measured over 8 cm, but there was no palpable disease at the end of treatment. Her dramatic complete remission was confirmed by direct biopsy. The patient also received radiation therapy to the breast and remains in complete clinical remission 2.5 years after TGV treatment according to the methods disclosed herein.

[0153] Example 12. TGV therapy for triple-negative, lobular and ductile carcinoma of the breast A 38-year-old woman presented with a large triple-negative mixed lobular and ductular carcinoma of the left breast with a dumbbell shape. Cytometric studies were performed on both the ductal and lobular components of this cancer, and both were highly sensitive to TGV. The patient was treated with TGV therapy, and all cancer disappeared after 8 cycles of TGV treatment (4 months) according to the methods disclosed herein, and the patient proceeded to radiation therapy to her breast, as re-biopsy showed complete pathological remission.

[0154] Example 13. TGV therapy for small cell lung cancer A 72-year-old woman with a massively enlarged liver from small cell carcinoma of the lung was subjected to a cytometry test. Her small cell lung cancer was shown to be insensitive to any standard drug but sensitive to TGV. The patient, who had a life expectancy of about one month, was treated with TGV therapy according to the methods disclosed herein, went into remission, and survived for 18 months.

[0155] Example 14. TGV therapy for pancreatic cancer The 51-year-old patient presented with pancreatic cancer. Cytometry studies were performed on the incompletely resected cancer. The patient's most active treatment from this analysis was TGV, with no evidence of response to standard drugs for this disease: 5-fluorouracil, gemcitabine, oxaliplatin, or taxotere. The patient received TGV for 6 months, and is disease-free with no evidence of disease 3.5 years after TGV treatment according to the methods disclosed herein.

[0156] Example 15. TGV therapy for acute myeloid leukemia A 54-year-old man who had failed standard induction chemotherapy for acute myeloid leukemia with adverse molecular markers and had failed two other experimental therapies presented with a white blood cell count of 234,000 cells per cubic millimeter (cmm) in hospice. Cytometry testing was performed that showed he was sensitive to TGV, and TGV treatment was initiated. Within one week of treating the patient with TGV treatment according to the methods disclosed herein, his white blood cell count, representing leukemia cells, was reduced from 234,000 to 1000.

[0157] Example 16. TGV therapy for nasal neuroblastoma The patient is a 58-year-old former professional hockey player who developed a slow-growing nasal neuroblastoma. The disease had not responded to surgery, radiation therapy, and multiple chemotherapy regimens over 12 years of treatment. The patient presented for TGV therapy and was shown to have TGV after cytometry testing. The patient has continued TGV treatment according to the methods disclosed herein and has a partial response as shown by MRI. The patient continues to feel that he is substantially better and is tolerating the treatment without significant toxicity.

[0158] Example 17. TGV therapy for urothelial carcinoma. A 76-year-old man with locally advanced bladder cancer presented with urothelial carcinoma in the trigone of his bladder. The patient was treated with radiation therapy and high-dose MVAC (M-methotrexate, V-vinblastine, A-doxorubicin, C-cisplatin). The patient was in complete remission until 6 months later, when retroperitoneal disease in the form of lymphadenopathy was found. The patient was then treated with gemcitabine and cisplatin, to which he did not respond. The patient was then irradiated to the retroperitoneal lymph nodes until a complete response. The patient was followed monthly, and when recurrent disease was found in the lungs and mediastinum, Padcev® (enfortumab vedotin) was started, to which he did not respond. The patient was then offered TGV. As the patient was heavily pretreated, Neulasta® (pegfilgrastim) was given with the TGV. The patient had neutropenia within 5 days and was hospitalized. A repeat PET-CT scan showed no evidence of disease anywhere. It was concluded that the patient should not undergo repeat chemotherapy until his bone marrow had recovered.

[0159] Example 18. TG as an adjuvant to prescribed treatment.

[0160] A 38-year-old woman presented with a 1-year history of metastatic carcinoma of the urachus. She had been treated with FOLFIRINOX (FOL-leucovorin calcium (folinic acid), F-fluorouracil, IRIN-irinotecan hydrochloride, and OX-oxaliplatin) without response. The patient was then referred for palliative care.

[0161] She had a large amount of ascites which was removed and sent for cytometry testing. Testing revealed that the patient had sensitivity to 5-fluorouracil and hypersensitivity to gemcitabine and oxaliplatin. The patient was started on oral capecitabine along with gemcitabine and oxaliplatin given every 2 weeks in a high-dose regimen.

[0162] Her initial carcinoembryonic antigen (CEA) antigen was 350. Over a period of 8 months, this decreased to a CEA of 21, and the patient found it difficult to tolerate further doses of chemotherapy, despite the disappearance of all cancer symptoms. The patient was evaluated for surgery. The patient's surgical intervention resulted in the removal of only the necrotic debris, none of which was microscopically or cytometrically passable.

[0163] The patient stopped chemotherapy. Her CEA rose to 600 and her symptoms increased. She was treated again with capecitabine, gemcitabine, and oxaliplatin. Her CEA went from 600 to 121, then skyrocketed again to 236 despite chemotherapy. The patient had become resistant to capecitabine, gemcitabine, and oxaliplatin treatment. With no other treatment options based on cytometric analysis, the patient was started on tamoxifen and gefitinib to inhibit P-glycoprotein, and with the same therapy her CEA decreased until it reached 62.

Claims

1. A pharmaceutical comprising tamoxifen and gefitinib for use in a method of treating cancer in a subject with a prescribed chemotherapy agent, said method comprising sequential and / or simultaneous administration of said tamoxifen, said gefitinib, and said prescribed chemotherapy agent to said subject, and optionally, wherein said subject has become resistant to said prescribed chemotherapy agent.

2. The pharmaceutical composition of claim 1, wherein the tamoxifen is administered at a dose of 10 to 500 mg / m2 per administration, the gefitinib is administered at a dose of 10 to 500 mg / m2 per administration, the prescribed chemotherapy agent is administered at a prescribed dose, and optionally, the subject has a body surface area of ​​0.5 to 3.6 m2, and / or the method is repeated every two weeks, or the method is repeated every three weeks.

3. A pharmaceutical comprising tamoxifen and gefitinib for use in a method of treating cancer in a human subject using vinorelbine, the method comprising sequential and / or simultaneous administration of the tamoxifen, the gefitinib, and the vinorelbine to the human subject.

4. the method comprising administering the tamoxifen and the gefitinib simultaneously twice daily, and the vinorelbine once daily, for one day, for two days, or for three days; 4. The pharmaceutical for use of claim 3, for example, wherein the method comprises administering the tamoxifen and the gefitinib simultaneously twice daily for three consecutive days and the vinorelbine once daily on the second day of the three consecutive days, and optionally the method is repeated every week, every two weeks, every three weeks, every four weeks, or less frequently, and / or the method is performed for four consecutive days, five consecutive days, six consecutive days, seven consecutive days, eight consecutive days, nine consecutive days, or ten consecutive days.

5. The gefitinib is administered at a dose of 10 to 500 mg / m 2 per administration; the tamoxifen is administered at a dose of 10-500 mg / m 2 per administration; and / or The medicament for use according to claim 3 or 4, wherein the vinorelbine is administered at a dose of 5 to 250 mg / m 2 per administration.

6. The method comprises: 150-225mg / m ２ orally administering the gefitinib to the subject twice daily on days 1, 2, and 3 of the method; 64-96 mg / m ２ orally administering to said subject tamoxifen twice daily on days 1, 2, and 3 of said method; 5. The method of claim 3, further comprising administering an effective amount of vinorelbine to the subject orally or intravenously on the second day of the method.

7. the vinorelbine is administered intravenously to the subject on day two of the method; or the vinorelbine is orally administered to the subject on day two of the method; or 10-96 mg / m 2 of said vinorelbine is administered to said subject on day 2 of said method; or 80 mg / m 2 of said vinorelbine is administered orally or intravenously on day 2 of said method; or The method of claim 3 or 4, wherein 30 mg / m 2 of the vinorelbine is administered orally or intravenously on day 2 of the method, and optionally the subject has a body surface area of ​​0.5 to 3.6 m 2 .

8. 187.5 mg / m ２ wherein said gefitinib is administered orally twice daily on days 1, 2, and 3 of said method; and / or 80 mg / m 2 of said tamoxifen is administered orally twice daily on days 1, 2, and 3 of said method; and / or 80 mg / m 2 of said vinorelbine is administered orally or intravenously on day 2 of said method; or 5. The method of claim 3, wherein 30 mg / m<2> of vinorelbine is administered orally or intravenously on day 2 of the method.

9. the cancer is a solid cancer, a blood cancer, a stage I cancer, a stage II cancer, a stage III cancer, or a stage IV cancer; For example, the cancer may be acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma / rhabdoid tumor, basal cell carcinoma of the skin, biliary tract cancer, bladder cancer, bone cancer (including Ewing's sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumor, brain (GBM) cancer, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, cancer of unknown primary origin, cardiac tumor, medulloblastoma and other CNS embryonal tumors, germ cell tumor, primary CNS lymphoma, cervical cancer, childhood cancer, bile duct cancer, Chordoma, childhood bone cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute myeloid leukemia, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, mycosis fungoides and Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer, stomach (abdominal) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, germ cell tumors , pediatric central nervous system germ cell tumors, ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumors, childhood, hepatocellular (liver) cancer, Langerhans cell histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer (head and neck cancer), islet cell tumor, Kaposi's sarcoma (soft tissue sarcoma), kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), leukemia, lip and oral cavity cancer (head and neck cancer), liver cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, and tracheobronchial tumor), lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eyeball) melanoma, Merkel cell carcinoma (skin cancer), malignant mesothelioma, metastatic cancer, metastatic squamous cell carcinoma of the neck of unknown primary (head and neck cancer), midline carcinoma with NUT gene alterations, oral cancer (head and neck cancer), multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides (lymphoma), myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, myeloid leukemia, chronic (CML), myeloid leukemia, acute (AML), chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer (head and neck cancer), nasopharyngeal carcinoma (head and neck cancer), neuroblastoma,Non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer, and oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated pleomorphic sarcoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (insulin cell tumor), paraganglioma, paranasal sinus and nasal cavity cancer (head and neck cancer), parathyroid cancer, penile cancer, pharyngeal cancer (head and neck cancer), pheochromocytoma, pituitary tumor, plasmacytoma / multiple myeloma, pleuropulmonary blastoma (lung cancer), pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rare childhood cancers, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma (pediatric soft tissue sarcoma), salivary gland cancer (head and neck cancer), sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumor (soft tissue sarcoma), Ewing's sarcoma (bone cancer), Kaposi's sarcoma (soft tissue sarcoma) ), osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma, Sezary syndrome (lymphoma), skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the neck of unknown primary, metastatic (head and neck cancer), abdominal (stomach) cancer, cutaneous T-cell lymphoma, testicular cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, tracheobronchial tumor (lung cancer), transitional cell carcinoma of the renal pelvis and ureter (kidney (renal cell) cancer), cancer of unknown primary, ureter and renal pelvis, transitional cell carcinoma (kidney (renal cell) cancer), urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, vascular tumor, vulvar cancer, Wilms' tumor, pediatric kidney tumor, intestinal (colon) cancer, non-Hodgkin's lymphoma, and meningeal cancer.

10. said use results in a reduction in the size of said cancer tumor compared to the size of said cancer tumor prior to said use; and / or said use results in a decrease in the level of the circulating cancer marker compared to the level of the circulating cancer marker before said use; and / or 5. The medicament for use according to any one of claims 1 to 4, wherein said use results in an improvement in the subject's anamnesis self-assessment (ACSA) compared to the subject's ACSA prior to said use.

11. A medicament comprising tamoxifen and gefitinib for use in a method of treating cancer with vinorelbine using metronomic dosing, the method comprising sequential and / or simultaneous administration of the tamoxifen, the gefitinib, and the vinorelbine with metronomic dosing, optionally the method comprising administering the tamoxifen at a dose of 5 to 500 mg / m2 per dose, the gefitinib administered at a dose of 5 to 500 mg / m2 per dose, and the vinorelbine administered at a dose of 5 to 500 mg / m2 per dose, and / or wherein the medicament is administered for a period of months or years, optionally wherein treatment using metronomic dosing occurs after treatment with the medicament for use according to any one of claims 1 to 4.

12. A kit comprising tamoxifen and gefitinib, and optionally vinorelbine, optionally in blister packs, each blister pack containing a dose of tamoxifen and gefitinib, and optionally vinorelbine, for daily use.

13. the gefitinib is provided in a solid unit dosage form of about 5-500 mg, for example, the gefitinib is provided in a solid unit dosage form of about 37.5 mg; and / or the tamoxifen is provided in a solid unit dosage form of about 5-500 mg, for example, the tamoxifen is provided in a solid unit dosage form of about 20 mg; and / or 13. The kit of claim 12, wherein the vinorelbine is provided in a liquid unit dosage form of about 5 to 500 mg, or the vinorelbine is provided in a solid unit dosage form of about 5 to 500 mg, and optionally the tamoxifen and the gefitinib are provided in a single dosage form, e.g., the tamoxifen and the gefitinib are provided in a single dosage form comprising about 20 mg of tamoxifen and about 37.5 mg of gefitinib.

14. A method comprising testing a drug combination in vitro on cancer cells of a subject for cancer cell survival, wherein the drug combination comprises tamoxifen, gefitinib, and vinorelbine, e.g., wherein the in vitro testing comprises measuring the cancer cell survival, and optionally, wherein the in vitro testing comprises administering the tamoxifen and gefitinib before, together with, and / or after administration of the vinorelbine.

15. 15. The method of claim 14, wherein if the in vitro test provides a substantial reduction in the cancer cell survival of cells obtained from the subject, wherein the substantial reduction in cancer cell survival comprises a 50% to 100% reduction in the cancer cell survival, it is decided to administer to the subject the method of any one of claims 3 or 4.