Combination Therapy of MIV-818 and Lenvatinib for Liver Cancer

Abstract

In the treatment of liver cancer or liver metastases, the compound of formula MIV-818: Use of lenvatinib, or a pharmaceutically acceptable salt thereof, in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof, of formula (I) 78144. Dosage regimens of each of the compounds may be delivered simultaneously or separately.

Description

Technical Field

[0001] The present invention relates to combination therapies for cancer, and more specifically, to treatment measures and products using the kinase inhibitor lenvatinib and the troxacitabine phosphoramidate nucleotide MIV-818 for liver cancer and liver metastases.

Background Art

[0002] Liver cancer (or hepatic carcinoma) is cancer that occurs in the liver. Primary liver cancer is the fifth most frequently diagnosed cancer worldwide and the second leading cause of cancer death. Liver cancer is a malignant tumor that grows on the surface or inside the liver. These are formed from the liver itself or from structures within the liver including blood vessels or bile ducts.

[0003] The main cause of liver cancer is viral infection with hepatitis B virus or hepatitis C virus. The cancer usually develops secondary to cirrhosis caused by these viruses. For this reason, the highest rates of liver cancer occur in regions where these viruses are endemic, including East Asia and sub-Saharan Africa. Liver cancer must not be confused with liver metastases, which are also known as secondary liver cancer, and which occur in organs in other parts of the body and then migrate to the liver.

[0004] The most frequent liver cancer is hepatocellular carcinoma (HCC), which accounts for approximately 75% of all primary liver cancers. HCC is a cancer formed by the malignant transformation of liver cells known as hepatocytes. Another type of cancer formed by hepatocytes is hepatoblastoma, which is formed particularly by immature hepatocytes. This is a rare malignant tumor that mainly develops in children and accounts for approximately 1% of all cancers in children and 79% of all primary liver cancers in children under 15 years of age.

[0005] Liver cancer can also arise from other structures within the liver, such as bile ducts, blood vessels, and immune cells. Cancers of the bile ducts (cholangiocarcinoma and cholangiocystadenocarcinoma) account for approximately 6% of primary liver cancers. There are also variants of HCC that consist of both HCC and cholangiocarcinoma. Tumors of the liver blood vessels include angiosarcoma and hemangioendothelioma. Embryonal sarcoma and fibrosarcoma arise from types of connective tissue known as mesenchyme. Cancers arising from muscle in the liver are leiomyosarcoma and rhabdomyosarcoma. Other less common liver cancers include carcinosarcoma, teratoma, yolk sac tumor, carcinoid tumor, and lymphoma. Lymphomas usually have a diffuse infiltration of the liver but, in rare cases, can also form liver masses.

[0006] For non-cirrhotic livers, surgical resection is often a treatment option. Resection of cirrhotic livers can carry an increased risk of complications such as liver failure. The 5-year survival rate after resection has improved dramatically over the past few decades and can now exceed 50%. The recurrence rate after resection due to spread of the initial tumor or formation of new tumors exceeds 70%. Liver transplantation can be used for this type of treatment if the tumor meets certain criteria (e.g., Milan criteria) and is also used in the case of HCC if the type of cancer is acceptable. Since this cancer is often detected at a late stage, less than 30 - 40% of HCC individuals are eligible for surgery and transplantation. Also, HCC can progress during the waiting time for liver transplantation, which can ultimately prevent transplantation.

[0007] Percutaneous ablation is the only non-surgical treatment that can offer a cure. There are many types of percutaneous ablation, which consist of either injecting a chemical (ethanol or acetic acid) into the liver or generating extreme temperatures using radiofrequency ablation, microwave, laser, or cryotherapy. Of these, radiofrequency ablation is one of those with the best reputation in HCC, but its limitations include the inability to treat tumors near other organs and blood vessels due to heat generation and heat sync effects, respectively.

[0008] Systemic chemotherapy is rarely available for HCC, while regional chemotherapy can be used in a procedure known as transarterial chemoembolization (TACE). In this procedure, a cytotoxic agent, such as doxorubicin or cisplatin, and lipiodol are administered, and the artery supplying the liver is blocked with gelatin sponge or other particles.

[0009] Because the liver is not tolerant to radiation, radiotherapy is not used much in HCC. Even with modern techniques that can provide well-targeted radiation to specific areas of the liver, collateral damage to the surrounding liver tissue is a problem, highlighting the need for better "liver-sparing" measures. In addition to radiotherapy, chemoembolization, regional chemotherapy, systemic chemotherapy, or dual therapy with targeted therapeutic agents may show more benefit than radiotherapy alone.

[0010] Lenvatinib (developed by Eisai as Lenvima® or Lenvanix® and marketed in various countries) is a drug approved by the FDA mainly for patients with thyroid or renal cell carcinoma, but is also approved for a limited subset of patients with hepatocellular carcinoma who are not candidates for surgical removal and who have not received oral or injectable therapy.

[0011] Lenvatinib has the chemical structure shown below and is generally presented as the mesylate salt.

[0012]

Chemical Structure

[0013] The preparation of lenvatinib is shown in WO00 / 742012. Preferred salts and polymorphs are shown in WO2005 / 063713. Preparation methods with enhanced purity are shown in WO2016 / 031841. The technical content of these three patent specifications is incorporated herein by reference.

[0014] Troxacitabine (beta-L-dioxolan cytosine) is a cytotoxic deoxycytidine analogue with an unnatural L-configuration and has shown broad activity against both solid and hematological malignancies in vitro and in vivo. In particular, impressive activity has been observed against human cancer cell lines and xenografts of hepatocellular, prostate, and renal origin (Cancer Res., 55, 3008-3011, 1995). Troxacitabine treatment has been shown to produce resistance mutations in deoxycytidine kinase (dCK), a kinase normally involved in the first phosphorylation step of nucleosides, and to eliminate or reduce troxacitabine monophosphate to very low levels.

[0015] Troxacitabine entered Phase III clinical trials in 2008 for the indication of acute myeloid leukemia but did not progress to registration. Those who discontinued the Phase II trial with troxacitabine included breast cancer, colorectal cancer, pancreatic cancer, melanoma, NSCLC, kidney tumors, prostate tumors, and ovarian tumors. Troxacitabine was generally injected as an intravenous infusion, thereby exposing many tissues to the drug regardless of the site of cancer. The clinical development of troxacitabine is considered to have been abandoned.

[0016] MIV-818 is an orally administered nucleotide derivative of troxacitabine with the following formula:

[0017]

Chemical formula

Prior art documents

Patent documents

[0018]

Patent Document 1

Patent Document 2

Patent Document 3

[0019] [Non-Patent Document 1] Cancer Res., 55, 3008-3011, 1995 [Summary of the Invention]

[0020] The present invention is based, at least in part, on the discovery that a particular therapeutic combination of lenvatinib and MIV-818 is particularly effective in inhibiting liver cancer cells and preventing their growth. This discovery can be described as synergistic or greater than additive effects, which are specific to lenvatinib and MIV-818 within the area of liver cancer (e.g., HCC). The inventors hypothesize that this beneficial interaction is extendable even to the treatment of liver metastases, i.e., other cancer types that have spread from the primary tissue to the liver.

[0021] Although not wishing to be bound by theory, the inventors hypothesize that the angiogenesis inhibition provided by lenvatinib induces the migration of T cell populations into cancerous tissue. Surprisingly, these T cells, particularly T-effector cells, will be stimulated to attack cancerous tissue by IL-2 production induced in situ in the liver by simultaneous or alternating administration of MIV-818. A further surprising interaction between lenvatinib and MIV-818 is thought to be caused by the anti-angiogenic activity of lenvatinib, which results in local hypoxia in liver tissue by restricting blood flow into solid tumors. This hypoxia then increases the metabolic activation of the cytotoxic triphosphate of the troxacitabine prodrug, thereby contributing to the cancer-suppressing effect of the claimed combination therapy.

[0022] Although it is also not desirable to be bound by theory, the interaction between lenvatinib and MIV-818, each administered orally, would have a mechanism similar to that between lenvatinib and pembrolizumab with respect to the migration and in situ stimulation of the T cell population. However, in contrast, pembrolizumab is a monoclonal antibody, with a strict temperature-controlled supply chain, must be administered intravenously in a hospital, and is orders of magnitude more difficult and expensive to manufacture compared to MIV-818.

[0023] Accordingly, the present invention provides methods, therapeutic measures and compositions for treating liver cancer and liver metastases, whereby lenvatinib and MIV-818 are administered in combination (as defined herein) to a human or mammalian individual.

[0024] The EMA and FDA approved daily doses for lenvatinib in HCC are 8 mg per day (<60 kg) or 12 mg per day (>60 kg) (2 or 3 x 4 mg hard capsules), but a detailed dose reduction scheme is mandated in the product summary.

[0025] Since clinical experience with MIV-818 has been very limited to date and the approved dose is not yet available, scaling from animal species and preclinical Phase 1 clinical trial data corresponds to a possible daily dose for a human of nn~nn mg / day, for example nn~nn mg / day in a nn kg human.

[0026] One of ordinary skill in the art will understand that the dosing and administration of lenvatinib and MIV-818 will follow medically approved guidelines, as well as medically approved deviations or modifications of such guidelines. Further explanation and details regarding the dosing and administration of lenvatinib and MIV-818 in the context of the present invention are provided in the following combination chemotherapy section.

[0027] Aspects of the present invention are methods or treatment measures for the treatment of liver cancer in a human or mammalian subject, said methods comprising the administration of a simultaneous, separate, alternating or combined unit dosage of an effective amount of MIV-818 and an effective amount of lenvatinib to said subject. Preferably, both MIV-818 and lenvatinib are administered orally. The treatment measure may optionally consist of a number of separate cycles of MIV-818 and lenvatinib, separated by treatment breaks of daily, weekly or monthly duration. Alternatively, MIV-818 and lenvatinib are each administered to the subject daily (i.e. QD, BiD or TiD or every other day), such that the liver is partially or entirely exposed to both active ingredients at the same time intervals.

[0028] Liver cancer The present invention is applicable in various aspects and embodiments to the treatment of liver cancer in a subject, which may be a primate such as a human. The subject may be a mammal, such as a mammal other than a mouse. The subject may be an adult (i.e. 18 years or older), or a juvenile human (i.e. less than 18 years).

[0029] In various embodiments, liver cancer (e.g. HCC) is not resistant to lenvatinib. Alternatively, liver cancer (e.g. HCC) may have primary or secondary resistance to lenvatinib, which is reversed or improved by the combination therapy of the present invention. Thus, the subject may be a responder to lenvatinib in the absence of MIV-818. The subject may be a non-responder to lenvatinib in the absence of MIV-818. In some embodiments, the subject has undergone prior treatment with lenvatinib lasting at least 2, 4, 6, 8, 10 months or longer. In other embodiments, the subject is a patient who has experienced one or more serious side effects to lenvatinib and thus requires a dose reduction.

[0030] In various aspects, liver cancer (e.g., HCC) is in the intermediate, advanced, or terminal stage. Liver cancer (e.g., HCC) may be metastatic or non-metastatic. Liver cancer (e.g., HCC) may be resectable or unresectable. Liver cancer (e.g., HCC) may include a single tumor, multiple tumors, or a tumor with no distinct features having an infiltrative growth pattern (into the portal vein or hepatic vein). Liver cancer (e.g., HCC) may include a fibrolamellar type, pseudoglandular (glandular-like), pleomorphic (giant cell), or clear cell pattern. Liver cancer (e.g., HCC) may include a well-differentiated type, and the tumor cells resemble hepatocytes, forming trabeculae, cords, and nests, and / or containing bile pigments in the cytoplasm. Liver cancer (e.g., HCC) may include a poorly-differentiated type, and the malignant epithelial cells do not adhere, are pleomorphic, undifferentiated, and / or giant. In some aspects, liver cancer (e.g., HCC) is associated with hepatitis B, hepatitis C, cirrhosis, or type 2 diabetes.

[0031] In some aspects, the subject is a human having an Eastern Cooperative Oncology Group (ECOG) performance status <2.

[0032] In some aspects, the subject is a human having acceptable liver function as defined by: (i) total bilirubin < 1.5 times the upper limit of normal (ULN); for hepatocellular carcinoma patients only, total bilirubin < 3 mg / dL (i.e., the Child-Pugh score for bilirubin does not exceed 2); (ii) aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) < 5xULN; or (iii) acceptable renal function: serum creatinine < 1.5 times the ULN, or for patients with creatinine levels > 1.5 times the institutional normal, calculated creatinine clearance > 60 mL / min / 1.73 m 2

[0033] In some aspects, the subject has an absolute neutrophil count (ANC) > 1500 cells / mm 3 ​; (ii) Platelet count > 100,000 pits / mm 3 (Without transfusion); For hepatocellular carcinoma patients only, 75,000 pits / mm 3 ; or (iii) A human having an acceptable hematological state defined as hemoglobin > 9 g / dL.

[0034] In some embodiments, the subject is a human having a prothrombin time (PT) or international normalized ratio (INR) < 1.25 x ULN; INR < 1.7 or prothrombin time (PT) or < ULN + 4 seconds (i.e., the Child - Pugh score for coagulation parameters does not exceed 1); or serum albumin > 2.8 g / dL (i.e., the Child - Pugh score for albumin does not exceed 2).

[0035] In some embodiments, the subject is a human having a Child - Pugh class A (score 5 - 6) liver disease. For the determination of the Child - Pugh class, the score for hepatic encephalopathy must be 1; the score for ascites must be no greater than 2 and must be clinically appropriate.

[0036] In some embodiments, the subject is a human having no New York Heart Association (NYHA) class III or IV heart disease, myocardial infarction within the past 6 months, unstable and / or symptomatic arrhythmia, or evidence of ischemia on ECG.

[0037] In some embodiments, the subject has no active, uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.

[0038] In some embodiments, the subject is not a pregnant or lactating woman.

[0039] In some embodiments, the subject is a human having no known infection with the human immunodeficiency virus (HIV).

[0040] In some embodiments, the subject is a human who does not have a serious non-malignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could impair the therapy.

[0041] In some embodiments, the subject is a human who does not have a recent history of bleeding and is not a patient with a tendency to bleed due to a coagulation disorder or structural abnormality.

[0042] In some embodiments, the subject is a human who does not require treatment at a therapeutic dose of a coumarin anticoagulant.

[0043] In some embodiments, the subject is a human who does not have cirrhosis classified as Child-Pugh B or C.

[0044] In some embodiments, the subject is a human having an alpha-fetoprotein (AFP) > 10, 50, 100, 200, 300, 400, or 500 ng / mL.

[0045] In some embodiments, the subject is a human having an elevated (> 10%) AFP-L3 level.

[0046] In some embodiments, the subject is a human having a des-gamma-carboxy (abnormal) prothrombin (DCP) > 5, 7.5, 10, 25, 50, 75, or 100 ng / mL.

[0047] In some embodiments, the subject is a human having an abnormal level of epidermal growth factor receptor (EGFR) (erbB-1), c-erb-2 (Her-2 / new), c-erb-3 (HER-3), c-erb-4 (HER-4), or a combination thereof.

[0100] In some embodiments, the subject is a human having an abnormal level of alpha-fetoprotein (AFP); glypican-3 (GPC3); des-gamma-carboxy (abnormal) prothrombin (DCP); serum gamma-glutamyltransferase (GGT); alpha-l-fucosidase (AFU); human carbonyl reductase 2; Golgi protein 2 (GOLPH2); transforming growth factor-beta (TGF-beta); tumor specific growth factor (TSGF); hepatocyte growth factor / scatter factor (HGF / SF); basic fibroblast growth factor; alpha-fetoprotein mRNA (AFP mRNA); gamma-glutamyltransferase mRNA (GGT mRNA); insulin-like growth factor II (IGF-II) mRNA; albumin mRNA; DK 1; Golgi protein 73 (GP73); protein induced by vitamin K absence or antagonist II (PIVKA-II); miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a, and miR-801, or a combination thereof.

[0048] In various embodiments, any or all of the aspects may be combined with one or more of any of the following features. For example: In some embodiments, the liver cancer is primary liver cancer.

[0049] In some embodiments, the liver cancer is hepatocellular carcinoma (HCC).

[0050] In some embodiments, the liver cancer is intrahepatic cholangiocarcinoma.

[0051] In some embodiments, liver metastases are derived from colorectal cancer, but also from breast cancer, esophageal cancer, lung cancer, melanoma, pancreatic cancer, and gastric cancer.

[0052] Combined chemotherapy As used herein, the term "combined administration" is not limited to situations where both lenvatinib and MIV-818 are co-administered to a human or mammal in a common dosage unit, such as a tablet or oral suspension, although such common dosage units may have advantages with respect to dosing convenience, patient compliance, and dosing accuracy.

[0053] More typically, lenvatinib and MIV-818 are presented in their respective dosage units, giving the prescribing physician greater freedom in dosage calibration. In the case of lenvatinib, currently commercially available products include 4 mg and 10 mg hard capsules.

[0054] The lenvatinib dosage and / or schedule may follow clinically approved or experimental guidelines. In various embodiments, the dosage of lenvatinib is about 4 - 12 mg / day or dosed every other day, as specified by the SPC. Lower body weight individuals, such as the young and the elderly, may require fractional dosing of the capsules.

[0055] MIV-818 is generally administered orally and most typically is administered as one or several tablets or capsules each containing between 10 mg and 600 mg of the active pharmaceutical ingredient. Representative tablets or capsules may contain between 25 mg and 500 mg, or between 50 mg and 450 mg, or between 100 mg and 400 mg, such as between 150 mg and 400 mg, between 200 mg and 500 mg or between 250 mg and 500 mg.

[0056] In various embodiments, MIV-818 is administered to a subject once daily for 1, 2, 3, 4, 5, 6, or 7 days over a one-week (7-day) period. MIV-818 may be administered to a subject once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days over a 14-day period. MIV-818 may be administered to a subject once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days over a 21-day period. MIV-818 may be administered to a subject once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days over a 28-day period.

[0057] In various embodiments, MIV-818 is administered according to a two-week administration (14 days in total); one-week administration, one-week drug holiday (14 days in total); three consecutive weeks of administration (21 days in total); two weeks of administration, one-week drug holiday (21 days in total); one week of administration, two weeks of drug holiday (21 days in total); four consecutive weeks of administration (28 days in total); three consecutive weeks of administration, one-week drug holiday (28 days in total); two weeks of administration, two weeks of drug holiday (28 days in total); one week of administration, three consecutive weeks of drug holiday (28 days in total).

[0058] In various embodiments, MIV-818 is administered on the first day in 7, 14, 21, or 28-day cycles; on the first and 15th days in 21 or 28-day cycles; on the first, 8th, and 15th days in 21 or 28-day cycles; or on the first, 2nd, 8th, and 15th days in 21 or 28-day cycles. MIV-818 may be administered once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0059] Lenvatinib and MIV-818 may be administered substantially simultaneously as a common dosage unit or as their respective dosage units, or the combined administration may be alternating or alternative, i.e., it may involve separate cycles of lenvatinib and MIV-818. For example, daily MIV-818 in a 1-day, 2-day, 3-day, 5-day or 7-day cycle may be interspersed with daily cycles of lenvatinib for 1 consecutive week.

[0060] Alternatively, a loading dose of one agent, e.g., the lenvatinib component, may be initiated, e.g., to affect angiogenesis in a tumor and / or to create local hypoxia in the liver, and then co-administration of MIV-818 may be initiated.

[0061] It may be suitable to monitor alternating combined administration with respect to the target molar or mg ratio between lenvatinib and MIV-818. In various embodiments, the ratio (e.g., the molar ratio of lenvatinib:MIV-818) is typically between about 20:1 and 1:20, such as 5:1, 2:1, 1:1, 1:2, 1:5 or 1:10.

[0062] The molar ratio of lenvatinib:MIV-818 may be measured over different periods. For example, the molar ratio may be the amount of lenvatinib:MIV-818 administered to a subject on a single day, a single week, 14 days, 21 days, or 28 days.

[0063] According to certain embodiments, the methods of the invention contemplate that the lenvatinib and MIV-818 components are each administered on the same day (as QD, BID or TID).

[0064] In such embodiments, lenvatinib and MIV-818 may be co-delivered in a common oral dosage unit, such as a capsule, soft gel capsule or tablet.

[0065] In other aspects, the methods of the invention contemplate that lenvatinib and MIV-818 are administered as separate oral dosage units.

[0066] In representative aspects of the immediately preceding paragraph, the dosage unit(s) of lenvatinib and the dosage unit(s) of MIV-818 are administered on any given day, for patient comfort, at least 6 hours apart, preferably at least 8 hours apart, and typically approximately 12 hours apart.

[0067] Certain aspects of the methods of the invention contemplate that lenvatinib and MIV-818 are administered alternately in a single therapy treatment cycle of 1 to 28 days, optionally interspersed with a treatment-free period of 1 to 28 days.

[0068] As used herein, “monotherapy” of a lenvatinib or MIV-818 component means that lenvatinib is not administered during a cycle of MIV-818 and vice versa. Monotherapy does not exclude co-administration of other therapeutic agents (including any other anti-cancer agents or palliative agents determined by the responsible physician).

[0069] As used herein, for the purposes of describing ranges, such as ratios, dosages, times, etc., the term “about” means essentially the same within an appropriate tolerance of error (e.g., within the confidence intervals recognized in the art, e.g., 95% for phenomena following a normal or Gaussian distribution) or includes variations that do not substantially change the effect of what is being quantified.

[0070] The lenvatinib-MIV-818 therapy course may be prescribed by a clinician. The MIV-818 component (and thus the combination therapy) may be administered over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles.

[0071] The lenvatinib-MIV-818 therapy cycle may continue until the clinical endpoint is met. In some embodiments, the therapy is continued until disease progression or unacceptable toxicity occurs. In some embodiments, the therapy is continued until a pathologic complete response (pCR) rate, defined as the absence of liver cancer (e.g., HCC), is achieved. In some embodiments, the therapy is continued until partial or complete remission of liver cancer. Administration of MIV-818 and lenvatinib to a plurality of subjects having HCC is thought to increase overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), response rate (RR), quality of life (QoL), or combinations thereof.

[0072] In various embodiments, the treatment reduces the size and / or number of liver cancer tumor(s). The treatment may prevent an increase in the size and / or number of liver cancer tumor(s). The treatment may prevent metastasis of liver cancer tumor(s).

[0073] In the methods of the invention, administration is not limited to any particular delivery system and includes, without limitation, parenteral (including subcutaneous, intravenous, intramedullary, intra-articular, intramuscular, or intraperitoneal injection), rectal, topical, transdermal, or preferably oral (e.g., in capsules, suspensions, or tablets).

[0074] Administration to an individual may be by single dose, or by repeated dosing, and in any of a variety of physiologically acceptable salt forms and / or with a pharmaceutically acceptable carrier and / or additive that is acceptable as part of a pharmaceutical composition.

[0075] Physiologically acceptable salt forms and standard pharmaceutical compounding techniques, dosage forms, and excipients are well known to those skilled in the art. (See, e.g., Physicians’ Desk Reference (PDR®) 2005, 59th Edition, Medical Economics Company, 2004; and Remington: The Science and Practice of Pharmacy, edited by Gennado et al., 21st Edition, Lippincott, Williams & Wilkins, 2005).

[0076] Furthermore, the effective dosage achieved in one animal may be extrapolated for use in another animal, including humans, using conversion factors known in the art. See, for example, Freireich et al., Cancer Chemother Reports 50(4):219-244 (1966), and the following table for equivalent surface area dosage factors.

[0077] Equivalent surface area dosage factors

[0078] [Table 1] The combination therapy of the present invention is not specifically limited to any particular cool or measure and can be used separately or in combination with other treatment modalities (e.g., chemotherapy or radiation therapy).

[0079] The combination therapies according to the present invention may include additional therapies (e.g., drugs, radiation, etc.) other than lenvatinib and MIV-818. Similarly, the present invention may be used as an adjuvant therapy (e.g., when combined with surgery). In various embodiments, the subject may also be treated by surgical resection, percutaneous ethanol or acetic acid injection, transarterial chemoembolization, radiofrequency ablation, laser ablation, cryoablation, stereotactic external beam radiation, stereotactic body radiation therapy, selective internal radiation therapy, intraarterial administration of iodine-131 lipiodol, and / or high-intensity focused ultrasound therapy.

[0080] The combination of MIV-818 and lenvatinib may be used as an adjuvant, neoadjuvant, concomitant, simultaneous, or palliative therapy. The combination of MIV-818 and lenvatinib may be used as a first-line therapy, second-line therapy, or crossover therapy.

[0081] In some embodiments, it is also possible to reduce the therapeutically effective dose of lenvatinib through combination with MIV-818. For example, the weekly or monthly dose of lenvatinib can be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to the maximum recommended dose or maximum tolerated dose. In other embodiments, lenvatinib can be administered at an effective dose that is at least 50%, 60%, 70%, 80%, 90% or lower than the dose required to be effective in the absence of MIV-818 administration. In some embodiments, the IC 50 of lenvatinib is reduced by at least 4, 5, 10, 20, 30, 40, 50, or 100-fold compared to the IC 50 in the absence of MIV-818.

[0082] Isotope variants of MIV-818 and / or lenvatinib, in which one or more atoms are replaced by isotopes of that atom, i.e., atoms having the same atomic number but a different atomic weight than typically found in nature, are within the scope of the invention for combination administration as provided herein. Examples of isotopes that may be incorporated into MIV-818 and / or lenvatinib include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H (each also denoted as D for deuterium and T for tritium), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 31 P and 32 P, fluorine, such as 18 F, chlorine, such as 36 Cl, and bromine, such as 75 Br, 76 Br, 77 Br and 82 Br are included. Isotope-labeled compounds include, for example, those in which a radioactive isotope, such as 3 H and 14 C are present, or those in which a non-radioactive isotope, such as 2 H and 13 C are present.

[0083] The choice of isotope included in an isotope-containing compound will depend on the particular application of that compound. For example, for drug or substrate tissue distribution assays, or in metabolic studies, compounds incorporating a radioactive isotope, such as 3 H or 14 C, will generally be most useful. For radiation imaging applications, such as positron emission tomography (PET), positron-emitting radioisotopes, such as 11 C, 18 F, 13 N or 15O might be useful. The incorporation of heavier isotopes, such as deuterium, i.e., 2 the incorporation of 2 H can provide certain therapeutic advantages resulting from conferring greater metabolic stability to the compounds of the invention, which can result in, for example, an increase in the in vivo half-life of the compound, a decrease in the dosing requirement, or an improvement in the therapeutic index.

[0084] Isotopically labeled variants of MIV-818 and / or lenvatinib can generally be prepared by conventional techniques known to those skilled in the art or by a process similar to those described in the schemes and / or patent references incorporated herein by using appropriate isotopically labeled reagents or starting materials in place of the corresponding non-isotopically labeled reagents or starting materials.

[0085] Further explanations and aspects of the combination therapy are provided in the following Examples section.

[0086] Exemplary embodiments of the invention are described in the following examples with reference to the accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS

[0087]

Figure 1-1

Figure 1-2

Figure 2

[0088] General method for in vivo evaluation of the combination of lenvatinib and MIV-818 The efficacy of MIV-818 in combination with lenvatinib may be evaluated in vivo in a subcutaneous xenograft model of hepatocellular carcinoma (HCC). The model is based on the inoculation of HCC cells (e.g., Hep3B, Huh-7 or HepG2) into the flank of immunocompromised mice. Tumor volume is evaluated approximately three times per week, and treatment with the compounds is typically initiated at a tumor size of 100-200 mm 3 Typical studies consist of four groups (n = 10 mice / group); 1) vehicle (control), 2) MIV-818, 3) lenvatinib alone, and 4) MIV-818 in combination with lenvatinib 8 MIV-818 is administered via oral gavage at a dose of 25-100 mg / kg once or twice daily for 5-21 days. Alternatively, taking into account the rapid metabolism in rodent blood, the synergistic effect may be modeled by administering the parent troxacitabine intraperitoneally (i.p.) at a dose of 2.5-25 mg / kg once or twice daily. Lenvatinib is administered via oral gavage at a dose of 3-30 mg / kg once daily for a total period of 21 days. Tumor growth is evaluated during the treatment period and, where applicable, after treatment discontinuation. Statistical analysis is performed to calculate tumor growth inhibition and tumor growth delay and to evaluate the significant effect of the treatment compared to the control group.

[0089] Cell culture

[0090] Experimental method HepG2 tumor cells are maintained in vitro as a monolayer culture in EMEM supplemented with 10% fetal bovine serum at 37 °C in an atmosphere of 5% CO2 in air. The tumor cells are routinely passaged twice a week by trypsin-EDTA treatment. Cells in the exponential growth phase are harvested and counted for tumor inoculation.

[0091] Tumor inoculation In the right flank of each mouse, Hep G2 tumor cells (1x10 7 ) in PBS (1:1) mixed with Matrigel are subcutaneously inoculated for tumor development. The day of tumor cell inoculation is designated as Day 0.

[0092] When the average tumor size reaches approximately 150 mm 3 (100 - 200 mm 3 ), randomization to different study groups is initiated. Typically, 8 - 12 mice per study group are enrolled in the study. Randomization is performed using the multitask method (Study Director TM software) based on the "matched distribution" method / "stratification" method. Treatment is started the day after randomization.

[0093] Drug Administration The preferred route of delivery is oral (p.o.). The dosing volume is 10 ml / kg (i.e., 0.25 ml for a 25 g mouse). The dose of MIV - 818 administered is between 30 - 100 mg / kg (corresponding to between 48 - 160 μmol / kg). The dosing of lenvatinib is 3 - 30 mg / kg p.o. once daily for 21 days.

[0094] Drug administration is accompanied by a 1 - hour separation between MIV - 818 and lenvatinib (i.e., MIV - 818 or vehicle is administered first, and then lenvatinib or vehicle is administered 1 hour later).

[0095] Observation and Data Collection After tumor cell inoculation, animals are checked daily for morbidity and mortality. Tumor volume is measured three times a week in two dimensions using calipers. Prior to termination, a final tumor reading is performed for each mouse.

[0096] The following formula: V=(LxWxW) / 2, where V is the tumor volume, L is the length of the tumor (the longest of the tumor dimensions), and W is the width of the tumor (the longest tumor dimension perpendicular to L), is used to express the tumor volume in mm 3 . Drug administration and tumor and body weight measurements are performed in a laminar flow cabinet.

[0097] For comparison between two groups, the Student's t-test is performed. For comparison among three groups, after performing one-way or two-way ANOVA, the multiple comparison method is carried out. All data are analyzed using SPSS 18.0 and / or GraphPad Prism 5.0. P < 0.05 is considered statistically significant.

Example

[0098] Example 1 Figure 1 shows in vivo tumor growth inhibition (TGI) in the HepG2 model in BALB / c nude mice. On day 15, oral administration is initiated with MIV-818 at 30 mg / kg BID for 5 days and lenvatinib at 3 mg / kg QD for 3 weeks, either as single agents or in combination. The TGI resulting from the combination therapy (MIV-818 + lenvatinib) was significantly improved compared to lenvatinib alone (two-way ANOVA p < 0.0001).

Claims

Claim 1 A pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof, in combination with a compound of formula MIV-818: 【Chemical 1】 for use in the treatment of liver cancer or liver metastases. Claim 2 The pharmaceutical composition according to claim 1, wherein lenvatinib and MIV-818, or pharmaceutically acceptable salts thereof, are each administered daily (as QD, BID or TID) on the same day. Claim 3 The pharmaceutical composition according to claim 2, wherein lenvatinib and MIV-818, or pharmaceutically acceptable salts thereof, are co-administered in a common oral dosage unit. Claim 4 The pharmaceutical composition according to claim 1, wherein lenvatinib and MIV-818, or pharmaceutically acceptable salts thereof, are administered as separate oral dosage units. Claim 5 The pharmaceutical composition according to claim 4, wherein the dosage unit(s) of lenvatinib and the dosage unit(s) of MIV-818 are administered at least 6 hours apart on any given day. Claim 6 The pharmaceutical composition according to claim 1, wherein lenvatinib and MIV-818, or pharmaceutically acceptable salts thereof, are administered alternately in a single treatment cycle of 1 to 28 days, optionally interspersed with a period of non-treatment of 1 to 28 days. Claim 7 The pharmaceutical composition according to claim 6, wherein the treatment begins with a lenvatinib cycle. Claim 8 The pharmaceutical composition according to any one of claims 1 to 7, wherein the liver cancer is hepatocellular carcinoma or intrahepatic cholangiocarcinoma. Claim 9 The pharmaceutical composition according to any one of claims 1 to 7, wherein the liver metastases are derived from colorectal cancer. Claim 10 The pharmaceutical composition according to any one of claims 1 to 7, wherein the liver metastases are derived from breast cancer, esophageal cancer, lung cancer, melanoma, pancreatic cancer or gastric cancer.

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