Combination therapy comprising an FGFR inhibitor and a nectin-4 targeting agent

Abstract

This disclosure relates to a method for treating cancer by combining a compound that acts as a fibroblast growth factor receptor (FGFR) inhibitor with enfortumab vedotin.

Description

[Technical Field]

[0001] This disclosure relates to a method of treating cancer by combining a compound that is an inhibitor of fibroblast growth factor receptor (FGFR) with enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4. [Previous Technology]

[0002] Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors that bind to fibroblast growth factor (FGF) ligands. Four FGFR proteins (FGFR1-4) can bind to ligands and participate in the regulation of a variety of physiological processes, including tissue development, angiogenesis, wound healing, and metabolic regulation. Upon ligand binding, these receptors undergo dimerization and phosphorylation, leading to stimulation of protein kinase activity and recruitment of various intracellular docking proteins. These interactions promote the activation of a series of intracellular signaling pathways essential for cell growth, proliferation, and survival, including Ras-MAPK, AKT-PI3K, and phospholipase C (described in Eswarakumar et al., Cytokine & Growth Factor Reviews, 2005).

[0003] Aberrant activation of this pathway, caused by overexpression of FGF ligands or FGFR, or by activating mutations in FGFR, can lead to tumor development, progression, and resistance to conventional cancer therapies. In human cancers, genetic alterations leading to ligand-independent receptor activation have been described, including gene amplification, chromosomal translocations, and somatic mutations. Large-scale DNA sequencing of thousands of tumor samples has shown that components of the FGFR pathway are among the most frequently mutated in human cancers. Many of these activating mutations are consistent with germline mutations leading to skeletal dysplasia syndrome. Mechanisms leading to aberrant ligand-dependent signaling in human diseases include FGF overexpression and FGFR splicing alterations that produce receptors with more disordered ligand-binding abilities (described in Knights and Cook Pharmacology & Therapeutics, 2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore, the development of inhibitors targeting FGFR could be applicable to the clinical treatment of diseases with increased FGF or FGFR activity.

[0004] The types of cancers involving FGF / FGFR include, but are not limited to: carcinomas (e.g., cholangiocarcinoma, adenocarcinoma), bladder, breast, cervix, colorectal, endometrium, stomach, head and neck, kidney, liver, lung, ovary, prostate); hematopoietic malignancies (e.g., multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenström macroglobulinemia); and other neoplasms (e.g., glioblastoma and sarcoma, melanoma, and rhabdomyosarcoma). In addition to its role in carcinogenic neoplasms, FGFR activation has also been involved in skeletal and chondrocyte disorders, including but not limited to achondroplasia and premature cranial suture closure syndrome.

[0005] FGFR inhibitors for the treatment of cancer are currently under development. For example, pemigatinib or 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one and other small molecule inhibitors of FGFR have been reported, for example, in U.S. Patent No. 9,611,267 and U.S. Publication No. 2012 / 0165. Among the following: No. 305; No. 2014 / 0045814; No. 2013 / 0338134; No. 2014 / 0171405; No. 2014 / 0315902; No. 2016 / 0115164; No. 2016 / 0244448; No. 2016 / 0244449; No. 2016 / 0244450; No. 2019 / 0337948 and No. 2020 / 0002338.

[0006] There is still a need for novel cancer treatment regimens that combine FGFR inhibitors with other therapeutic agents. This disclosure addresses this need and other needs. [Summary of the Invention]

[0008] This application provides, in particular, a method of treating a patient’s cancer, comprising administering to the patient: (i) pemitinib having the following structure: pemitinib; or a pharmaceutically acceptable salt thereof; and (ii) enrofloxacin.

[0009] This application further provides a method of treating a patient’s cancer, comprising administering to the patient pemitinib or a pharmaceutically acceptable salt thereof and enrofloxacin.

[0010] This application also provides the use of pemitinib or a pharmaceutically acceptable salt thereof and enrofloxacin in the preparation of a medicament for the treatment of cancer.

[0011] This application further provides pemitinib or its pharmaceutically acceptable salt and enrofloxacin for use in any of the methods described herein.

Implementation Method

[0013] This application provides a method for treating cancer in a patient, comprising administering pemitinib in combination with enrofloxacin, wherein pemitinib is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one:pemitinib.

[0014] Pemitinib is described in U.S. Patent No. 9,611,267, the entire contents of which are incorporated herein by reference. Pemitinib is further described in U.S. Publications Nos. 2019 / 0337948 and 2020 / 0002338, the entire contents of which are incorporated herein by reference. Pemitinib may be referred to as "pemi". As described herein, pemitinib inhibits the activity of the FGFR enzyme. For example, by administering an inhibitory dose of pemitinib to cells, individuals, or patients, pemitinib can be used to inhibit the activity of the FGFR enzyme in cells or individuals or patients who require inhibition of the FGFR enzyme. As an FGFR inhibitor, pemitinib can be used to treat a variety of diseases associated with abnormal expression or activity of the FGFR enzyme or FGFR ligands. Compounds that inhibit FGFR can be used to provide a means of preventing tumor growth or inducing tumor cell apoptosis, specifically through angiogenesis inhibition. The methods described in this article can be used to treat or prevent proliferative diseases such as cancer. Specifically, tumors with receptor tyrosine kinase activation mutants or upregulated receptor tyrosine kinase may be particularly sensitive to the methods described in this article.

[0015] Enroximateb is an antibody-drug conjugate approved by the U.S. Food and Drug Administration for the treatment of Nectin-4 manifested cancers, including urothelial carcinoma (e.g., bladder cancer), in adult patients who have previously received PD-1 or PD-L1 inhibitors and platinum-based chemotherapy. Enroximateb is a conjugate of a Nectin-4 targeted antibody and a microtubule inhibitor. Specifically, enroximateb is a Nectin-4 targeted antibody-drug conjugate comprising a complete human anti-Nectin-4 IgG1κ monoclonal antibody (AGS-22C3) bound to auristatin E, a small molecule microtubule disruptor. Binding occurs on a cysteine ​​residue containing an interchain disulfide bond of the antibody. Enroximateb is also known as "enroximateb-ejfv" and "PADCEV".

[0016] This article provides a method of treating a patient with cancer, comprising administering to the patient: (i) pemitinib having the following structure: pemitinib; or a pharmaceutically acceptable salt thereof; and (ii) enrofloxacin.

[0017] This article provides a method of treating a patient with cancer, comprising administering to the patient: (i) pemitinib or a medically acceptable salt thereof; and (ii) enrofloxacin.

[0018] This article provides a method for treating a patient’s cancer, comprising administering to the patient: (i) pemitinib; and (ii) enrofloxacin.

[0019] In some embodiments, the cancer is bladder cancer.

[0020] In some embodiments, the cancer is a cancer of the genitourinary system (e.g., a tumor of the genitourinary system).

[0021] In vivo studies have shown that, at certain doses, the combination of pemitinib and enrofloxacin has a synergistic effect in the treatment of bladder cancer (Example C).

[0022] In some embodiments, pemitinib or a pharmaceutically acceptable salt thereof and enrofloxacin are administered to the patient simultaneously or sequentially. In some embodiments, pemitinib or a pharmaceutically acceptable salt thereof and enrofloxacin are administered to the patient simultaneously. In some embodiments, pemitinib or a pharmaceutically acceptable salt thereof and enrofloxacin are administered to the patient sequentially.

[0023] Pemitinib and its pharmaceutically acceptable salts can be administered to individuals, such as individuals in need, such as human individuals, by a variety of methods. For many applications, the route of administration is oral. In some embodiments, pemitinib or its pharmaceutically acceptable salts are administered in the form of a pharmaceutical composition.

[0024] In some embodiments, pemitinib is administered orally. In some embodiments, pemitinib is administered once daily.

[0025] In some embodiments, pemitinib is administered at a daily dose of about 1 mg to about 50 mg. In some embodiments, pemitinib is administered at a daily dose of about 1 mg to about 20 mg. In some embodiments, pemitinib is administered at a daily dose of about 1 mg to about 15 mg. In some embodiments, pemitinib is administered at a daily dose of about 1 mg to about 10 mg. In some embodiments, pemitinib is administered at a daily dose of about 1 mg to about 5 mg. In some embodiments, pemitinib is administered at a daily dose of about 5 mg to about 20 mg. In some embodiments, pemitinib is administered at a daily dose of about 5 mg to about 10 mg. In some embodiments, pemitinib is administered at a daily dose of about 10 mg to about 15 mg. In some embodiments, pemitinib is administered at a daily dose of about 4.5 mg. In some embodiments, pemitinib is administered at a daily dose of about 9 mg. In some embodiments, pemitinib is administered at a daily dose of about 13.5 mg.

[0026] In some embodiments, pemitinib is administered at a daily dose of about 20 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 15 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 13.5 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 10 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 9 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 8 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 7 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 6 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 5 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 4 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 3 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 2 mg or less. In some embodiments, pemitinib is administered at a daily dose of about 1 mg or less.

[0027] In some embodiments, pemitinib is administered in tablet form. In some embodiments, the tablet contains about 0.5 mg to about 10 mg of pemitinib. In some embodiments, the tablet contains about 0.5 mg to about 5 mg of pemitinib. In some embodiments, the tablet contains about 2 mg, about 4.5 mg, about 9 mg, about 13.5 mg, or about 18 mg of pemitinib. In some embodiments, the tablet contains about 0.5 mg of pemitinib. In some embodiments, the tablet contains about 2 mg of pemitinib. In some embodiments, the tablet contains about 4.5 mg of pemitinib. In some embodiments, the tablet contains about 9 mg of pemitinib. In some embodiments, the tablet contains about 13.5 mg of pemitinib. In some embodiments, the tablet contains about 18 mg of pemitinib.

[0028] In some embodiments, pemitinib is administered once daily in a continuous dosing regimen. In some embodiments, pemitinib is administered in a 21-day dosing regimen, wherein the 21-day dosing regimen comprises: (a) a first phase in which pemitinib is administered once daily for 14 days; and (b) a second phase in which pemitinib is not administered for 7 days.

[0029] In some embodiments, pemitinib is administered in a 21-day dosing regimen, wherein the 21-day dosing regimen includes: (a) Phase 1, wherein pemitinib is administered once daily for 14 days; and (b) Phase 2, wherein pemitinib is not administered for 7 days.

[0030] In some embodiments, enroximatel is administered intravenously. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 0.5 mg / kg to about 5.0 mg / kg. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 0.5 mg / kg to about 2.0 mg / kg. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 0.5 mg / kg to about 1.5 mg / kg. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 0.5 mg / kg to about 1.25 mg / kg. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 1.0 mg / kg to about 5.0 mg / kg. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 1.0 mg / kg to about 2.0 mg / kg. In some embodiments, enroximatel is administered via intravenous infusion at a dose of about 1.0 mg / kg to about 1.5 mg / kg. In some embodiments, for patients weighing 100 kg or more, enrofloxacin is administered intravenously at a dose of up to 125 mg. In some embodiments, for patients weighing 100 kg or more, enrofloxacin is administered intravenously at a dose of up to 100 mg. In some embodiments, for patients weighing 100 kg or more, enrofloxacin is administered intravenously at a dose of up to 75 mg. In some embodiments, for patients weighing 100 kg or more, enrofloxacin is administered intravenously at a dose of about 1.25 mg / kg at a dose of up to 125 mg. In some embodiments, enrofloxacin is administered intravenously at a dose of about 1.25 mg / kg.

[0031] In some embodiments, enroximateb is administered once weekly in a continuous dosing regimen.

[0032] In some embodiments, enroximateb is administered in a 28-day dosing regimen, wherein the 28-day dosing regimen includes: (a) Phase I, wherein enroximateb is administered once a week for 21 days; and (b) Phase II, wherein enroximateb is not administered for 7 days.

[0033] In some embodiments, enroximate is administered in a 28-day dosing regimen, wherein the 28-day dosing regimen includes administration of enroximate on days 1, 8 and 15 of the 28-day period.

[0034] The methods disclosed in this article can be used to treat cancer. Example cancers include bladder cancer, breast cancer (e.g., hormone R positive, triple negative), cervical cancer, colorectal cancer, small bowel cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumor), head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, oral cancer, squamous cell head and neck cancer), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma, hepatic angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial cancer, bronchial adenoma, pleural pulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), and stomach cancer. Cancers including thyroid cancer, parathyroid cancer, neuroendocrine cancers (e.g., pheochromocytoma, Merkel cell cancer, neuroendocrine cancer), skin cancers (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and brain cancers (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0035] Other examples of cancers include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia vera, essential thrombocythemia, and essential myelofibrosis), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenström macroglobulinemia, pilocellular lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0036] In some embodiments, this document provides a method for treating a patient with a myeloid / lymphoid spur in need. In some embodiments, the myeloid / lymphoid spur is 8p11 myeloproliferative syndrome. As used herein, the term "8p11 myeloproliferative syndrome" (EMS) refers to a myeloid / lymphoid spur associated with eosinophilia and FGFR1 abnormalities or a myeloid / lymphoid spur (MLN) with FGFR1 rearrangement. Jackson, Courtney C. et al., Human Pathology, 2010, 41, 461-476, outline 8p11 myeloproliferative syndrome. In some embodiments, the myeloid / lymphoid spur exhibits 8p11 translocation. In some embodiments, the 8p11 translocation is associated with FGFR1 activation. In some embodiments, the patient has failed at least one prior treatment for the myeloid / lymphoid spur (e.g., 8p11 myeloproliferative syndrome). In some embodiments, prior treatment was surgery or radiation therapy. In some embodiments, the patient has a history of hepatitis. In some embodiments, the hepatitis is chronic hepatitis B or hepatitis C. In some embodiments, the patient has no history of hepatitis.

[0037] In some embodiments, the cancer is bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma). In some embodiments, the bladder cancer is the luminal papillary subtype of bladder cancer. In some embodiments, the bladder cancer is characterized by FGFR3 mutations, such as FGFR3 fusions. Examples of FGFR3 fusions include, but are not limited to, FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR3-AES, FGFR3-ELAVL3, FGFR3-JAKMIP1, FGFR3-TNIP2, and FGFR3-WHSC1, as described by De Luca et al., Int. J. Mol. Sci. 2020, 21(8):6856, pp. 1-18.

[0038] In some embodiments, the cancer is a genitourinary cancer (e.g., a genitourinary tumor). Genitourinary cancers include, but are not limited to, bladder cancer, kidney cancer, testicular cancer, and prostate cancer. In some embodiments, the genitourinary cancer is characterized by a tumor with altered FGF / FGFR genes. In some embodiments, the genitourinary cancer is characterized by an FGFR3 mutation, such as an FGFR3 fusion. Examples of FGFR3 fusions include, but are not limited to, FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR3-AES, FGFR3-ELAVL3, FGFR3-JAKMIP1, FGFR3-TNIP2, and FGFR3-WHSC1, as described by De Luca et al., Int. J. Mol. Sci. 2020, 21(8):6856, pp. 1-18.

[0039] In some embodiments, the cancer is glioblastoma or lung cancer, wherein the glioblastoma or lung cancer is characterized by an FGFR3 mutation, such as an FGFR3 fusion. Examples of FGFR3 fusions include, but are not limited to, FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR3-AES, FGFR3-ELAVL3, FGFR3-JAKMIP1, FGFR3-TNIP2 and FGFR3-WHSC1, as described by De Luca et al. Int. J. Mol. Sci. 2020, 21(8):6856, pp. 1-18.

[0040] In some embodiments, the hepatocellular carcinoma is cholangiocarcinoma (e.g., intrahepatic, hilar, or perihilar, or distal extrahepatic). As used herein, cholangiocarcinoma is synonymous with cholangiocarcinoma or bile duct cancer. In some embodiments, the cholangiocarcinoma is advanced or metastatic. In some embodiments, the cholangiocarcinoma is unresectable. In some embodiments, the cholangiocarcinoma is intrahepatic. In some embodiments, the cholangiocarcinoma is extrahepatic. In some embodiments, the cholangiocarcinoma exhibits an FGFR2 tyrosine kinase fusion, which defines a unique molecular subtype, as described in Arai, Yasuhito, et al., Hepatology, 2014, 59, 1427-1434. In some embodiments, the cholangiocarcinoma is characterized by tumors with altered FGF / FGFR genes. In some embodiments, the tumor exhibits an FGFR2 fusion. The FGFR2 fusion may be a translocation, a stromal deletion, or a chromosomal inversion. In some embodiments, the FGFR2 fusion is an FGFR2 translocation. FGFR2 translocations can be selected from, but are not limited to, FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1, and FGFR2 intron 17 rearrangements. In some embodiments, the tumor exhibits FGF / FGFR alterations other than FGFR2 translocation. In some embodiments, cholangiocarcinomas do not exhibit FGF / FGFR gene alterations.

[0041] Other cancers that can be treated with the methods provided herein include ocular tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, leiomyosarcoma, urothelial carcinoma (e.g., ureter, urethra, bladder, urachus), and osteosarcoma.

[0042] The method disclosed herein can also be used to treat metastatic cancer, particularly metastatic cancer exhibiting PD-L1.

[0043] In some embodiments, diseases and indications that can be treated using the methods of this disclosure include, but are not limited to, hematologic cancers, lenticule cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0044] Exemplary hematologic cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and non-Hodgkin's lymphoma (including relapsed or refractory N). HL), follicular lymphoma (FL), Hodgkin's lymphoma, lymphoblastic lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Waldenström macroglobulinemia, pilocellular lymphoma, chronic myeloma, and Burkitt lymphoma.

[0045] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0046] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (small bronchus) carcinoma, bronchial adenoma, chondroma, and mesothelioma.

[0047] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, and bile duct cancer.

[0048] Exemplary urogenital cancers include renal cancer (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate cancer (adenocarcinoma, sarcoma) and testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma).

[0049] Exemplary liver cancers include hepatocellular carcinoma (HCC), bile duct epithelial carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0050] Exemplary bone cancers include, for example, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoma, osteoid osteoma, and giant cell tumor.

[0051] Exemplary nervous system cancers include skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancer (brain and spinal cord meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), and spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma, Lhermitte-Duclos disease, central nervous system (CNS) spurs, primary CNS lymphoma, and spinal cord axis tumors.

[0052] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical cancer, pretumoral cervical dysplasia), ovarian cancer (ovarian cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)) and fallopian tube cancer (cancer).

[0053] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and scar tumor.

[0054] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal carcinoma, nasal and paranasal carcinoma, thyroid cancer and parathyroid cancer.

[0055] In some embodiments, this disclosure provides a method for treating hepatocellular carcinoma in a patient in need. In some embodiments, this disclosure provides a method for treating rhabdomyosarcoma, esophageal cancer, breast cancer, or head and neck cancer in a patient in need.

[0056] The methods described herein relate to the treatment of cancer, such as solid tumors.

[0057] In some embodiments, the solid tumor is selected from skin cancer, lung cancer, lymphoma, sarcoma, bladder cancer, ureteral cancer, urethral cancer and urachal cancer, gastric cancer, cervical cancer, liver cancer, breast cancer, kidney cancer, squamous cell carcinoma, colorectal cancer, endometrial cancer, anal cancer, and tumors with high microsatellite instability (MSI-H), mismatch repair deficiency (dMMR) and / or DNA polymerase ε exonuclease domain mutation positive diseases.

[0058] In some embodiments, the solid tumor is selected from cholangiocarcinoma, melanoma, non-small cell lung cancer, small cell lung cancer, Hodgkin's lymphoma, urothelial carcinoma, gastric cancer, hepatocellular carcinoma, Merkel cell carcinoma, triple-negative breast cancer, renal cell carcinoma, head and neck squamous cell carcinoma, and colorectal cancer.

[0059] In some embodiments, the solid tumor is selected from sarcoma, head and neck cancer, melanoma, and non-small cell lung cancer. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is non-small cell lung cancer.

[0060] As used herein, the terms “individual” or “patient” may be used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and most preferably humans.

[0061] As used herein, the phrase “therapeutic effective amount” means the amount of an active compound or pharmaceutical agent that elicits a biological or medical response sought by an investigator, veterinarian, physician or other clinician in a tissue, system, animal, individual or human.

[0062] As used herein, the term "treatment" means one or more of the following: (1) suppressing a disease; for example, suppressing the disease, illness, or condition of an individual who is experiencing or exhibiting the pathology or symptoms of the disease, illness, or condition (i.e., preventing the pathology and / or symptoms from progressing further); and (2) alleviating a disease; for example, alleviating the disease, illness, or condition of an individual who is experiencing or exhibiting the pathology or symptoms of the disease, illness, or condition (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease. In some embodiments, the term "treatment" means suppressing or alleviating a disease.

[0063] As used herein, the terms "co-administration" or "parallel administration" mean administration of pemitinib and one or more other drugs (e.g., enrofloxacin) simultaneously or nearly simultaneously. For example, pemitinib may be administered as one or more other drugs, for example, on the same day, within a week, or within a month. In some embodiments, one or more other drugs are administered between administrations of pemitinib.

[0064] As used herein, the term "therapy" means administration of a compound intended for the treatment of cancer. For example, a therapy may mean administration of pemitinib for the treatment of cancer.

[0065] As used herein, and unless otherwise stated, the term "about," when used in conjunction with a numerical value or range of numerical values, means that the numerical value or range of numerical values ​​may deviate from what is considered reasonable by a person skilled in the art. Specifically, the term "about," when used in this context, means that the numerical value or range of numerical values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the referenced numerical value or range of numerical values.

[0066] As used herein, the term "cell" means an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be a portion of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell line is a cell living in an organism such as a mammal.

[0067] As used herein, the term "contact" means bringing together a specified portion in an in vitro or in vivo system. For example, "contacting" an FGFR enzyme with pemitinib includes administering the compound described herein to an individual or patient having an FGFR, such as a human, and, for example, introducing pemitinib into a sample containing cells or a purified formulation containing an FGFR enzyme.

[0068] The phrase "medically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms applicable within the scope of reasonable medical judgment to tissues of humans and animals in contact without excessive toxicity, irritation, allergic reactions or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0069] As used herein, the tablet "a medically acceptable carrier or excipient" refers to a medically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, solvent, or encapsulation material. Excipients or carriers are usually safe, non-toxic and biologically or otherwise desirable and include excipients or carriers acceptable for veterinary use and human medical and pharmaceutical use. In one embodiment, each fraction is “medically acceptable” as defined herein. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition;Edited by Gibson;CRC Press LLC: Boca Raton, Fla., 2009.

[0070] In some embodiments, a medically acceptable salt of pemetinib is used in the methods and combination therapies described herein. The salt form of pemetinib is described in U.S. Public Case No. 2019 / 0337948.

[0071] The solid form of pemetinib (e.g., crystalline form) can also be used in the methods and combination therapies described herein. The solid form of pemetinib and the method for preparing the solid form of pemetinib are described in U.S. Public Case No. 2020 / 0002338.

[0072] It should be understood that, for clarity, certain features of the invention set forth in the context of a single embodiment may also be provided in combination in a single embodiment (and embodiments are intended to be combined as if written in a multi-dependency manner). Conversely, various features of the invention set forth in the context of a single embodiment for simplicity may also be provided individually or in any suitable sub-combination. Combination therapy with other agents

[0073] This article also provides a method of treating a patient with cancer, comprising administering to the patient: (i) pemitinib having the following structure: pemitinib; or a pharmaceutically acceptable salt thereof; (ii) enrofloxacin; and (iii) one or more other therapeutic agents.

[0074] Other exemplary therapeutic agents are described below. I. Cancer Therapy

[0075] Cancer cell growth and survival can be affected by dysfunction of multiple signal transduction pathways. Therefore, it is useful to combine different enzyme / protein / receptor inhibitors to treat these diseases, as these different enzyme / protein / receptor inhibitors exhibit different preferences for their regulatory targets. Targeting more than one signal transduction pathway (or more than one biomolecule involved in a given signal transduction pathway) can reduce the likelihood of drug resistance in cell populations and / or reduce treatment toxicity.

[0076] One or more other pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immuno-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, CDK2, and CDK4 / 6 kinase inhibitors (such as those described in WO 2006 / 056399), may be combined with the treatment methods and regimens of this disclosure for the treatment of cancer and solid tumors. Other agents, such as therapeutic antibodies, may be combined with the treatment methods and regimens of this disclosure for the treatment of cancer and solid tumors. These one or more other pharmaceutical agents may be administered to the patient simultaneously or sequentially.

[0077] The treatments disclosed herein may be combined with one or more other enzyme / protein / receptor inhibitor therapies for the treatment of diseases such as cancer and other diseases or conditions described herein. For example, the treatment methods and regimens disclosed herein can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (α, β, γ, δ, and multiple or selective), CSF1R, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM Kinases (Axl, Mer, Tyro3), FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Non-limiting examples of inhibitors that can be combined with the treatment methods and regimens disclosed herein for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1);For example, erlotinib, gefitinib, vandetanib, orsimertinib, cetuximab, necitumumab, or panitumumab, VEGFR inhibitors, or pathway blockers (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib). Ingredients include ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept, PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), and JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib). (INCB39110), LSD1 inhibitors (e.g., INCB59872 and INCB60003), TDO inhibitors, PI3K-δ inhibitors (e.g., INCB50465 and INCB50797), PI3K-γ inhibitors (such as selective PI3K-γ inhibitors), Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, and histone deacetylase inhibitors (HDAC). (such as HDAC8 inhibitors), angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928); or combinations thereof.

[0078] In some embodiments, the treatment methods described herein are combined with a PI3Kδ inhibitor. In some embodiments, the treatment methods described herein are combined with a JAK inhibitor. In some embodiments, the treatment methods described herein are combined with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxotinib). In some embodiments, the treatment methods described herein are combined with a JAK1 inhibitor. In some embodiments, the treatment methods described herein are combined with a JAK1 inhibitor that is selective for JAK2.

[0079] Examples of antibodies administered in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g., anti-CD20), and antibodies against c-MET.

[0080] One or more of the following agents may be administered to patients in combination with the treatment methods disclosed herein and are provided as a non-limiting list: cell growth inhibitors, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies against EGFR introns, ara-C, adriamycin, cytoxan, gemcitabine, uracil Mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipebroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™ (Oxaliplatin), pentostatin, vinblastine, vincristine, vindesine, bleomycin, actinomycin D(dactinomycin), daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-aspartate aminotransferase, teniposide 17.alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone Propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea ea), amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrozole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTINTM (trastuzumab), BEXXARTM (tositumomab), VELCADETM (bortezomib), ZEVALINTM (ibritumomab tiuxetan)TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, letrozole, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), Camppath (alemtuzumab), clofarabine, cladribine, aphidicolon, rutuxin, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP and MDL-101,731.

[0081] The treatment methods and regimens disclosed herein can be further combined with other methods of treating cancer, such as chemotherapy, radiotherapy, targeted cancer therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include intercellular therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody-drug conjugates, adoptive T-cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic viral therapy, and immunomodulatory small molecules (including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, and the like). The compounds can be administered in combination with one or more anticancer drugs (such as chemotherapeutic agents). Examples of chemotherapy agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, and oral busulfan. oral), calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, dalteparin sodium, dasatinib, doxorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, drotaloferrin propionate, eculizumab, epacadostat, epirubicin, erlotinib, estradiol, etoposide phosphate, etoposide, exemestane, fentanyl citrate. citrate, filgrastim, fluorouridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histamine acetate, tiimomab, idarubicin, ifosfamide, imatinib mesylatemesylate), interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, medroxyprogesterone acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed Disodium, pentostatin, piperobromidine, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxotinib, sorafenib, streptozotocin, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testrolide, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tosimomumab, trastuzumab, tretinoin, uracil mustard, valrubicin, vincristine, vinorelbine, vorinostat, and zoledronate.

[0082] Other examples of chemotherapeutic agents include protein body inhibitors (such as bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0083] Examples of steroids include corticosteroids such as dexamethasone or prisone.

[0084] Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts thereof. Other example suitable Bcr-Abl inhibitors include compounds of the class and species disclosed in U.S. Patent No. 5,521,184, WO 04 / 005281, and U.S. Patent No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0085] Examples of suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215, and their pharmaceutically acceptable salts. Other examples of suitable Flt-3 inhibitors include compounds disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120, and their pharmaceutically acceptable salts.

[0086] Examples of suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, as well as their pharmaceutically acceptable salts. Other examples of suitable RAF inhibitors include compounds disclosed in WO 00 / 09495 and WO 05 / 028444, as well as their pharmaceutically acceptable salts.

[0087] Examples of suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptable salts. Other examples of suitable FAK inhibitors include compounds disclosed in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595, and WO 01 / 014402, and their pharmaceutically acceptable salts.

[0088] Examples of suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, lerociclib, and abemaciclib, and their pharmaceutically acceptable salts. Other examples of suitable CDK4 / 6 inhibitors include compounds disclosed in WO 09 / 085185, WO 12 / 129344, WO 11 / 101409, WO 03 / 062236, WO 10 / 075074, and WO 12 / 061156, and their pharmaceutically acceptable salts.

[0089] The treatment methods and regimens disclosed herein may be further used in combination with one or more other kinase inhibitors (including imatinib), especially for the treatment of patients who are resistant to imatinib or other kinase inhibitors.

[0090] In some embodiments, the treatment methods of this disclosure can be combined with chemotherapy agents to treat cancer, and can improve the treatment response compared to the response to chemotherapy agents alone, without worsening their toxic effects. In some embodiments, the treatment methods of this disclosure can be used in combination with the chemotherapy agents provided herein. For example, other pharmaceutical agents for treating multiple myeloma may include, but are not limited to, melphalan, melphalan plus presbyron [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Other agents for treating multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM). The additive or synergistic effect refers to the desired outcome of combining the treatment method disclosed herein with other agents.

[0091] The treatment method disclosed herein may be combined with antibodies or antigen-binding fragments that bind to human PD-1 or human PD-L1.

[0092] In some embodiments, a corticosteroid (such as dexamethasone) is administered to the patient in combination with the treatment method of this disclosure, wherein the dexamethasone is administered intermittently rather than continuously.

[0093] The treatment methods described herein can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells genetically modified to encode immunostimulatory cytokines. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens, such as gp100, MAGE antigen, Trp-2, MARTI, and / or tyrosinase peptides, or tumor cells modified to express the cytokine GM-CSF.

[0094] The treatment methods described herein can be used in combination with vaccination regimens for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, the tumor vaccine comprises proteins derived from viruses involved in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the treatment methods and regimens disclosed herein can be used in combination with tumor-specific antigens such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the treatment methods described herein can be combined with dendritic cell immunization to activate an effective anti-tumor response.

[0095] The treatment method disclosed herein can be used in combination with a bispecific macrocyclic peptide that targets tumor cells with effector cells expressing Feα or Feγ receptors. The treatment method disclosed herein can also be used in combination with macrocyclic peptides that activate host immune reactivity.

[0096] In some other embodiments, the treatment methods of this disclosure are combined with other therapeutic agents administered to the patient before, during, and / or after bone marrow transplantation or stem cell transplantation. The treatment methods and regimens of this disclosure can be used in combination with bone marrow transplantation for the treatment of various hematopoietic tumors.

[0097] When more than one pharmaceutical agent is administered to a patient, as described in any of the foregoing embodiments, they may be administered simultaneously, individually, sequentially, or in combination (e.g., for more than two agents).

[0098] Safe and effective methods for administering most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference in its entirety. II. Immune Checkpoint Therapy

[0099] The treatment methods described herein can be used in combination with one or more immune checkpoint inhibitors to treat diseases such as cancer or infection. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecules are selected from stimulatory checkpoint molecules such as CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecules are selected from inhibitory checkpoint molecules such as A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from: KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR β inhibitors.

[0100] In some embodiments, the salt therapy method provided herein may be used in combination with one or more agonists of immune checkpoint molecules such as OX40, CD27, GITR and CD137 (also known as 4-1BB).

[0101] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0102] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 anti-systems include nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), and AB122. (GLS-010), AMP-224, AMP-514 / MEDI-0680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI 4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502 (TQB2450), A167 (KL-A167), STI-A101 (ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042 or LY3300054.In some embodiments, the inhibitors of PD-1 or PD-L1 are U.S. Patents 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, or 10,308,644; U.S. Patent Publication Nos. 2017 / 0145025, 2017 / 0174671, 2017 / 0174679, 2017 / 0320875, 2017 / 0342060, 2017 / 0362253, 2018 / 0016260, 2018 / 0057486, and 201... Case Nos. 8 / 0177784, 2018 / 0177870, 2018 / 0179179, 2018 / 0179201, 2018 / 0179202, 2018 / 0273519, 2019 / 0040082, 2019 / 0062345, 2019 / 0071439, 2019 / 0127467, 2019 / 0144439, 2019 / 0202824, 2019 / 0225601, 2019 / 0300524 or 2019 / 0345170; PCT Publication No. WO Inhibitors of PD-1 or PD-L1 disclosed in patents No. 03042402, WO 2008156712, WO 2010089411, WO 2010036959, WO 2011066342, WO 2011159877, WO 2011082400, or WO 2011161699 are each incorporated herein by reference in their entirety. In some embodiments, the PD-L1 inhibitor is INCB086550.

[0103] In some embodiments, the anti-PD-1 anti-system is an anti-PD-1 antibody, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 anti-system is nivorumab, retifanlimab, pembrolizumab, semipilimab, spartazolizumab, camrelizumab, cetralimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 anti-system is nivorumab, pembrolizumab, semipilimab, spartazolizumab, camrelizumab, cetralimab, toripalimab, or sintilimab. In some embodiments, the anti-PD-1 anti-system is pembrolizumab. In some embodiments, the anti-PD-1 anti-system is nivorumab. In some embodiments, the anti-PD-1 monoclonal anti-system is retivamarilab. In some embodiments, the anti-PD-1 anti-system is semipirimilab. In some embodiments, the anti-PD-1 anti-system is spartazumab. In some embodiments, the anti-PD-1 anti-system is camrelizumab. In some embodiments, the anti-PD-1 anti-system is cetralimumab. In some embodiments, the anti-PD-1 anti-system is toripalimab. In some embodiments, the anti-PD-1 anti-system is sintilimab. In some embodiments, the anti-PD-1 anti-system is AB122. In some embodiments, the anti-PD-1 anti-system is AMP-224. In some embodiments, the anti-PD-1 anti-system is JTX-4014. In some embodiments, the anti-PD-1 anti-system is BGB-108. In some embodiments, the anti-PD-1 anti-system is BCD-100. In some embodiments, the anti-PD-1 anti-system is BAT1306. In some embodiments, the anti-PD-1 anti-system is LZM009. In some embodiments, the anti-PD-1 anti-system is AK105. In some embodiments, the anti-PD-1 antibody system HLX10. In some embodiments, the anti-PD-1 antibody system TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody system nivorumab or pembrolizumab. In some embodiments, the anti-PD-1 antibody system SHR-1210. Other anticancer agents include antibody therapeutics, such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of immune checkpoint molecules is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody.In some embodiments, the anti-PD-L1 monoclonal antibody system includes atezolizumab, avelumumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (MPDL3280A; also known as RG7446), avelumumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody system includes atezolizumab, avelumumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody system includes atezolizumab. In some embodiments, the anti-PD-L1 antibody system includes avelumumab. In some embodiments, the anti-PD-L1 antibody system is durvalumab. In some embodiments, the anti-PD-L1 antibody system is tislelizumab. In some embodiments, the anti-PD-L1 antibody system is BMS-935559. In some embodiments, the anti-PD-L1 antibody system is MEDI4736. In some embodiments, the anti-PD-L1 antibody system is FAZ053. In some embodiments, the anti-PD-L1 antibody system is KN035. In some embodiments, the anti-PD-L1 antibody system is CS1001. In some embodiments, the anti-PD-L1 antibody system is SHR-1316. In some embodiments, the anti-PD-L1 antibody system is CBT-502. In some embodiments, the anti-PD-L1 antibody system is A167. In some embodiments, the anti-PD-L1 antibody system is STI-A101. In some embodiments, the anti-PD-L1 antibody system is CK-301. In some embodiments, the anti-PD-L1 antibody system is BGB-A333. In some embodiments, the anti-PD-L1 antibody system is MSB-2311. In some embodiments, the anti-PD-L1 antibody system is HLX20. In some embodiments, the anti-PD-L1 anti-system is LY3300054.

[0104] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharmaceutically acceptable salt thereof. In some embodiments, the inhibitor of the immune checkpoint molecule is a compound selected from US 2018 / 0179201, US 2018 / 0179197, US 2018 / 0179179, US 2018 / 0179202, US 2018 / 0177784, US 2018 / 0177870, U.S. Patent No. 16 / 369,654 (filed March 29, 2019) and U.S. Patent No. 62 / 688,164, each of which is incorporated herein by reference in its entirety.

[0105] In some embodiments, the inhibitors of immune checkpoint molecules are inhibitors of KIR, TIGIT, LAIR1, CD160, 2B4 and TGFR β.

[0106] In some embodiments, the inhibitor is MCLA-145.

[0107] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AAGEN1884, or CP-675,206.

[0108] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody system is BMS-986016, LAG525, INCAGN2385, or eftimod α (IMP321).

[0109] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleclumab.

[0110] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0111] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0112] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0113] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0114] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0115] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TGF-β. In some embodiments, the inhibitor of TGF-β is trabedersen, galusertinib, or M7824.

[0116] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PI3K-γ. In some embodiments, the inhibitor of PI3K-γ is IPI-549.

[0117] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0118] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0119] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0120] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody system is INCAGN2390, MBG453, or TSR-022.

[0121] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0122] In some embodiments, the activators of immune checkpoint molecules are activators of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8 and CD137 (also known as 4-1BB).

[0123] In some embodiments, the CD137 activator is urelumab. In some embodiments, the CD137 activator is utometabolumab.

[0124] In some embodiments, the activator of the immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the activator of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the activator of the immune checkpoint molecule is an activator of OX40, such as an OX40 activator antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 anti-system is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0125] In some embodiments, the activator of the immune checkpoint molecule is a CD40 activator. In some embodiments, the CD40 activator is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0126] In some embodiments, the activator of the immune checkpoint molecule is an ICOS activator. In some embodiments, the ICOS activator is GSK-3359609, JTX-2011, or MEDI-570.

[0127] In some embodiments, the activator of the immune checkpoint molecule is a CD28 activator. In some embodiments, the CD28 activator is theralizumab.

[0128] In some embodiments, the activator of the immune checkpoint molecule is a CD27 activator. In some embodiments, the CD27 activator is varlilumab.

[0129] In some embodiments, the activator of the immune checkpoint molecule is a activator of TLR7 / 8. In some embodiments, the activator of TLR7 / 8 is MEDI9197.

[0130] The compounds disclosed herein can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptors. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody system MCLA-136 binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody system AK104 binds to PD-L1 and CTLA-4.

[0131] In some embodiments, the compounds of this disclosure may be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include icardolstat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196. Inhibitors of arginase include INCB1158.

[0132] As provided throughout this document, other compounds, inhibitors, agents, etc., may be combined with the compounds of the present invention in single or sequential dosage forms, or may be administered simultaneously or sequentially in individual dosage forms. Pharmaceutical formulations and dosage forms

[0133] When used as a medicine, the pemitinib described herein can be administered as a pharmaceutical composition, which refers to a combination of the pemitinib described herein and at least one medically acceptable carrier. These compositions can be prepared in a manner well known in pharmaceutical technology and can be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be local (including ocular and mucosal administration, including intranasal, vaginal, and rectal delivery), pulmonary administration (e.g., by inhalation or blowing of powder or aerosol, including via nebulizer; intratracheal, intranasal, epidermal, or transdermal delivery), ocular, oral, or non-enteric administration. Methods for ocular delivery may include local administration (eye drops), subconjunctival, perivitelline, or intravitreal injection, or introduction via a balloon catheter or surgically placed ophthalmic insertion into the conjunctival sac. Non-enteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration, such as intrathecal or intraventricular administration. Non-enteral administration may be in the form of a single concentrated dose, or may be achieved, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Known pharmaceutical carriers, aqueous, powdered, or oily bases, thickeners, and the like may be necessary or optional.

[0134] This disclosure also includes pharmaceutical compositions comprising a combination of pemitinib as an active ingredient and one or more pharmaceutically acceptable carriers. In preparing the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in a carrier in the form of, for example, capsules, sacs, paper, or other containers. When the excipient acts as a diluent, it can be a solid, semi-solid, or liquid material, serving as a mordant, carrier, or medium for the active ingredient. Therefore, the compositions can be tablets, pills, powders, lozenges, small capsules, flat capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0135] In preparing a formulation, the active compound can be ground to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0136] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. These formulations may further include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. The compositions described herein can be formulated to provide a rapid, sustained, or delayed release of the active ingredient upon administration to a patient using procedures known in this art.

[0137] The composition may be formulated into unit dosage forms, each dose containing about 4 to about 5 mg, or about 4.5 mg, of the active ingredient. In some embodiments, the unit dosage form contains about 9 mg of the active ingredient. In some embodiments, the unit dosage form contains about 13.5 mg of the active ingredient. The term "unit dosage form" means a physically discrete unit suitable as a unit dose for human individuals and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect and suitable pharmaceutical excipients.

[0138] The active compound is effective over a wide dose range and is usually administered in a pharmaceutically effective amount. However, it should be understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the disease to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight and response, the severity of the patient's symptoms and similar circumstances.

[0139] To prepare solid compositions such as tablets, a major active ingredient is mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of pemitinib. When such preformed compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed in the composition, allowing the composition to be readily further divided into equivalent effective unit dosage forms, such as tablets, pills, and capsules. The solid preformed composition is then further subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to 500 mg of the active ingredient disclosed herein.

[0140] In some embodiments, pemitinib is administered orally. In some embodiments, pemitinib is administered once daily. In some embodiments, pemitinib is administered at a daily dose of about 5 mg to about 20 mg. In some embodiments, pemitinib is administered at a daily dose of about 10 mg to about 15 mg. In some embodiments, pemitinib is administered at a daily dose of about 13.5 mg. In some embodiments, pemitinib is administered in tablet form. In some embodiments, the tablet contains about 0.5 mg to about 10 mg of pemitinib. In some embodiments, the tablet contains about 0.5 mg to about 5 mg of pemitinib. In some embodiments, the tablet contains about 2 mg, about 4.5 mg, about 9 mg, about 13.5 mg, or about 18 mg of pemitinib. In some embodiments, the tablet contains about 0.5 mg of pemitinib. In some embodiments, the tablet contains about 2 mg of pemitinib. In some embodiments, the tablet contains about 4.5 mg of pemitinib. In some embodiments, the tablet contains about 9 mg of pemitinib. In some embodiments, the tablet contains about 13.5 mg of pemitinib. In some embodiments, the tablets contain about 18 mg of pemitinib.

[0141] The tablets or pills of this disclosure can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action. For example, the tablets or pills may contain an internal dose component and an external dose component, the latter being in the form of a coating over the former. The two components may be separated by an enteric coating layer that resists disintegration in the stomach and allows the internal component to enter the duodenum intact or delay release. A variety of materials can be used for such enteric coatings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, hexadecyl alcohol, and cellulose acetate.

[0142] The pemitinib or its composition described herein may be incorporated into the liquid form, including aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0143] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via oral or nasal inhalation to produce local or systemic effects. The composition may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be connected to a mask tent or intermittent positive pressure ventilator. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0144] The amount of compound or composition administered to a patient will vary depending on the drug administered, the purpose of administration (such as prevention or therapy), the patient's condition, and the method of administration. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially prevent the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease being treated and the judgment made by the attending physician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0145] The composition administered to the patient may be in the form of the pharmaceutical composition described above. These compositions may be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions may be packaged for use as is or lyophilized, with the lyophilized formulation combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation is typically between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It should be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0146] The therapeutic dose of pemitinib can vary depending on factors such as the specific therapeutic purpose to be achieved, the route of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The ratio or concentration of pemitinib in the pharmaceutical composition can vary depending on many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, pemitinib can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10 g / kg of the compound for non-enteral administration. Some typical dosage ranges are about 1 µg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage may depend on variables such as the type and progression of the disease or condition, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients, and the route of administration. The effective dose can be deduced from dose-response curves derived from in vitro or animal model testing systems.

[0147] Pemitinib may also be formulated in combination with one or more other active ingredients, such as any pharmaceutical agent, such as antiviral agents, vaccines, antibodies, immune enhancers, immunosuppressants, anti-inflammatory agents, etc.

[0148] The enroximateb described herein can be administered in the form of a pharmaceutical composition and at least one pharmaceutically acceptable excipient. These compositions can be prepared in a manner well known in pharmaceutical technology and can be administered via a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. The pharmaceutical composition can be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. A preferred form may depend on the intended mode of administration and therapeutic application. Typically, the composition of the formulation described herein is in the form of an injectable or infusionable solution.

[0149] Enroximateb can be administered by a variety of methods. For many applications, the administration route is one of the following: intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneal injection (IP), or intramuscular injection. Intra-articular delivery may also be used. Other non-enteral administration methods may also be used. Examples of such methods include: intra-arterial, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, tracheal, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, and epidural and intrasternal injections. Labeled compound

[0150] Another aspect of this disclosure relates to labeled pemitinib (radiolabeled, fluorescently labeled, isotope labeled, etc.), which can be used not only in imaging technology but also in in vitro and in vivo assays.

[0151] This disclosure further includes isotopically labeled pemitinib. A "colorotopically labeled" or "radiolabeled" compound is pemitinib in which one or more atoms have been replaced or substituted with atoms having a different atomic mass or mass number than those normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of this disclosure include, but are not limited to, 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I, and 131I. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced by deuterium atoms, as appropriate.

[0152] One or more constituent atoms of pemitinib may be naturally or non-naturally substituted by isotopic substitutions. In some embodiments, pemitinib comprises at least one deuterium atom. For example, one or more hydrogen atoms in the compounds presented herein may be substituted by deuterium. In some embodiments, the compound comprises two or more deuterium atoms. In some embodiments, the compound comprises 1-2, 1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all hydrogen atoms in the compound may be substituted by deuterium atoms.

[0153] Synthetic methods that incorporate isotopes into organic compounds are known in this field (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. 2007, 7744-7765; James R. Hanson, The Organic Chemistry of Isotopic Labelling, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies, such as NMR spectroscopy, metabolic experiments and / or assays.

[0154] Substitution with a heavier isotope (such as deuterium) may provide certain therapeutic advantages due to increased metabolic stability, such as a longer in vivo half-life or a reduced dose requirement, and may therefore be preferred in some cases. (See, for example, A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). Specifically, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

[0155] It should be understood that "radiolabeled compound" or "labeled compound" refers to a compound that has been incorporated with at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3H and 14C. In some embodiments, the radionuclide is selected from the group consisting of 11C, 18F, 75Br, 76Br, and 77Br. Set

[0156] This disclosure also includes kits that can be used, for example, to treat cancer, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of pemitinib or any of its formulations. Such kits may further include one or more different known pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, other containers, etc., as will be readily apparent to those skilled in the art. The kit may also include instructions in the form of inserts or labels specifying the amount of components to be administered, administration guidelines, and / or instructions for mixing such components. Example

[0157] The invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results. Example A. In vitro proliferation assay of RT112 / 84 and UM-UC-14

[0158] The effect of pemitinib plus enrofloxacin (EV) (Padcev, Refdrug Inc.) on proliferation was evaluated in vitro in the RT112 / 84 and UM-UC-14 bladder cancer cell lines. Briefly, RT112 / 84 and UM-UC-14 cells were incubated overnight at 1000 cells / well in 96-well plates. Pemitinib (dose-response profile from 1 to 100 nM) was added to the wells alone or in combination with 300, 100, or 10 ng / mL EV. Viability was measured on a PHERAStar (BMG LABTECH) plate reader after 5 days of treatment with Cell Titer glo (Promega). Data showed that treatment of RT112 / 84 cells with pemitinib in combination with intermediates and high-dose EV resulted in reduced proliferation of low-dose pemitinib. In contrast, treatment of UM-UC-14 cells with pemitinib in combination with EV produced only a moderate effect at high EV concentrations.

[0159] Figure 1A depicts the effect of different concentrations of pemitinib, alone or in combination with 300, 100 or 10 ng / mL EV, on the cell proliferation of the RT112 / 84 bladder cancer cell line, ranging from 1 to 100 nM.

[0160] Figure 1B depicts the effect of different concentrations of pemitinib, alone or in combination with 300, 100, or 10 ng / mL EV, in the range of 1 to 100 nM on the cell proliferation of the UM-UC-14 bladder cancer cell line. Example B. Effect of pemitinib on Nectin-4 levels RT112 / 84 in vitro Nectin-4 receptor density

[0161] The effect of pemitinib plus enrofloxacin ("EV") (Padcev, Refdrug Inc.) on Nectin-4 receptor density was evaluated in vitro in the RT112 / 84 bladder cancer cell line. Briefly, RT112 / 84 cells were treated with 100 nM pemitinib, 100 nM EV, or a combination of both. Nectin-4 receptor density was then evaluated at different time points post-treatment using flow cytometry on an LSR Tortessa X-20 instrument (BD Biosciences) equipped with Quantibrite phycoerythrin (PE) beads (BD Biosciences catalog number 340495) and an anti-Nectin-4 PE-binding antibody (RnD Systems catalog number FAB2659) (Figure 2A). The data showed that treatment of RT112 / 84 cells with 100 nM EV alone or in combination with 100 nM pemitinib resulted in a decrease in receptor density associated with target internalization. In contrast, treatment of RT112 / 84 cells with 100 nM pemitinib did not cause changes in the density of Nectin-4 receptors associated with target internalization.

[0162] Figure 2A depicts the density of Nectin-4 receptors in RT112 / 84 cells treated with (i) 100 nM pemitinib, (ii) 100 nM EV, or (iii) 100 nM pemitinib and 100 nM EV. Nectin-4 receptor density in RT112 / 84 cells.

[0163] The effect of pemitinib plus EV (Padcev, Refdrug Inc.) on Nectin-4 receptor density was also evaluated in vivo in a 6- to 8-week-old NSG mouse (Jackson laboratories) RT112 / 84 bladder cancer xenograft model (Fig. 2B). Pemitinib was administered orally in 0.5% methylcellulose suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer, and EV was administered intravenously in saline. Briefly, the left flank of mice was shaved one day before subcutaneous inoculation with 2x106 RT112 / 84 suspended in matrix gel (Corning Life Sciences, Tewksbury, Mass). On day 16, mice were administered (i) a mediator; (ii) 0.3 mg / kg pemitinib; (iii) 1 mg / kg pemitinib; (iv) 3 mg / kg EV; (v) 0.3 mg / kg pemitinib and 3 mg / kg EV; or (vi) 1 mg / kg pemitinib and 3 mg / kg EV, with tumors collected 4 hours after administration. The tumors were then processed into single-cell suspensions, and Nectin-4 receptor density was assessed by flow cytometry using an LSR Tortessa X-20 instrument (BD Biosciences) equipped with Quantibrite phycoerythrin (PE) beads (BD Biosciences catalog number 340495) and an anti-Nectin-4 PE-binding antibody (RnD Systems catalog number FAB2659). Data showed that treatment of RT112 / 84 tumor-bearing mice with EV alone or in combination with pemitinib resulted in a decrease in receptor density associated with target internalization. In contrast, treatment of RT112 / 84 tumor-bearing mice with pemitinib did not cause changes in the density of Nectin-4 receptors associated with target internalization.

[0164] Figure 2B depicts the density of Nectin-4 receptors in tumor cells of RT112 / 84 tumor-bearing mice after administration of (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 0.3 mg / kg pemitinib and 3 mg / kg EV, or (vi) 1 mg / kg pemitinib and 3 mg / kg EV. RT112 / 84 pERK inhibition in vivo.

[0165] The effect of pemitinib plus EV (Padcev, Refdrug Inc.) on pERK inhibition was evaluated in vivo in a 6- to 8-week-old NSG mouse (Jackson laboratories) RT112 / 84 bladder cancer xenograft model (Figure 3). Pemitinib was administered orally in 0.5% methylcellulose suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer, and EV was administered intravenously in saline. Briefly, the left flank of mice was shaved one day before subcutaneous inoculation with 2x10⁶ RT112 / 84 suspended in matrix gel (Corning Life Sciences, Tewksbury, Mass). On day 16, mice were administered (i) a mediator; (ii) 1 mg / kg pemitinib; (iii) 3 mg / kg EV; or (vi) 1 mg / kg pemitinib and 3 mg / kg EV, with tumors collected 4 hours after administration. The tumors were then treated, and the phosphorylated ERK levels of tumor lysates were assessed using MSD (Mesoscale). Data showed that treatment with pemitinib alone or in combination with EV resulted in decreased ERK phosphorylation in RT112 / 84 tumor-bearing mice. In contrast, treatment with EV alone in RT112 / 84 tumor-bearing mice did not alter ERK phosphorylation levels compared to mediator-treated tumors.

[0166] Figure 3 depicts ERK phosphorylation in tumor cells of RT112 / 84 tumor-bearing mice treated with (i) a mediator, (ii) 1 mg / kg pemitinib, (iii) 3 mg / kg EV, or (iv) 1 mg / kg pemitinib and 3 mg / kg EV. Example C. The combination of pemitinib and enrofloxacin resulted in increased tumor growth control in an RT112 / 84 xenograft model.

[0167] The in vivo effects of the combination of pemitinib and EV (Padcev, Refdrug Inc.) were evaluated in a 6- to 8-week-old NSG mouse (Jackson laboratories) RT112 / 84 bladder cancer (85061106, Sigma / ECACC, UK) xenograft model (Figure 4). Pemitinib was administered orally in 0.5% methylcellulose suspended in 5% N,N-dimethylacetamide (DMAC) + 50 mM citrate buffer, and EV was administered intravenously in saline. Briefly, the left flank of mice was shaved one day before subcutaneous inoculation with 2 x 10⁶ RT112 / 84 suspended in matrix gel (Corning Life Sciences, Tewksbury, Mass). On day 7, tumor size was measured with calipers and volume was estimated using the formula: volume = [L (long dimension) x W² (short dimension)] / 2. Mice were randomly assigned to 6 groups of 10 mice each, with an average tumor volume of approximately 200 mm³. Tumors were measured three times weekly during the study period. Starting on day 7, mice were administered (i) the mediator; (ii) 0.3 mg / kg pemitinib; (iii) 1 mg / kg pemitinib; (iv) 3 mg / kg EV; (v) 0.3 mg / kg pemitinib and 3 mg / kg EV; or (vi) 1 mg / kg pemitinib and 3 mg / kg EV. Pemitinib was administered orally once daily (QD) for 10 days, while EV was administered every 4 days (for a total of 2 doses). Data showed that, compared with the control mediator group, all treatments except for pemitinib 0.3 mg / kg had a therapeutic effect in delaying tumor growth. Bliss-independent (unaffected portion) analysis of the data showed that the combination of 0.3 mg / kg pemitinib and 3 mg / kg EV produced a synergistic effect of tumor growth delay when compared with their respective controls.

[0168] Figure 4 depicts the tumor volume of RT112 / 84 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 0.3 mg / kg pemitinib and 3 mg / kg EV, or (vi) 1 mg / kg pemitinib and 3 mg / kg EV.

[0169] In the individual experiments, mice were randomly divided into 9 groups of 10 mice each on day 7, with an average volume of approximately 200 mm3. Tumors were measured 3 times per week during the efficacy study period (day 21). Starting from day 7, mice were administered (i) a mediator; (ii) 0.3 mg / kg pemitinib; (iii) 1 mg / kg pemitinib; (iv) 3 mg / kg EV; (v) 10 mg / kg EV; (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV; (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV; (viii) 1 mg / kg pemitinib and 3 mg / kg EV; or (ix) 1 mg / kg pemitinib and 10 mg / kg EV. Pemitinib was administered orally once daily for 10 days, while EV was administered every 4 days (for a total of 2 doses). Data showed that high-dose EV achieved greater tumor growth inhibition, independent of the pemitinib combination, and was similar to the level achieved by the combination of low-dose 3 mg / kg EV and high-dose 1 mg / kg pemitinib. Furthermore, mice were observed to determine overall survival (Figure 6). Data showed that the combination of high-dose EV and high-dose pemitinib produced better overall survival in these mice compared to control or single-group treatment.

[0170] Figure 5 depicts the tumor volume of RT112 / 84 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 10 mg / kg EV, (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV, (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV, (viii) 1 mg / kg pemitinib and 3 mg / kg EV or (ix) 1 mg / kg pemitinib and 10 mg / kg EV.

[0171] Figure 6A depicts the overall survival of RT112 / 84 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 10 mg / kg EV, (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV, (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV, (viii) 1 mg / kg pemitinib and 3 mg / kg EV or (ix) 1 mg / kg pemitinib and 10 mg / kg EV.

[0172] Figure 6B depicts the overall survival of RT112 / 84 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 10 mg / kg EV, (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV, (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV, (viii) 1 mg / kg pemitinib and 3 mg / kg EV, or (ix) 1 mg / kg pemitinib and 10 mg / kg EV at 100 days post-inoculation. UM-UC-14 xenograft model

[0173] The in vivo effects of the combination of pemitinib and EV were also evaluated in another cancer xenograft model in NSG mice, UM-UC-14 (08090509, Sigma / ECACC, UK) (Figure 7). Pemitinib was administered orally in 0.5% methylcellulose suspended in 5% DMAC + 50 mM citrate buffer, and EV was administered intravenously in 1 x PBS. Briefly, mice were shaved on the left flank one day before subcutaneous inoculation with 5 x 10⁶ UM-UC-14 suspended in matrix gel (Corning Life Sciences, Tewksbury, Mass). On day 5, tumor size was measured with calipers and volume was estimated using the formula volume = [L (long dimension) x W² (short dimension)] / 2. Mice were randomly assigned to 6 groups of 10 mice each, with an average volume of approximately 100 mm³. Tumors were measured 3 times per week during the study period. Starting on day 5, mice were administered (i) the mediator; (ii) 0.3 mg / kg pemitinib; (iii) 1 mg / kg pemitinib; (iv) 3 mg / kg EV; (v) 0.3 mg / kg pemitinib and 3 mg / kg EV; or (vi) 1 mg / kg pemitinib and 3 mg / kg EV. Pemitinib was administered orally once daily for 10 days, while EV was administered every 4 days (for a total of 2 doses). Data showed that, compared to the control mediator group, pemitinib 1 mg / kg alone had a therapeutic effect in delaying tumor growth, while the combination of pemitinib 0.3 mg / kg and 1 mg / kg with EV 3 mg / kg had a significant therapeutic effect in delaying tumor growth. Bliss-independent (unaffected portion) analysis of the data showed that the combination of 0.3 mg / kg pemitinib and 3 mg / kg EV produced a synergistic effect of tumor growth delay when compared with their respective controls.

[0174] Figure 7 depicts the tumor volume of UM-UC-14 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 0.3 mg / kg pemitinib and 3 mg / kg EV, or (vi) 1 mg / kg pemitinib and 3 mg / kg EV.

[0175] In addition to the modifications described herein, various modifications to the present invention will be readily apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Every reference cited in this application (including all patents, patent applications and publications) is incorporated herein by reference in its entirety. [Simplified Explanation of the Diagram]

[0012] Figure 1A depicts the effect of different concentrations of pemitinib (alone or in combination with 300, 100, or 10 ng / mL EV) in the RT112 / 84 bladder cancer cell line on cell proliferation. Figure 1B depicts the effect of different concentrations of pemitinib (alone or in combination with 300, 100, or 10 ng / mL EV) in the UM-UC-14 bladder cancer cell line on cell proliferation. Figure 2A depicts the Nectin-4 receptor density in RT112 / 84 cells treated with (i) 100 nM pemitinib, (ii) 100 nM enrofloxacin (EV), or (iii) 100 nM pemitinib and 100 nM EV. Figure 2B depicts the density of Nectin-4 receptors in tumor cells of RT112 / 84 tumor-bearing mice after administration of (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 0.3 mg / kg pemitinib and 3 mg / kg EV, or (vi) 1 mg / kg pemitinib and 3 mg / kg EV. Figure 3 depicts ERK phosphorylation in tumor cells of RT112 / 84 tumor-bearing mice after administration of (i) a mediator, (ii) 1 mg / kg pemitinib, (iii) 3 mg / kg EV, or (iv) 1 mg / kg pemitinib and 3 mg / kg EV. Figure 4 depicts the tumor volume of RT112 / 84 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 0.3 mg / kg pemitinib and 3 mg / kg EV, or (vi) 1 mg / kg pemitinib and 3 mg / kg EV. Figure 5 depicts the tumor volume of RT112 / 84 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 10 mg / kg EV, (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV, (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV, (viii) 1 mg / kg pemitinib and 3 mg / kg EV, or (ix) 1 mg / kg pemitinib and 10 mg / kg EV.Figure 6A depicts the overall survival of RT112 / 84 tumor-bearing mice administered (i) the mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 10 mg / kg EV, (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV, (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV, (viii) 1 mg / kg pemitinib and 3 mg / kg EV, or (ix) 1 mg / kg pemitinib and 10 mg / kg EV. Figure 6B depicts the overall survival of RT112 / 84 tumor-bearing mice administered (i) the mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 10 mg / kg EV, (vi) 0.3 mg / kg pemitinib and 3 mg / kg EV, (vii) 0.3 mg / kg pemitinib and 10 mg / kg EV, (viii) 1 mg / kg pemitinib and 3 mg / kg EV, or (ix) 1 mg / kg pemitinib and 10 mg / kg EV 10 days post-inoculation using a Kaplan-Mail plot. Figure 7 depicts the tumor volume of UM-UC-14 tumor-bearing mice administered (i) a mediator, (ii) 0.3 mg / kg pemitinib, (iii) 1 mg / kg pemitinib, (iv) 3 mg / kg EV, (v) 0.3 mg / kg pemitinib and 3 mg / kg EV, or (vi) 1 mg / kg pemitinib and 3 mg / kg EV.

Claims

1. Use of pemigatinib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer in patients, wherein the medicament further comprises or is used in combination with enfortumab vedotin.

2. As requested in item 1, wherein pemitinib and enrofloxacin are administered simultaneously.

3. As requested in item 1, wherein pemitinib and enrofloxacin are administered sequentially.

4. As requested in item 1, wherein pemitinib is administered orally.

5. As requested in item 1, wherein pemitinib is administered at a daily dose of 1 mg to 20 mg.

6. As requested in claim 1, wherein pemitinib is administered at a daily dose of 13.5 mg.

7. As requested in item 1, wherein pemitinib is administered at a daily dose of 9 mg.

8. As requested in item 1, wherein enroximateb is administered intravenously.

9. As requested in paragraph 1, wherein enroximateb is administered intravenously at a dose of 0.5 mg / kg to 2.0 mg / kg.

10. As requested in claim 1, wherein enroximateb is administered intravenously at a dose of 1.25 mg / kg.

11. The use of any of claims 1 to 10 further includes administering one or more other therapeutic agents.

12. As used in claim 11, it includes administering an other therapeutic agent.

13. As claimed in claim 12, wherein the other therapeutic agent is an inhibitor of PD-1 or PD-L1.

14. For any of the uses of claims 1 to 10, wherein the cancer is bladder cancer.

15. For any of the uses specified in items 1 to 10, wherein the cancer is selected from hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, anal cancer, Merkel cell carcinoma, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglubulinemia, pilocellular lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, and adenocarcinoma.

16. The use of any one of claims 1 to 10, wherein the cancer is selected from sarcoma, head and neck cancer, melanoma and non-small cell lung cancer.

17. The use of any of claims 1 to 10, wherein the cancer is bile duct cancer.

18. For any of the uses of claims 1 to 10, wherein the cancer is a medullary / lymphoid sarcoma.

19. As requested in claim 18, wherein the medullary / lymphoid lesion is 8p11 myeloproliferative syndrome.

20. For any of the uses described in claims 1 to 10, wherein the cancer is a cancer of the genitourinary system.

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