WO2019094832A1 - A combination therapy with apatinib for the treatment of cancer - Google Patents

A combination therapy with apatinib for the treatment of cancer Download PDF

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Publication number
WO2019094832A1
WO2019094832A1 PCT/US2018/060179 US2018060179W WO2019094832A1 WO 2019094832 A1 WO2019094832 A1 WO 2019094832A1 US 2018060179 W US2018060179 W US 2018060179W WO 2019094832 A1 WO2019094832 A1 WO 2019094832A1
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Prior art keywords
administered
amount
rivoceranib
cancer
nivolumab
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English (en)
French (fr)
Inventor
Arlo N. MCGINN
Bumjin KIM
Sung Chul Kim
Cheol Hee Park
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Lsk Biopharma
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Lsk Biopharma
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Priority to JP2020544367A priority Critical patent/JP2021502415A/ja
Priority to KR1020207016475A priority patent/KR20200107934A/ko
Priority to CA3082095A priority patent/CA3082095A1/en
Priority to US16/762,881 priority patent/US20200282052A1/en
Priority to EP18876849.3A priority patent/EP3706746A4/en
Publication of WO2019094832A1 publication Critical patent/WO2019094832A1/en
Anticipated expiration legal-status Critical
Priority to JP2024063774A priority patent/JP2024095791A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Tumor angiogenesis plays a critical role in malignant tumor growth and metastasis. When tumors grow beyond 1 mm 3 , angiogenesis, or generation of vascular arborizations by budding from existing vessels, is necessary to provide enough blood for the survival of tumor cells. The growth speed and tendency of metastasis of tumors are associated with the level of neovascularization factors and the quantity of nascent microvessels. Since the hypothesis of "anti-angiogenesis therapy" was put forward by Folkman in early 1970s, people have made considerable progress in this field, and inhibiting angiogenesis of tumors has been universally accepted as a promising anticancer strategy.
  • immunotherapy 1) the normalization of tumor vasculature, and 2) the amelioration of immune- suppressive tumor microenvironment.
  • Vessels formed by tumors are immature, and leaky, with endothelial cells that express lower levels of chemokines, and adhesion factors, which are responsible for recruiting activated immune cells. Consequently, these features limit the ability of immune cells to effectively infiltrate into the tumor and achieve extravasation.
  • anti-angiogenesis therapy help immune cells infiltrate into the tumor, but it also helps create a more favorable tumor microenvironment for immunotherapy.
  • High levels of proangiogenic factors are known to create a local environment that is extremely hostile towards immune cells, allowing tumors to evade host immune surveillance.
  • angiogenic factors such as vascular endothelial growth factor (VEGF), which is overexpressed in tumor tissues are known to induce the secretion of immune-suppressive cytokines and to recruit regulatory T-cells (T re g), tumor-associated macrophages, sTie2-expressing monocytes, and myeloid-derived suppressor cells (MDSCs), all of which are responsible for immune
  • VEGF vascular endothelial growth factor
  • Anti-angiogenesis therapy reverses these effects, leading to increased anti-tumor immunity.
  • Rivoceranib (also known as YN968D1, developed in China as apatinib and marketed as Aitan®) is an orally administered small molecule tyrosine kinase inhibitor with selectivity towards the VEGFR-2/kinase insert domain receptor. Rivoceranib has received approval in China, for treatment of advanced gastric cancer, and has received orphan medicinal product designation for the treatment of gastric cancer from Europe, the FDA, and the MFDS in South Korea. According to a recent review (see L. J.
  • Nivolumab is an immunotherapeutic agent, approved for the treatment of non-small cell lung cancer, advanced small cell lung cancer, metastatic melanoma, kidney cancer (renal cell carcinoma), advanced renal cell carcinoma, squamous cell carcinoma, liver cancer,
  • lymphoma hepatocellular carcinoma
  • bladder cancer urothelial carcinoma
  • colon cancer hepatocellular carcinoma
  • Hodgkin lymphoma It is administered by intravenous injection.
  • Pembrolizumab is an immunotherapeutic agent, approved for the treatment of melanoma, non-small cell lung cancer.
  • permbrolizumab is used to treat metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) in certain situations, as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy, and for the treatment of adult and pediatric patients with refractory classic
  • Hodgkin's lymphoma It is administered by intravenous injection.
  • the disclosure provides a combination therapy comprising apatinib, or a pharmaceutically acceptable salt thereof, and an immunotherapeutic agent.
  • the disclosure also provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of apatinib in combination with a therapeutically effective amount of an immunotherapeutic agent.
  • the immunotherapeutic agent is selected from the group consisting of an antibody, a peptide, pembrolizumab, nivolumab, pidilizumab, BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, atezolizumab, avelumab, durvalumab, ipilimumab, tumor vaccines (e.g., sipuleucel-T), CAR T-cell therapies (e.g., tisagenlecleucel, axicabtagene ciloleucel), and naked monoclonal antibodies (e.g., alemtuzumab).
  • an antibody e.g., a peptide, pembrolizumab, nivolumab, pidilizumab, BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, atezolizumab, avelumab, durvalumab
  • the antibody can be a monoclonal or polyclonal antibody.
  • the antibody can be an anti-programmed death 1 (PD-1) antibody.
  • PD-1 anti-programmed death 1
  • the antibody can be an anti-muPD-1 antibody.
  • the antibody can be an anti-PD-Ll antibody. [0029] In one aspect, the antibody can be an anti-CTLA-4 antibody.
  • a method for treating cancer comprising administering: a) rivoceranib, or a pharmaceutically acceptable salt thereof; and b)
  • a method for treating cancer comprising administering: a) rivoceranib, or a pharmaceutically acceptable salt thereof; and b) nivolumab.
  • a pharmaceutically acceptable salt of rivoceranib is administered.
  • the pharmaceutically acceptable salt of rivoceranib is a mesylate salt.
  • the rivoceranib is administered in an amount of from 100 mg to 1000 mg.
  • the rivoceranib is administered in an amount of from 150 mg to 800 mg.
  • the rivoceranib is administered in an amount of from 200 mg to 700 mg.
  • the total daily dose of the rivoceranib is less than 685 mg.
  • the rivoceranib is administered orally.
  • the rivoceranib is administered as a dried powder, a liquid, a capsule, a pellet or a tablet.
  • the rivoceranib is administered as a tablet.
  • the tablet is a film coated tablet.
  • the tablet comprises the rivoceranib in an amount of about 100 mg. In some embodiments, the tablet comprises the rivoceranib in an amount of about 200 mg.
  • the tablet further comprises one or more of pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, povidone (K-30), colloidal silicon dioxide, magnesium stearate and Opadry white.
  • the rivoceranib is administered once daily. In some embodiments, the rivoceranib is administered twice daily.
  • disclosed herein is a method for treating cancer, comprising administering: a) rivoceranib, or a pharmaceutically acceptable salt thereof; and b) pembrolizumab.
  • the pembrolizumab is administered in a dosage amount of about 200 mg. In some embodiments, the pembrolizumab is administered in a dosage amount of 150 mg to 250 mg.
  • the pembrolizumab is administered orally or parenterally. In some embodiments, the pembrolizumab is administered parenterally. In some embodiments, the parenteral administration is selected from intravenous, intradermal, intramuscular or subcutaneous administration. In some embodiments, the pembrolizumab is administered intravenously. In some embodiments, the pembrolizumab is administered after the administration of the rivoceranib. In some embodiments, the pembrolizumab is administered about an hour after the administration of the rivoceranib. In some embodiments, the
  • the pembrolizumab is administered three times a month.
  • a method for treating cancer comprising administering: a) rivoceranib, or a pharmaceutically acceptable salt thereof; and b) nivolumab.
  • the nivolumab is administered in a dosage amount of about 240 mg.
  • the nivolumab is administered in a dosage amount of 200 mg to 300 mg.
  • the nivolumab is administered orally or parenterally.
  • the nivolumab is administered parenterally.
  • the parenteral administration is selected from intravenous, intradermal, intramuscular or subcutaneous administration.
  • the nivolumab is administered intravenously.
  • the nivolumab is administered after the administration of the rivoceranib.
  • the nivolumab is administered about an hour after the administration of the rivoceranib.
  • the nivolumab is administered over a period of less than one hour.
  • the nivolumab is administered over a period of about an hour.
  • the nivolumab is administered over a period of 30-60 minutes.
  • the nivolumab is administered no more than once a week. In some embodiments, the nivolumab is administered at least once a week. In some embodiments, the nivolumab is administered every two weeks. In some embodiments, the nivolumab is administered once a week. In some embodiments, the nivolumab is administered once a month. In some embodiments, the nivolumab is administered twice a month. In some embodiments, the nivolumab is administered three times a month.
  • the cancer is selected from lung cancer, small-cell lung cancer, non-small cell lung cancer, carcinoma, lymphoma, blastoma, sarcoma, leukemia, breast cancer, prostate cancer, colon cancer, squamous cell cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
  • the cancer is melanoma or non-small cell lung cancer.
  • the cancer is non-small cell lung cancer, advanced small cell lung cancer, metastatic melanoma, kidney cancer (renal cell carcinoma), advanced renal cell carcinoma, squamous cell carcinoma, liver cancer, (hepatocellular carcinoma), bladder cancer (urothelial carcinoma), colon cancer, or Hodgkin lymphoma.
  • the method further comprises administering radiation therapy.
  • the cancer comprises a lesion.
  • the lesion is measured before the treatment and either during the treatment or after the treatment or both.
  • the lesion is measured by radiological assessments using computerized tomography scan or magnetic resonance imaging.
  • the lesion has reduced in size after the treatment.
  • the lesion has reduced in size by at least 10%. In some embodiments, the lesion has reduced in size by at least 20%. In some embodiments, the lesion has reduced in size by at least 50%. In some embodiments, the lesion has reduced in size by at least 75%.
  • a method for treating cancer comprising administering a combination of: a) a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof; and b) an immunotherapeutic agent, or a pharmaceutically acceptable salt thereof.
  • the tyrosine kinase inhibitor is a vascular endothelial growth factor receptor (VEGF) inhibitor.
  • the tyrosine kinase inhibitor is a selective vascular endothelial growth factor receptor-2 (VEGF2) inhibitor.
  • the tyrosine kinase inhibitor is afatinib, alectinib, apatinib, axitinib, bosutinib, brigatinib, canertinib, crizotinib, ceritinib, dasatinib, danusertib, dabrafenib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, pegaptanib, ponatinib, rebastinib, regorafenib, ribociclib, rivoceranib, ruxolitinib, semaxinib, sorafenib, sunitinib,
  • the tyrosine kinase inhibitor is administered in an amount of about 300 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 400 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 500 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 600 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is less than 700 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is less than 685 mg. In some embodiments, the tyrosine kinase inhibitor is administered orally.
  • the tyrosine kinase inhibitor is administered as a tablet. In some embodiments, the tyrosine kinase inhibitor is administered once daily. In some embodiments, the tyrosine kinase inhibitor is administered twice daily.
  • the immunotherapeutic agent is a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from nivolumab (Opdivo®), pembrolizumab (Keytruda®), MEDI0680 (AMP-514), AMP-224, AMP-514 (Amplimmune), BGB-A317, PDR001, REGN2810, JS001, AGEN2034, and variants and biosimilars thereof.
  • the immunotherapeutic agent is administered about an hour after the administration of the tyrosine kinase inhibitor. In some embodiments, the immunotherapeutic agent is administered over a period of less than one hour. In some embodiments, the immunotherapeutic agent is
  • the immunotherapeutic agent is administered over a period of about an hour. In some embodiments, the immunotherapeutic agent is administered over a period of 30-60 minutes. In some embodiments, the
  • the immunotherapeutic agent is administered no more than once a week. In some embodiments, the immunotherapeutic agent is administered at least once a week. In some embodiments, the immunotherapeutic agent is administered every two weeks. In some embodiments, the immunotherapeutic agent is administered once a week. In some embodiments, the
  • immunotherapeutic agent is administered once a month.
  • the immunotherapeutic agent is administered once a month.
  • immunotherapeutic agent is administered twice a month.
  • the immunotherapeutic agent is administered twice a month.
  • immunotherapeutic agent is administered three times a month.
  • disclosed herein is a method for treating cancer, comprising administering a combination of: a) no more than 685 mg rivoceranib, or a pharmaceutically acceptable salt thereof; and b) no more than 80 mg/m2 pembrolizumab.
  • a method for treating cancer comprising administering a combination of: a) rivoceranib, or a pharmaceutically acceptable salt thereof; and b) pembrolizumab; wherein the rivoceranib and the pembrolizumab act synergistically.
  • a method for treating cancer comprising administering a combination of: a) rivoceranib, or a
  • a method for treating cancer comprising administering a combination of: a) no more than 685 mg rivoceranib, or a pharmaceutically acceptable salt thereof; and b) nivolumab.
  • a method for treating cancer comprising administering a combination of: a) no more than 685 mg rivoceranib, or a pharmaceutically acceptable salt thereof; and b) no more than 80 mg/m2 nivolumab.
  • a method for treating cancer comprising administering a combination of: a) rivoceranib, or a pharmaceutically acceptable salt thereof; and b) nivolumab; wherein the rivoceranib and the nivolumab act synergistically.
  • Figure 1 is a graph of tumor growth curve demonstrating synergistic anti-tumor efficacy of a combination of apatinib mesylate and anti-muPD-1 antibody on mouse LL/2 lung carcinoma transplanted in syngeneic mice.
  • Figure 2 is graph of body weight curve demonstrating negligible toxicity of a combination of apatinib mesylate and anti muPD-1 antibody on mouse LL/2 lung carcinoma transplanted in syngeneic mice.
  • the methods comprise administering a combination of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and an immunotherapeutic agent, or a pharmaceutically acceptable salt thereof.
  • methods for enhancing the efficacy of a tyrosine kinase inhibitor to treat cancer comprising administering the tyrosine kinase inhibitor in combination with an immunotherapeutic agent.
  • methods for enhancing the efficacy of an immunotherapeutic agent to treat cancer comprising administering the immunotherapeutic agent in combination with a tyrosine kinase inhibitor.
  • the combination of the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof with the immunotherapeutic agent, or a pharmaceutically acceptable salt thereof act synergistically to treat cancer.
  • methods for inhibiting a cancer associated tumor growth comprising administering a combination of a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, and an immunotherapeutic agent, or a pharmaceutically acceptable salt thereof.
  • immunotherapeutic agent synergistically suppress tumor growth.
  • the present disclosure relates to the use of apatinib mesylate combining with current immunotherapeutic agents to treat tumors.
  • therapeutically active agents encompassed in single or multiple compositions.
  • the therapeutically active agents may be administered together at the same time to a patient in need thereof or separately (each or in any combinations thereof) in any sequential manner prescribed by a medical care taker.
  • the term "subject" can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment of a disorder of uncontrolled cellular proliferation, such as cancer.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the
  • causal treatment that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, zebra fish etc.).
  • domesticated animals e.g., cats, dogs, etc.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, zebra fish etc.
  • prevent refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • administration can be performed by one who subsequently performed the administration.
  • administering and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • contacting refers to bringing a disclosed compound and a cell, target receptor, or other biological entity together in such a manner that the compound can affect the activity of the target (e.g., receptor, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.
  • the target e.g., receptor, cell, etc.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • pharmaceutically acceptable carrier relates to pharmaceutically-acceptable, nontoxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. Such carriers may include, however not limited to, buffering agents, solubilizing agents, stabilizing agents or taste additives.
  • ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 ⁇ ' means “about 5 ⁇ _,” and also “5 ⁇ ” Generally, the term “about” includes an amount that would be expected to be within experimental error. Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers + ⁇ 0% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.
  • VEGFR family members include VEGFR 1, VEGFR2 and VEGFR3.
  • the family of receptors has seven immunoglobulin like domains and a hydrophilic insert sequence in the intracellular tyrosine kinase region.
  • VEGF plays an important role in the proliferation, migration, and vascularization of endothelial cells as the most powerful vascular penetrant and
  • VEGF/VEGFR inhibitors include but are not limited to aflibercept, allantoin, bevacizumab, lenvatinib, pazopanib, pegaptanib, ramucirumab, ranibizumab, sunitinib, tivozanib, and vandetanib.
  • Rivoceranib (chemical name N-[4-(l-cyanocyclopentyl)phenyl]-2- ⁇ [(pyridin-4- yl)methyl]amino ⁇ pyridine-3-carboxamide, also known as YN968D1, developed in China as apatinib and marketed as Aitan®) is an orally administered small molecule tyrosine kinase inhibitor. It selectively inhibits vascular endothelial growth factor receptor (VEGFR)-2 leading to blockage of tumor vascular angiogenesis, diminishes survival of existing blood vessels, and retards growth of tumors. Proliferation of endothelial cells is targeted directly, and inhibition of the release of proangiogenic growth factors by cancer or stromal cells is targeted indirectly.
  • VEGFR vascular endothelial growth factor receptor
  • Rivoceranib selectively binds to VEGFR-2 and is efficacious in various tumor bearing animal models.
  • Rivoceranib has been clinically tested in over 1,000 patients and has demonstrated efficacy in numerous cancers including gastric cancer, colorectal cancer (CRC), hepatocellular carcinoma (HCC), non-small-cell lung cancer (NSCLC), esophageal cancer, thyroid cancer, mesothelioma, and neuroendocrine tumors.
  • CRC colorectal cancer
  • HCC hepatocellular carcinoma
  • NSCLC non-small-cell lung cancer
  • esophageal cancer esophageal cancer
  • thyroid cancer mesothelioma
  • mesothelioma mesothelioma
  • neuroendocrine tumors Several clinical studies of rivoceranib have been completed and are briefly described below.
  • a Phase 1 study (46 patients) revealed a once daily dose-limiting toxicity of 805 mg rivoceranib (1000 mg rivoceranib mesylate) and a maximum tolerated dose of 685 mg (850 mg mesylate salt). Partial response was noted in 7 patients (19%), stable disease in 24 patients (65%)), and a disease control rate of 84%> at 8 weeks.
  • rivoceranib was dosed daily at 685 mg (850 mg rivoceranib mesylate). This study provided placebo-controlled evidence that rivoceranib has significant activity against gastric cancer with a manageable safety profile.
  • a Phase 3 multi-center, randomized, double-blind, and placebo-controlled study was conducted.
  • efficacy, median overall survival (OS) and median progression-free survival (PFS) were prolonged in the rivoceranib group compared to placebo.
  • the recommended dose for clinical use was 685 mg rivoceranib (850 mg mesylate salt) once daily.
  • Treatment with rivoceranib was generally well tolerated with most of the adverse reactions manageable by dose interruptions or reductions.
  • Grade 3/4 adverse reactions that occurred in more than 2% of patients were hypertension, HFS, proteinuria, fatigue, anorexia, and elevated aminotransferase.
  • the methods for treating diseases comprise administering a combination of two or more therapies, wherein one of the therapies is a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof.
  • the tyrosine kinase inhibitor is administered in the form of a free base. In some embodiments, the tyrosine kinase inhibitor is administered in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt includes, but is not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, ⁇ , ⁇ '-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like;
  • organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, p- toluenesulfonate salts, and the like; and amino acid salts, such as arginate salts, asparginate salts, glutamate salts, and the like.
  • Pharmaceutically acceptable salts also include bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate, pentafluoropropionate, hydrobromide, mucate, oleate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bis(heptafuorobutyrate), bis(pentaflu oropropionate), bis(pyridine carboxylate), bis(trifluoroacetate), chlorhydrate, and sulfate pentahydrate.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorsulfonate, camsylate, carbonate, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate
  • the tyrosine kinase inhibitor selective vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor.
  • the tyrosine kinase inhibitor isafatinib, alectinib, apatinib, axitinib, bosutinib, brigatinib, canertinib, crizotinib, ceritinib, dasatinib, danusertib, dabrafenib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, pegaptanib, ponatinib, rebastinib, regorafenib, rib
  • the tyrosine kinase inhibitor is rivoceranib. In some embodiments, the tyrosine kinase inhibitor is a pharmaceutically acceptable salt of rivoceranib. In some embodiments, the tyrosine kinase inhibitor is rivoceranib mesylate.
  • the tyrosine kinase inhibitor is administered in an amount of at least 10 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 50 mg.In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 100 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 150 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 200 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 225 mg.
  • the tyrosine kinase inhibitor is administered in an amount of at least 250 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 275 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 300 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 310 mg. In some
  • the tyrosine kinase inhibitor is administered in an amount of at least 320 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 325 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 330 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 340 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 350 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 360 mg.
  • the tyrosine kinase inhibitor is administered in an amount of at least 370 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 375 mg. In some embodiments, the tyrosine kinase inhibitor is
  • the tyrosine kinase inhibitor is administered in an amount of at least 380 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 400 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 410 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 420 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 425 mg. In some
  • the tyrosine kinase inhibitor is administered in an amount of at least 430 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 440 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 450 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 460 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 470 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 475 mg.
  • the tyrosine kinase inhibitor is administered in an amount of at least 480 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 490 mg. In some embodiments, the tyrosine kinase inhibitor is
  • the tyrosine kinase inhibitor is administered in an amount of at least 500 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 525 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 550 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 575 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 600 mg. In some
  • the tyrosine kinase inhibitor is administered in an amount of at least 625 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 650 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 675 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of at least 700 mg. In some embodiments, the tyrosine kinase inhibitor is rivoceranib. In some
  • the tyrosine kinase inhibitor is a pharmaceutically acceptable salt of rivoceranib. In some embodiments, the tyrosine kinase inhibitor is rivoceranib mesylate.
  • the tyrosine kinase inhibitor is administered in an amount of about 10 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 50 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 100 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 150 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 200 mg. In some embodiments, the tyrosine kinase inhibitor is
  • the tyrosine kinase inhibitor is administered in an amount of about 225 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 250 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 275 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 300 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 310 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 320 mg. In some
  • the tyrosine kinase inhibitor is administered in an amount of about 410 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 420 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 425 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 430 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 440 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 450 mg. In some
  • the tyrosine kinase inhibitor is administered in an amount of about 525 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 550 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 575 mg. In some embodiments, the tyrosine kinase inhibitor is
  • the tyrosine kinase inhibitor is administered in an amount of about 600 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 625 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 650 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 675 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of about 700 mg. In some embodiments, the tyrosine kinase inhibitor is rivoceranib. In some embodiments, the tyrosine kinase inhibitor is a pharmaceutically acceptable salt of rivoceranib. In some embodiments, the tyrosine kinase inhibitor is rivoceranib mesylate.
  • rivoceranib is administered in an amount of about 10 mg. In some embodiments, rivoceranib is administered in an amount of about 50 mg. In some embodiments, rivoceranib is administered in an amount of about 100 mg. In some embodiments, rivoceranib is administered in an amount of about 105 mg. In some embodiments, rivoceranib is administered in an amount of about 110 mg. In some embodiments, rivoceranib is administered in an amount of about 115 mg. In some embodiments, rivoceranib is administered in an amount of about 120 mg. In some embodiments, rivoceranib is administered in an amount of about 125 mg.
  • rivoceranib is administered in an amount of about 130 mg. In some embodiments, rivoceranib is administered in an amount of about 135 mg. In some embodiments, rivoceranib is administered in an amount of about 140 mg. In some embodiments, rivoceranib is administered in an amount of about 145 mg. In some embodiments, rivoceranib is administered in an amount of about 150 mg. In some embodiments, rivoceranib is administered in an amount of about 200 mg. In some embodiments, rivoceranib is administered in an amount of about 225 mg. In some embodiments, rivoceranib is administered in an amount of about 250 mg.
  • rivoceranib is administered in an amount of about 275 mg. In some embodiments, rivoceranib is administered in an amount of about 300 mg. In some embodiments, rivoceranib is administered in an amount of about 310 mg. In some embodiments, rivoceranib is administered in an amount of about 320 mg. In some embodiments, rivoceranib is administered in an amount of about 325 mg. In some embodiments, rivoceranib is administered in an amount of about 330 mg. In some embodiments, rivoceranib is administered in an amount of about 340 mg. In some embodiments, rivoceranib is administered in an amount of about 350 mg.
  • rivoceranib is administered in an amount of about 360 mg. In some embodiments, rivoceranib is administered in an amount of about 370 mg. In some embodiments, rivoceranib is administered in an amount of about 375 mg. In some embodiments, rivoceranib is administered in an amount of about 380 mg. In some embodiments, rivoceranib is administered in an amount of about 400 mg. In some embodiments, rivoceranib is administered in an amount of about 410 mg. In some embodiments, rivoceranib is administered in an amount of about 420 mg. In some embodiments, rivoceranib is administered in an amount of about 425 mg.
  • rivoceranib is administered in an amount of about 430 mg. In some embodiments, rivoceranib is administered in an amount of about 440 mg. In some embodiments, rivoceranib is administered in an amount of about 450 mg. In some embodiments, rivoceranib is administered in an amount of about 460 mg. In some embodiments, rivoceranib is administered in an amount of about 470 mg. In some embodiments, rivoceranib is administered in an amount of about 475 mg. In some embodiments, rivoceranib is administered in an amount of about 480 mg. In some embodiments, rivoceranib is administered in an amount of about 490 mg.
  • rivoceranib is administered in an amount of about 500 mg. In some embodiments, rivoceranib is administered in an amount of about 525 mg. In some embodiments, rivoceranib is administered in an amount of about 550 mg. In some embodiments, rivoceranib is administered in an amount of about 575 mg. In some embodiments, rivoceranib is administered in an amount of about 600 mg. In some embodiments, rivoceranib is administered in an amount of about 625 mg. In some embodiments, rivoceranib is administered in an amount of about 650 mg. In some embodiments, rivoceranib is administered in an amount of about 675 mg. In some embodiments, rivoceranib is administered in an amount of about 700 mg.
  • rivoceranib mesylate is administered in an amount of about 275 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 300 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 310 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 320 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 325 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 330 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 340 mg.
  • rivoceranib mesylate is administered in an amount of about 350 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 360 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 370 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 375 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 380 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 400 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 410 mg.
  • rivoceranib mesylate is administered in an amount of about 420 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 425 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 430 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 440 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 450 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 460 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 470 mg.
  • rivoceranib mesylate is administered in an amount of about 475 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 480 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 490 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 500 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 525 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 550 mg. In some embodiments, rivoceranib mesylate is administered in an amount of about 575 mg.
  • the tyrosine kinase inhibitor is administered in an amount of no more than 10 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 50 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 100 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 150 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 200 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 225 mg.
  • the tyrosine kinase inhibitor is administered in an amount of no more than 330 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 340 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 350 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 360 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 370 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 375 mg.
  • the tyrosine kinase inhibitor is administered in an amount of no more than 380 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 400 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 410 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 420 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 425 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 430 mg.
  • the tyrosine kinase inhibitor is administered in an amount of no more than 440 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 450 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 460 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 470 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 475 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 480 mg.
  • the tyrosine kinase inhibitor is administered in an amount of no more than 490 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 500 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 525 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 550 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 575 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 600 mg.
  • the tyrosine kinase inhibitor is administered in an amount of no more than 625 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 650 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 675 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of no more than 700 mg. In some embodiments, the tyrosine kinase inhibitor is rivoceranib. In some embodiments, the tyrosine kinase inhibitor is a pharmaceutically acceptable salt of rivoceranib. In some embodiments, the tyrosine kinase inhibitor is rivoceranib mesylate.
  • the tyrosine kinase inhibitor is administered in an amount of from 100 mg to 900 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 150 mg to 850 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 175 mg to 825 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 200 mg to 800 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 225 mg to 775 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 750 mg.
  • the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 725 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 700 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 675 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 650 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 600 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 550 mg.
  • the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 500 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 250 mg to 450 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 275 mg to 425 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 300 mg to 600 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 300 mg to 550 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 300 mg to 500 mg.
  • the tyrosine kinase inhibitor is administered in an amount of from 300 mg to 450 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 300 mg to 400 mg. In some embodiments, the tyrosine kinase inhibitor is administered in an amount of from 350 mg to 450 mg. In some embodiments, the tyrosine kinase inhibitor is rivoceranib. In some embodiments, the tyrosine kinase inhibitor is a
  • rivoceranib mesylate is administered in an amount of less than 685 mg.
  • the total daily dose of the tyrosine kinase inhibitor is about 10 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 50 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 100 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 150 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 200 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 225 mg.
  • the total daily dose of the tyrosine kinase inhibitor is about 250 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 275 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 300 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 310 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 320 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 325 mg.
  • the total daily dose of the tyrosine kinase inhibitor is about 330 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 340 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 350 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 360 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 370 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 375 mg.
  • the total daily dose of the tyrosine kinase inhibitor is about 440 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 450 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 460 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 470 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 475 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 480 mg.
  • the total daily dose of the tyrosine kinase inhibitor is about 490 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 500 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 525 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 550 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 575 mg. In some embodiments, the total daily dose of the tyrosine kinase inhibitor is about 600 mg.
  • the total daily dose of rivoceranib is about 10 mg. In some embodiments, the total daily dose of rivoceranib is about 50 mg. In some embodiments, the total daily dose of rivoceranib is about 100 mg. In some embodiments, the total daily dose of rivoceranib is about 150 mg. In some embodiments, the total daily dose of rivoceranib is about 200 mg. In some embodiments, the total daily dose of rivoceranib is about 225 mg. In some embodiments, the total daily dose of rivoceranib is about 250 mg. In some embodiments, the total daily dose of rivoceranib is about 275 mg.
  • the total daily dose of rivoceranib is about 300 mg. In some embodiments, the total daily dose of rivoceranib is about 310 mg. In some embodiments, the total daily dose of rivoceranib is about 320 mg. In some embodiments, the total daily dose of rivoceranib is about 325 mg. In some embodiments, the total daily dose of rivoceranib is about 330 mg. In some embodiments, the total daily dose of rivoceranib is about 340 mg. In some embodiments, the total daily dose of rivoceranib is about 350 mg. In some embodiments, the total daily dose of rivoceranib is about 360 mg.
  • the total daily dose of rivoceranib is about 370 mg. In some embodiments, the total daily dose of rivoceranib is about 375 mg. In some embodiments, the total daily dose of rivoceranib is about 380 mg. In some embodiments, the total daily dose of rivoceranib is about 400 mg. In some embodiments, the total daily dose of rivoceranib is about 410 mg. In some embodiments, the total daily dose of rivoceranib is about 420 mg. In some embodiments, the total daily dose of rivoceranib is about 425 mg. In some embodiments, the total daily dose of rivoceranib is about 430 mg.
  • the total daily dose of rivoceranib is about 525 mg. In some embodiments, the total daily dose of rivoceranib is about 550 mg. In some embodiments, the total daily dose of rivoceranib is about 575 mg. In some embodiments, the total daily dose of rivoceranib is about 600 mg. In some embodiments, the total daily dose of rivoceranib is about 625 mg. In some embodiments, the total daily dose of rivoceranib is about 650 mg. In some embodiments, the total daily dose of rivoceranib is about 675 mg. In some embodiments, the total daily dose of rivoceranib is about 700 mg.
  • the total daily dose of rivoceranib mesylate is about 10 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 50 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 100 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 150 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 200 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 225 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 250 mg.
  • the total daily dose of rivoceranib mesylate is about 275 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 300 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 310 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 320 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 325 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 330 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 340 mg.
  • the total daily dose of rivoceranib mesylate is about 350 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 360 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 370 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 375 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 380 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 400 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 410 mg.
  • the total daily dose of rivoceranib mesylate is about 420 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 425 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 430 mg. In some
  • the total daily dose of rivoceranib mesylate is about 460 mg.
  • the total daily dose of rivoceranib mesylate is about 470 mg.
  • the total daily dose of rivoceranib mesylate is about 480 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 480 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 480 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 480 mg. In some embodiments, the total daily dose of rivoceranib mesylate is about 480 mg. In some
  • the total daily dose of rivoceranib mesylate is about 490 mg.
  • the total daily dose of rivoceranib mesylate is about 500 mg.
  • the total daily dose of rivoceranib mesylate is about 525 mg.
  • the total daily dose of rivoceranib mesylate is about 550 mg.
  • the total daily dose of rivoceranib mesylate is about 575 mg.
  • the total daily dose of rivoceranib mesylate is about 600 mg.
  • the total daily dose of rivoceranib mesylate is about 625 mg.
  • the total daily dose of rivoceranib mesylate is about 650 mg.
  • the total daily dose of rivoceranib mesylate is about 675 mg.
  • the total daily dose of rivoceranib mesylate is about 700 mg.
  • the tyrosine kinase inhibitor is administered orally. In some embodiments, the tyrosine kinase inhibitor is administered in an oral liquid, solid or semisolid dosage form. In some embodiments, the tyrosine kinase inhibitor is administered as a solid oral dosage form. In some embodiments, the tyrosine kinase inhibitor is administered as a pill, tablet, chewable tablet, specialty tablet, buccal tablet, sub-lingual tablet, orally-disintegrating tablet, capsule, gel capsule, soft gel capsule, hard gel capsule, sachet, powder, granule, crystal or orally dispersible film.
  • the tyrosine kinase inhibitor is administered as a dried powder, a liquid, a capsule, a pellet or a tablet. In some embodiments, the tyrosine kinase inhibitor is administered as a tablet. In some embodiments, the tyrosine kinase inhibitor is administered as a film coated tablet.
  • the tyrosine kinase inhibitor may be admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or
  • solid dosage forms may be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain pacifying agents, and can also be of such composition that they release the tyrosine kinase inhibitor in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The tyrosine kinase inhibitor may also be in
  • the tyrosine kinase inhibitor is administered as a liquid oral dosage form. In some embodiments, the tyrosine kinase inhibitor is administered as a solution, suspension, drink, syrup, elixir, ampoule, dispersion, semi-solid or soft gel.
  • the tyrosine kinase inhibitor is administered parenterally. In some embodiments, the tyrosine kinase inhibitor is administered intradermaly, subcutaneously, intramuscularly, intraosseously, intraperitoneally or intravenously. In some embodiments, the tyrosine kinase inhibitor is administered intraperitoneally. In some embodiments, the tyrosine kinase inhibitor is administered intravenously.
  • rivoceranib is administered orally. In some embodiments, rivoceranib is administered in an oral liquid, solid or semisolid dosage form. In some embodiments, rivoceranib is administered as a solid oral dosage form.
  • rivoceranib is administered as a pill, tablet, chewable tablet, specialty tablet, buccal tablet, sublingual tablet, orally-disintegrating tablet, capsule, gel capsule, soft gel capsule, hard gel capsule, sachet, powder, granule, crystal or orally dispersible film.
  • rivoceranib is administered as a dried powder, a liquid, a capsule, a pellet or a tablet.
  • rivoceranib is administered as a tablet.
  • rivoceranib is administered as a film coated tablet.
  • the tablet comprises rivoceranib in an amount of about 100 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 150 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 200 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 250 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 300 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 350 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 400 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 450 mg.
  • the tablet comprises rivoceranib in an amount of about 500 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 550 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 600 mg. In some embodiments, the tablet comprises rivoceranib in an amount of about 650 mg. In some embodiments, the tablet further comprises one or more of pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, povidone (K-30), colloidal silicon dioxide, magnesium stearate and Opadry white.
  • rivoceranib is administered as a liquid oral dosage form. In some embodiments, rivoceranib is administered as a solution, suspension, drink, syrup, elixir, ampoule, dispersion, semi-solid or soft gel.
  • rivoceranib is administered parenterally. In some embodiments, rivoceranib is administered intradermaly, subcutaneously, intramuscularly, intraosseously, intraperitoneally or intravenously. In some embodiments, rivoceranib is administered intraperitoneally. In some embodiments, rivoceranib is administered intravenously.
  • rivoceranib mesylate is administered in an oral liquid, solid or semisolid dosage form. In some embodiments, rivoceranib mesylate is administered as a solid oral dosage form. In some embodiments, rivoceranib mesylate is administered as a pill, tablet, chewable tablet, specialty tablet, buccal tablet, sub-lingual tablet, orally-disintegrating tablet, capsule, gel capsule, soft gel capsule, hard gel capsule, sachet, powder, granule, crystal or orally dispersible film. In some embodiments, rivoceranib mesylate is administered as a dried powder, a liquid, a capsule, a pellet or a tablet. In some embodiments, rivoceranib mesylate is administered as a tablet. In some embodiments, rivoceranib mesylate is administered as a film coated tablet.
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet comprises rivoceranib mesylate in an amount of about
  • the tablet further comprises one or more of pregelatinized starch microcrystalline cellulose, sodium starch glycolate, povidone (K-30), colloidal silicon dioxide, magnesium stearate and Opadry white.
  • rivoceranib mesylate is administered as a liquid oral dosage form. In some embodiments, rivoceranib mesylate is administered as a solution, suspension, drink, syrup, elixir, ampoule, dispersion, semi-solid or soft gel.
  • rivoceranib mesylate is administered parenterally. In some embodiments, rivoceranib mesylate is administered intradermaly, subcutaneously,
  • rivoceranib mesylate is administered intraperitoneally. In some embodiments, rivoceranib mesylate is administered intravenously.
  • the tyrosine kinase inhibitor is administered once daily. In some embodiments, the tyrosine kinase inhibitor is administered twice daily.
  • rivoceranib is administered once daily. In some embodiments, rivoceranib is administered twice daily.
  • rivoceranib mesylate is administered once daily. In some embodiments, rivoceranib mesylate is administered twice daily.
  • the disclosure provides a combination therapy comprising apatinib, or a pharmaceutically acceptable salt thereof, and an immunotherapeutic agent.
  • the disclosure also provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of apatinib in combination with a therapeutically effective amount of an immunotherapeutic agent.
  • the pharmaceutically acceptable salt is apatinib mesylate.
  • Cancers treatable by the combination therapies of the disclosure include, but are not limited to lung cancer, small-cell lung cancer, non-small cell lung cancer, carcinoma, lymphoma, blastoma, sarcoma, leukemia, breast cancer, prostate cancer, colon cancer, squamous cell cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
  • lung cancer small-cell lung cancer, non-small cell lung cancer, carcinoma, lymphoma, blastoma, sarcoma, leukemia, breast cancer, prostate cancer, colon cancer, squamous cell cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
  • the immunotherapeutic agent is an antibody.
  • the antibody can be a monoclonal or polyclonal antibody.
  • the antibody can be a human or humanized antibody.
  • the antibody can be an anti -programmed death 1 (PD-1) antibody.
  • the antibody can be an anti-muPD-1 antibody.
  • the antibody can be an anti-PD-Ll antibody.
  • the antibody can be an anti-CTLA-4 antibody.
  • Apatinib also known as YN968D1
  • YN968D1 is a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2 (VEGFR2, also known as KDR).
  • VAGFR2 vascular endothelial growth factor receptor-2
  • apatinib inhibits VEGF-mediated endothelial cell migration and proliferation thus blocking new blood vessel formation in tumor tissue. This agent also mildly inhibits c-Kit and c-SRC tyrosine kinases.
  • Apatinib mesylate is described in more detail in U.S. Patent No. 8,362,256, the contents of which are hereby incorporated in their entirety.
  • the term "apatinib” encompasses all pharmaceutically acceptable apatinib salts, and in particular, apatinib mesylate. IMMUNOTHERAPEUTIC AGENTS
  • tyrosine kinase inhibitors in combination with an immunotherapeutic agent.
  • the immunotherapeutic agent is a PD-1 or PD-Ll inhibitor.
  • the PD-1 (programmed cell death - 1) receptor (also known as CD279) is expressed on the surface of activated T cells. Its ligand, PD-Ll, is commonly expressed on the surface of dendritic cells or macrophages. In some instances, PDl and PD-Ll interaction halts or limits the development of the T cell response.
  • PD-Ll binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses T-cell proliferation.
  • cancer or tumor cells exploit this signaling pathway as a mechanism to evade detection and inhibit the immune response.
  • PD-Ll is overexpressed on cancer or tumor cells or on non -transformed cells in the tumor
  • PD-Ll expressed on the tumor cells binds to PD-1 receptors on the activated T cells, which leads to the inhibition of the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
  • the PD1/PD-L1 pathway represents an adaptive immune resistance mechanism that is exerted by cancer or tumor cells in response to endogenous anti-tumor activity.
  • any suitable PD-1 inhibitor or PD-Ll inhibitor may be used in combination with a tyrosine kinase inhibitor described herein.
  • the PD-1 inhibitor is an antagonist of PD-1.
  • the PD-Ll inhibitor is an antagonist of PD-Ll .
  • the PD-1 inhibitor or PD-Ll inhibitor is an antibody, variant, or biosimilar thereof.
  • the PD-1 inhibitor or PD-Ll inhibitor is a monoclonal antibody.
  • the method of treating cancer with a tyrosine kinase inhibitor described herein in combination with a PD-1 or PD-Ll inhibitor results in a transient reduction in the level of systemic immunosuppression.
  • PD-1 inhibitors for use in pharmaceutical compositions and methods provided herein include, but are not limited to, nivolumab (Opdivo®), pembrolizumab (Keytruda®), MEDI0680 (AMP-514), AMP-224, AMP-514 (Amplimmune), BGB-A317, PDR001, REGN2810, JS001, AGEN2034, and variants and biosimilars thereof.
  • the PD-1 inhibitor is to nivolumab (Opdivo®), pembrolizumab
  • the PD-1 inhibitor is pidilzumab (CT-011), or a variant or biosimilar thereof.
  • the PD-1 inhibitor is nivolumab (Opdivo®), or pembrolizumab (Keytruda®), or a variant or biosimilar thereof.
  • the PD-1 inhibitor is nivolumab (Opdivo®), a nivolumab variant, or a nivolumab biosimilar.
  • compositions or methods for using the pharmaceutical compositions comprising a tyrosine kinase inhibitor described herein in combination with a PD-L1 inhibitor.
  • PD-L1 inhibitors for use in
  • Atezolizumab (Tecentriq® or MPDL3280A), avelumab (Bavencio®), Durvalumab (MEDI4736), MPDL3280A (RG7446), BMS-936559 (MDX-1105), MSB0010718C, YW243.55.S70, and variants and biosimilars thereof.
  • the PD-L1 inhibitor is Atezolizumab (Tecentriq® or MPDL3280A), avelumab (Bavencio®), or Durvalumab (MEDI4736), or variants or biosimilars thereof.
  • the PD-L1 inhibitor is avelumab (Bavencio®), avelumab variant, or an avelumab biosimilar.
  • the PD-L1 inhibitor is BMS-936559 (MDX-1105), BMS-936559 variant, or a BMS-936559 biosimilar.
  • the PD-L1 inhibitor is durvalumab (MEDI4736), a
  • durvalumab variant or a durvalumab biosimilar.
  • the combination therapy described herein avoids, reduces, or minimizes the incidence of neutropenia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of diarrhea, including severe diarrhea. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of colon inflammation. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of colitis. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of lung tissue inflammation (pneumonitis). In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of intestinal perforation.
  • the combination therapy described herein avoids, reduces, or minimizes the incidence of abdominal pain. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of chills. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of rash. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of vomiting. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of hypertriglyceridemia.
  • the combination therapy described herein avoids, reduces, or minimizes the incidence of hyperglycemia. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of elevated levels of liver enzymes (e.g., ALT and ALST). In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of liver toxicity. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of swelling in the extremities.
  • liver enzymes e.g., ALT and ALST
  • the combination therapy described herein avoids, reduces, or minimizes the incidence of liver toxicity. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of swelling in the extremities.
  • apatinib in particular, apatinib mesylate
  • any immunotherapeutic agent that can induce or enhance immune response to cancer.
  • Atezolizumab atezolizumab, avelumab, durvalumab, ipilimumab, tumor vaccines (sipuleucel-T), CAR T-cell therapies (tisagenlecleucel, axicabtagene ciloleucel), and naked monoclonal antibodies (e.g., alemtuzumab).
  • Some of the preferred antibodies that can be used in the compositions and methods of the present disclosure include anti-muPD-1, anti-PD-Ll and anti-CTLA-4 antibodies.
  • drugs dosages are determined as a factor of patient body surface area (BSA).
  • BSA patient body surface area
  • BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass, e.g., a patient with a larger BSA would presumably have larger organs for a drug to clear through. Indeed, there can be a 4-10 fold variation in drug clearance between individuals.
  • the average adult male BSA is 2.060m 2 .
  • the average adult female BSA is 1.830m 2 .
  • pembrolizumab doses are given in units of mg/m 2 .
  • nivolumab doses are given in units of mg/m 2 .
  • the methods for treating diseases comprise administering a combination of two or more therapies, wherein one of the therapies is an immunotherapeutic agent.
  • the immunotherapeutic agent is selected from a peptide, an antibody, pembrolizumab, nivolumab, pidilizumab, BMS-936559, MPDL3280A, MEDI4736, MSB0010718C atezolizumab, avelumab, durvalumab, ipilimumab, tumor vaccines (sipuleucel- T), CAR T-cell therapies (tisagenlecleucel, axicabtagene ciloleucel), and naked monoclonal antibodies (e.g., alemtuzumab)
  • the immunotherapeutic agent is administered in an amount of about 25 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 30 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 35 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 40 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 45 mg/m 2 . In some embodiments, the
  • immunotherapeutic agent is administered in an amount of about 50 mg/m 2 .
  • the immunotherapeutic agent is administered in an amount of about 55 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 60 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 65 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 70 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 75 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 80 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 85 mg/m 2 . In some embodiments, the
  • immunotherapeutic agent is administered in an amount of about 90 mg/m 2 .
  • the immunotherapeutic agent is administered in an amount of about 95 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 100 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 105 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 110 mg/m 2 . In some embodiments, the immunotherapeutic agent is
  • the immunotherapeutic agent is administered in an amount of about 115 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 120 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 125 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 130 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 135 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 140 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 145 mg/m 2 . In some embodiments, the immunotherapeutic agent is
  • the immunotherapeutic agent is administered in an amount of about 160 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 160 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 160 mg/m 2 .
  • immunotherapeutic agent is administered in an amount of about 170 mg/m 2 .
  • the immunotherapeutic agent is administered in an amount of about 175 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 180 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 190 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of about 200 mg/m 2 . In some embodiments, the immunotherapeutic agent is a PD-1 or PD-IL inhibitor. In some embodiments, the immunotherapeutic agent is pembrolizumab. In some embodiments, the immunotherapeutic agent is nivolumab.
  • the immunotherapeutic agent is administered in an amount of no more than 70 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of no more than 80 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of no more than 90 mg/m 2 . In some embodiments, the
  • the immunotherapeutic agent is administered in an amount of no more than 100 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of no more than 125 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of no more than 150 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of no more than 175 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of no more than 200 mg/m 2 . In some embodiments, the
  • the immunotherapeutic agent is administered in an amount of no more than 250 mg/m 2 .
  • the immunotherapeutic agent is a PD-1 or PD-IL inhibitor.
  • the immunotherapeutic agent is pembrolizumab.
  • the immunotherapeutic agent is nivolumab.
  • pembrolizumab is administered in an amount of about 25 mg/m 2 . In some embodiments, pembrolizumab is administered in an amount of about 30 mg/m 2 . In some embodiments, pembrolizumab is administered in an amount of about 35 mg/m 2 . In some embodiments, pembrolizumab is administered in an amount of about 40 mg/m 2 . In some embodiments, pembrolizumab is administered in an amount of about 45 mg/m 2 . In some embodiments, pembro izumab is admini stered in an amount of about 50 mg/m 2 . in some embodiments, pembro izumab is admini stered in an amount of about 55 mg/m 2 .
  • pembro izumab is admini stered in an amount of about 60 mg/m 2 . [n some embodiments, pembro izumab is admini stered in an amount of about 65 mg/m 2 . [n some embodiments, pembro izumab is admini stered in an amount of about 70 mg/m 2 . [n some embodiments, pembro izumab is admini stered in an amount of about 75 mg/m 2 . [n some embodiments, pembro izumab is admini stered in an amount of about 80 mg/m 2 . [n some embodiments, pembro izumab is admini stered in an amount of about 85 mg/m 2 .
  • pembro izumab is admini stered in an amount of about 90 mg/m 2 .
  • pembro izumab is admini stered in an amount of about 95 mg/m 2 .
  • pembro izumab is admini stered in an amount of about 100 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 105 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 1 10 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 1 15 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 120 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 125 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 130 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount of about 135 mg/m 2 In some embodiments, pembro izumab is admini stered in an amount
  • pembro izumab is administered in an amount of about 300 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 310 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 320 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 330 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 340 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 350 mg/m 2 .
  • pembro izumab is administered in an amount of about 375 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 400 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 425 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 450 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 475 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 500 mg/m 2 .
  • pembro izumab is administered in an amount of about 525 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 550 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 575 mg/m 2 . In some embodiments, pembro izumab is administered in an amount of about 600 mg/m 2 .
  • nivolumab is administered in an amount of about 25 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 30 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 35 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 40 mg/m 2 . In some
  • nivolumab is administered in an amount of about 45 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 50 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 55 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 60 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 65 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 70 mg/m 2 .
  • nivolumab is admini stered in an amount of about 105 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 110 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 115 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 120 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 125 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 130 mg/m 2 .
  • nivolumab is admini stered in an amount of about 135 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 140 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 145 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 150 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 160 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 170 mg/m 2 .
  • nivolumab is admini stered in an amount of about 230 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 240 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 250 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 260 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 270 mg/m 2 . In some embodiments, nivolumab is admini stered in an amount of about 280 mg/m 2 .
  • nivolumab is administered in an amount of about 290 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 300 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 310 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 320 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 330 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 340 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 350 mg/m 2 .
  • nivolumab is administered in an amount of about 375 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 400 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 425 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 450 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 475 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 500 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 525 mg/m 2 .
  • nivolumab is administered in an amount of about 550 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 575 mg/m 2 . In some embodiments, nivolumab is administered in an amount of about 600 mg/m 2 .
  • nivolumab is administered in an amount of no more than 200 mg/m 2 . In some embodiments, nivolumab is administered in an amount of no more than 250 mg/m 2 . In some embodiments, nivolumab is administered in an amount of no more than 300 mg/m 2 . In some embodiments, nivolumab is administered in an amount of no more than 350 mg/m 2 . In some embodiments, nivolumab is administered in an amount of no more than 400
  • the immunotherapeutic agent is administered in a dosage amount of about 25 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 30 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 35 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 40 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 45 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 50 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 55 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 60 mg.
  • the immunotherapeutic agent is administered in a dosage amount of about 65 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 70 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 75 mg. In some embodiments, the
  • the immunotherapeutic agent is administered in a dosage amount of about 80 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 85 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 90 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 95 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 100 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 105 mg. In some embodiments, the
  • the immunotherapeutic agent is administered in a dosage amount of about 110 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 115 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 120 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 125 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 130 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 135 mg. In some embodiments, the
  • the immunotherapeutic agent is administered in a dosage amount of about 140 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 145 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 150 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 160 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 170 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 175 mg. In some embodiments, the
  • the immunotherapeutic agent is administered in a dosage amount of about 180 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 190 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of about 200 mg. In some embodiments, the immunotherapeutic agent is a PD-1 or PD-1L inhibitor. In some embodiments, the immunotherapeutic agent is pembrolizumab. In some embodiments, the immunotherapeutic agent is nivolumab. [00131] In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 70 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 80 mg. In some embodiments, the
  • the immunotherapeutic agent is administered in a dosage amount of no more than 90 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 100 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 125 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 150 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 175 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 200 mg. In some embodiments, the immunotherapeutic agent is administered in a dosage amount of no more than 250 mg. In some embodiments, the immunotherapeutic agent is a PD-1 or PD-IL inhibitor. In some embodiments, the immunotherapeutic agent is pembrolizumab. In some embodiments, the immunotherapeutic agent is nivolumab.
  • pembrolizumab is administered in a dosage amount of about 25 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 30 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 35 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 40 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 45 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 50 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 55 mg.
  • pembro izumab is administered in a dosage amount of about 60 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 65 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 70 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 75 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 80 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 85 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 90 mg.
  • pembro izumab is administered in a dosage amount of about 95 mg. In some embodiments, pembro izumab is administered in a dosage amount of about 100 mg. In some embodiments, pembrolizumab is administered in a dosage amount of about 105 mg. In some embodiments, pembrolizumab is administered in a dosage amount of about 110 mg. In some embodiments, pembrolizumab is administered in a dosage amount of about 115 mg. In some embodiments, pembrolizumab is administered in a dosage amount of about 120 mg. In some embodiments, pembrolizumab is administered in a dosage amount of about 125 mg.
  • pembrolizumab is administered in a dosage amount of no more than 70 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 80 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 90 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 100 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 125 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 150 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 175 mg. In some embodiments,
  • pembrolizumab is administered in a dosage amount of no more than 200 mg.
  • pembrolizumab is administered in a dosage amount of no more than 250 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 300 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 350 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 400 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 425 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 450 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 475 mg. In some embodiments, pembrolizumab is administered in a dosage amount of no more than 500 mg.
  • nivolumab is administered in a dosage amount of about 25 mg. In some embodiments, nivolumab is administered in a dosage amount of about 30 mg. In some embodiments, nivolumab is administered in a dosage amount of about 35 mg. In some embodiments, nivolumab is administered in a dosage amount of about 40 mg. In some embodiments, nivolumab is administered in a dosage amount of about 45 mg. In some embodiments, nivolumab is administered in a dosage amount of about 50 mg. In some embodiments, nivolumab is administered in a dosage amount of about 55 mg.
  • nivolumab is administered in a dosage amount of about 60 mg. In some embodiments, nivolumab is administered in a dosage amount of about 65 mg. In some embodiments, nivolumab is administered in a dosage amount of about 70 mg. In some embodiments, nivolumab is administered in a dosage amount of about 75 mg. In some embodiments, nivolumab is administered in a dosage amount of about 80 mg. In some embodiments, nivolumab is administered in a dosage amount of about 85 mg. In some embodiments, nivolumab is administered in a dosage amount of about 90 mg. In some embodiments, nivolumab is administered in a dosage amount of about 95 mg.
  • nivolumab is admini stered in a dosage amount of about 100 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 105 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 110 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 115 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 120 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 125 mg.
  • nivolumab is admini stered in a dosage amount of about 130 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 135 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 140 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 145 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 150 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 160 mg.
  • nivolumab is admini stered in a dosage amount of about 170 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 175 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 180 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 190 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 200 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 210 mg.
  • nivolumab is admini stered in a dosage amount of about 220 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 230 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 240 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 250 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 260 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 270 mg.
  • nivolumab is admini stered in a dosage amount of about 280 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 290 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 300 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 310 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 320 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 330 mg.
  • nivolumab is admini stered in a dosage amount of about 340 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 350 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 375 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 400 mg. In some embodiments, nivolumab is admini stered in a dosage amount of about 425 mg. In some embodiments, nivolumab is administered in a dosage amount of about 450 mg.
  • nivolumab is administered in a dosage amount of about 475 mg. In some embodiments, nivolumab is administered in a dosage amount of about 500 mg. In some embodiments, nivolumab is administered in a dosage amount of about 525 mg. In some embodiments, nivolumab is administered in a dosage amount of about 550 mg. In some embodiments, nivolumab is administered in a dosage amount of about 575 mg. In some embodiments, nivolumab is administered in a dosage amount of about 600 mg.
  • nivolumab is administered in a dosage amount of no more than 70 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 80 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 90 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 100 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 125 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 150 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 175 mg.
  • nivolumab is administered in a dosage amount of no more than 200 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 250 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 300 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 350 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 400 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 425 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 450 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 475 mg. In some embodiments, nivolumab is administered in a dosage amount of no more than 500 mg.
  • the immunotherapeutic agent is administered in an amount of from 10 mg/m 2 to 150 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 20 mg/m 2 to 140 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 30 mg/m 2 to 130 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 40 mg/m 2 to 125 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 50 mg/m 2 to 110 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 50 mg/m 2 to 90 mg/m 2 .
  • the immunotherapeutic agent is administered in an amount of from 60 mg/m 2 to 100 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 65 mg/m 2 to 95 mg/m 2 . In some embodiments, the immunotherapeutic agent is administered in an amount of from 70 mg/m 2 to 90 mg/m 2 . In some embodiments, the immunotherapeutic agent is a PD-1 or PD-IL inhibitor. In some embodiments, the immunotherapeutic agent is pembrolizumab. In some embodiments, the immunotherapeutic agent is nivolumab.
  • pembrolizumab is administered in an amount of from 50 mg/m 2 to 90 mg/m 2 . In some
  • pembrolizumab is administered in an amount of from 60 mg/m 2 to 100 mg/m 2 . In some embodiments, pembrolizumab is administered in an amount of from 65 mg/m 2 to 95 mg/m 2 . In some embodiments, pembrolizumab is administered in an amount of from 70 mg/m 2 to 90 mg/m 2 .
  • nivolumab is administered in an amount of from 10 mg/m 2 to 150 mg/m 2 . In some embodiments, nivolumab is administered in an amount of from 20 mg/m 2 to 140 mg/m 2 . In some embodiments, nivolumab is administered in an amount of from 30 mg/m 2 to 130 mg/m 2 . In some embodiments, nivolumab is administered in an amount of from 40 mg/m 2 to 125 mg/m 2 . In some embodiments, nivolumab is administered in an amount of from 50 mg/m 2 to 110 mg/m 2 .
  • pembrolizumab is administered in a dosage amount of from 10 mg to 100 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 50 mg to 150 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 75 mg to 175 mg. In some embodiments, pembrolizumab is
  • pembrolizumab is administered in a dosage amount of from 125 mg to 225 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 150 mg to 250 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 175 mg to 275 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 200 mg to 300 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 225 mg to 325 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 250 mg to 350 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 275 mg to 375 mg. In some embodiments, pembrolizumab is administered in a dosage amount of from 300 mg to 400 mg. In some embodiments, pembrolizumab is
  • pembrolizumab is administered in a dosage amount of from 200 mg to 400 mg.
  • nivolumab is administered in a dosage amount of from 10 mg to 100 mg. In some embodiments, nivolumab is administered in a dosage amount of from 50 mg to 150 mg. In some embodiments, nivolumab is administered in a dosage amount of from 75 mg to 175 mg. In some embodiments, nivolumab is administered in a dosage amount of from 100 mg to 200 mg. In some embodiments, nivolumab is administered in a dosage amount of from 125 mg to 225 mg. In some embodiments, nivolumab is administered in a dosage amount of from 150 mg to 250 mg.
  • nivolumab is administered in a dosage amount of from 175 mg to 275 mg. In some embodiments, nivolumab is administered in a dosage amount of from 200 mg to 300 mg. In some embodiments, nivolumab is administered in a dosage amount of from 225 mg to 325 mg. In some embodiments, nivolumab is administered in a dosage amount of from 250 mg to 350 mg. In some embodiments, nivolumab is
  • nivolumab is administered in a dosage amount of from 275 mg to 375 mg. In some embodiments, nivolumab is administered in a dosage amount of from 300 mg to 400 mg. In some embodiments, nivolumab is administered in a dosage amount of from 100 mg to 300 mg. In some embodiments, nivolumab is administered in a dosage amount of from 200 mg to 400 mg.
  • the immunotherapeutic agent is administered orally or parenterally. In some embodiments, the immunotherapeutic agent is administered orally. In some embodiments, the immunotherapeutic agent is administered parenterally. In some embodiments, the immunotherapeutic agent is administered intravenously. In some
  • the immunotherapeutic agent is a PD-1 or PD-IL inhibitor. In some embodiments, the immunotherapeutic agent is pembrolizumab. In some embodiments, the immunotherapeutic agent is nivolumab.
  • pembrolizumab is administered orally or parenterally. In some embodiments, pembrolizumab is administered orally. In some embodiments,
  • pembrolizumab is administered parenterally. In some embodiments, pembrolizumab is administered intravenously.
  • nivolumab is administered orally or parenterally. In some embodiments, nivolumab is administered orally. In some embodiments, nivolumab is
  • nivolumab is administered intravenously.
  • the immunotherapeutic agent is administered over a period of less than one hour. In some embodiments, the immunotherapeutic agent is
  • the immunotherapeutic agent is administered over a period of about 1.5 hours. In some embodiments, the
  • immunotherapeutic agent is administered over a period of about two hours.
  • the immunotherapeutic agent is administered over a period of about the hours. In some embodiments, the immunotherapeutic agent is administered over a period of less than two hours. In some embodiments, the immunotherapeutic agent is administered over a period of 30- 60 minutes. In some embodiments, the immunotherapeutic agent is administered over a period of about 45 minutes. In some embodiments, the immunotherapeutic agent is a PD-1 or PD-1L inhibitor. In some embodiments, the immunotherapeutic agent is pembrolizumab. In some embodiments, the immunotherapeutic agent is nivolumab.
  • pembrolizumab is administered over a period of less than one hour. In some embodiments, pembrolizumab is administered over a period of about one hour. In some embodiments, pembrolizumab is administered over a period of about 1.5 hour. In some embodiments, pembrolizumab is administered over a period of about two hours. In some embodiments, pembrolizumab administered over a period of about the hours. In some embodiments, pembrolizumab is administered over a period of less than two hours. In some embodiments, pembrolizumab is administered over a period of 30-60 minutes. In some embodiments, pembrolizumab is administered over a period of about 45 minutes.
  • pembrolizumab mesylate is administered over a period of less than one hour. In some embodiments, pembrolizumab mesylate is administered over a period of about one hour. In some embodiments, pembrolizumab mesylate is administered over a period of about 1.5 hour. In some embodiments, pembrolizumab mesylate is administered over a period of about two hours. In some embodiments, pembrolizumab mesylate administered over a period of about the hours. In some embodiments, pembrolizumab mesylate is administered over a period of less than two hours. In some embodiments, pembrolizumab mesylate is administered over a period of 30-60 minutes. In some embodiments, pembrolizumab mesylate is administered over a period of about 45 minutes.
  • nivolumab is administered over a period of less than one hour. In some embodiments, nivolumab is administered over a period of about one hour. In some embodiments, nivolumab is administered over a period of about 1.5 hour. In some embodiments, nivolumab is administered over a period of about two hours. In some
  • nivolumab administered over a period of about the hours In some embodiments, nivolumab is administered over a period of less than two hours. In some embodiments, nivolumab is administered over a period of 30-60 minutes. In some embodiments, nivolumab is administered over a period of about 45 minutes.
  • nivolumab mesylate is administered over a period of less than one hour. In some embodiments, nivolumab mesylate is administered over a period of about one hour. In some embodiments, nivolumab mesylate is administered over a period of about 1.5 hour. In some embodiments, nivolumab mesylate is administered over a period of about two hours. In some embodiments, nivolumab mesylate administered over a period of about the hours. In some embodiments, nivolumab mesylate is administered over a period of less than two hours. In some embodiments, nivolumab mesylate is administered over a period of 30- 60 minutes. In some embodiments, nivolumab mesylate is administered over a period of about 45 minutes.
  • the immunotherapeutic agent is administered no more than once a week. In some embodiments, the immunotherapeutic agent is administered at least once a week. In some embodiments, the immunotherapeutic agent is administered once a week. In some embodiments, the immunotherapeutic agent is administered twice a month. In some embodiments, the immunotherapeutic agent is administered three times a month. In some embodiments, the immunotherapeutic agent is administered once a month. In some embodiments,
  • pembrolizumab is administered no more than once a week.
  • pembrolizumab is administered at least once a week. In some embodiments, pembrolizumab is administered at least once a week.
  • pembrolizumab is administered twice a month. In some embodiments, pembrolizumab is administered three times a month. In some embodiments, pembrolizumab is administered once a month. In some embodiments, pembrolizumab is administered in a 28 day cycle, once a week for 3 weeks.
  • the disease is a proliferative or a hyper-proliferative condition including, but not limited to cancer, hyperplasias, restenosis, inflammation, immune disorders, cardiac hypertrophy, atherosclerosis, fibrosis, pain, migraine, psoriasis, angiogenesis- related conditions or disorders, proliferation induced after medical conditions, including but not limited to surgery, angioplasty, or other conditions.
  • Angiogenesis-related conditions or disorders include, but are not limited to, cancers, diabetic retinopathy, proliferative retinopathy, corneal graft rejection, neovascular glaucoma, blindness and macular degeneration, erythema, psoriasis, hemophiliac joints, capillary proliferation within atherosclerotic plaques, keloids, wound granulation, vascular adhesions, rheumatoid arthritis, osteoarthritis, autoimmune diseases, Crohn's disease, restenosis, atherosclerosis, intestinal adhesions, cat scratch disease, ulcers, liver cirrhosis,
  • microangiopathy organ transplant rejection, glomerulopathy, diabetes, inflammation, and rodegenerative diseases.
  • the proliferative disease is cancer. In some embodiments, the proliferative disease is non-cancerous. In some embodiments, the proliferative disease is a benign or malignant tumor. Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer are mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, regardless of the location of the tumor and/or metastasis. In some embodiments, the methods include treating, inhibiting and preventing tumor growth.
  • the disease is cancer.
  • the cancer is selected from Acanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute megakaryoblastic leukemia, Acute monocytic leukemia, Acute myeloblastic leukemia with maturation, Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acute
  • Adenoma Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia, Aggressive K-cell leukemia, AIDS-Related Cancers, AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basal cell carcinoma, Basal - like carcinoma, B-cell leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt
  • Carcinoma in situ Carcinoma of the penis, Carcinoma of Unknown Primary Site,
  • Carcinosarcoma Castleman's Disease, Central Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma, Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma, Chronic
  • Lymphocytic Leukemia Chronic monocytic leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease,
  • Dermatofibrosarcoma protuberans Dermoid cyst, Desmoplastic small round cell tumor, Diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma, Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget's disease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma, Follicular lymphoma, Follicular
  • Malignant rhabdoid tumor Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma, Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplastic Disease,
  • Myelodysplastic Syndromes Myeloid leukemia, Myeloid sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer, Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Paget'
  • Somatostatinoma Soot wart, Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma, Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface epithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T- cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethral cancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner Morrison syndrome, Verrucous
  • the cancer is anal cancer, bowel cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder and biliary tract cancer, gastric cancer, gastrointestinal stromal tumor (gist), gastroesophageal junction cancer, intestinal cancer, liver cancer, neuroendocrine tumors, pancreatic cancer, peritoneal cancer, rectal cancer, small bowel cancer, stomach cancer, or a combination thereof.
  • the cancer is gastric cancer. In some embodiments, the cancer is gastroesophageal junction cancer. In some embodiments, the cancer is advanced gastric cancer. In some embodiments, the cancer is advanced gastroesophageal junction cancer. In some embodiments, the cancer is recurrent gastric cancer. In some embodiments, the cancer is recurrent gastroesophageal junction cancer. In some embodiments, the cancer is metastatic gastric cancer. In some embodiments, the cancer is metastatic gastroesophageal junction cancer.
  • the cancer comprises one or more lesions.
  • the lesion is measured before the treatment and either during the treatment or after the treatment or both. In some embodiments, the lesion is measured by radiological assessments using computerized tomography scan or magnetic resonance imaging. In some embodiments, the lesion has reduced in size after the treatment. In some embodiments, the lesion has reduced in size by at least 10%. In some embodiments, the lesion has reduced in size by at least 20%. In some embodiments, the lesion has reduced in size by at least 25%. In some embodiments, the lesion has reduced in size by at least 30%. In some embodiments, the lesion has reduced in size by at least 40%. In some embodiments, the lesion has reduced in size by at least 50%.
  • the lesion has reduced in size by at least 60%. In some embodiments, the lesion has reduced in size by at least 70%. In some embodiments, the lesion has reduced in size by at least 75%). In some embodiments, the lesion has reduced in size by at least 80%. In some embodiments, the lesion has reduced in size by at least 90%.
  • Described herein are methods for treating diseases where the methods comprise administering a combination of two or more therapies, in particular a combination comprising a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof and an immunotherapeutic agent or a pharmaceutically acceptable salt thereof.
  • the methods are a first line of therapy for treating diseases.
  • the methods are a second or a third line of therapy after the prior treatment for the disease has failed or substantially failed or the disease is substantially refractory to the first line therapy.
  • a patient has received at least one line of therapy for treating the disease prior to receiving the combination comprising a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof and an immunotherapeutic agent or a pharmaceutically acceptable salt thereof.
  • the prior line of therapy may be a line of chemotherapy or immunotherapy.
  • the methods further comprise administering one or more additional agents selected from the group consisting of anti -cancer agents, anti-proliferative agents, chemotherapeutic agents, immunomodulatory agents, anti -angiogenic agents, anti-inflammatory agents, alkylating agents, steroidal and non-steroidal anti-inflammatory agents, pain relievers, leukotriene
  • antagonists .beta.2-agonists, anticholinergic agents, hormonal agents, biological agents, immunotherapeutic agents, glucocorticoids, corticosteroid agents, antibacterial agents, antihistamines, anti-malarial agents, anti-viral agents, and antibiotics; and, optionally with radiation therapy.
  • the combination is administered for at least 2 months. In some embodiments, the combination is administered for about 2 months. In some embodiments, the combination is administered for about 3 months. In some embodiments, the combination is administered for about 4 months. In some embodiments, the combination is administered for about 5 months. In some embodiments, the combination is administered for about 6 months. In some embodiments, the combination is administered for about 7 months. In some embodiments, the combination is administered for about 8 months. In some embodiments, the combination is administered for about 9 months. In some embodiments, the combination is administered for about 10 months. In some embodiments, the combination is administered for about 11 months. In some embodiments, the combination is administered for about 12 months. In some embodiments, the combination is administered for more than 2 months.
  • cancer refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • the cancer may be multidrug resistant (MDR) or drug-sensitive.
  • MDR multidrug resistant
  • Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include breast cancer, prostate cancer, colon cancer, squamous cell cancer, small -cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, pancreatic cancer, cervical cancer, ovarian cancer, peritoneal cancer, liver cancer, e.g., hepatic carcinoma, bladder cancer, colorectal cancer, endometrial carcinoma, kidney cancer, and thyroid cancer.
  • cancers are basal cell carcinoma, biliary tract cancer; bone cancer; brain and CNS cancer; choriocarcinoma; connective tissue cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer; intra-epithelial neoplasm; larynx cancer; lymphoma including Hodgkin's and Non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; uterine cancer; cancer of the urinary system, as well as other carcinomas and sarcomas
  • the cancer is a hematological cancer.
  • the hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), Hodgkin lymphoma, Non-Hodgkin lymphoma, multiple myeloma, solitary myeloma, localized myeloma, and extramedullary myeloma.
  • the cancer is selected from chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell non-Hodgkin lymphoma, and large B-cell lymphoma.
  • the cancer is a cancer of the brain.
  • the cancer of the brain is selected from a glioma, medulloblastoma, primitive neuroectodermal tumor (PNET), acoustic neuroma, glioma, meningioma, pituitary adenoma, schwannoma, CNS lymphoma, primitive neuroectodermal tumor, craniopharyngioma, chordoma, medulloblastoma, cerebral neuroblastoma, central neurocytoma, pineocytoma, pineoblastoma, atypical teratoid rhabdoid tumor, chondrosarcoma, chondroma, choroid plexus carcinoma, choroid plexus papilloma, craniopharyngioma, dysembryoplastic neuroepithelial tumor, gangliocytoma, germinoma, he
  • PNET neuroectodermal tumor
  • the glioma is selected from ependymoma, astrocytoma, oligodendroglioma, and oligoastrocytoma. In an even further aspect, the glioma is selected from juvenile pilocytic astrocytoma, subependymal giant cell astrocytoma, ganglioglioma, subependymoma,
  • pleomorphic xanthoastrocytom anaplastic astrocytoma, glioblastoma multiforme, brain stem glioma, oligodendroglioma, ependymoma, oligoastrocytoma, cerebellar astrocytoma,
  • astrocytoma desmoplastic infantile astrocytoma, subependymal giant cell astrocytoma, diffuse astrocytoma, mixed glioma, optic glioma, gliomatosis cerebri, multifocal gliomatous tumor, multicentric glioblastoma multiforme tumor, paraganglioma, and ganglioglioma.
  • the cancer can be a cancer selected from cancers of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, kidney, lymphatic system, stomach, lung, pancreas, and skin.
  • the cancer is selected from prostate cancer, glioblastoma multiforme, endometrial cancer, breast cancer, and colon cancer.
  • the cancer is selected from a cancer of the breast, ovary, prostate, head, neck, and kidney.
  • the cancer is selected from cancers of the blood, brain, genitourinary tract, gastrointestinal tract, colon, rectum, breast, liver, kidney, lymphatic system, stomach, lung, pancreas, and skin.
  • the cancer is selected from a cancer of the lung and liver. In an even further aspect, the cancer is selected from a cancer of the breast, ovary, testes and prostate. In a still further aspect, the cancer is a cancer of the breast. In a yet further aspect, the cancer is a cancer of the ovary. In an even further aspect, the cancer is a cancer of the prostate. In a still further aspect, the cancer is a cancer of the testes.
  • the combination of the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof and the immunotherapeutic agent or a pharmaceutically acceptable salt thereof acts to produce synergistic therapeutic results.
  • the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof and the immunotherapeutic agent or a pharmaceutically acceptable salt thereof work together to produce a therapeutic effect greater than the sum of their individual effects.
  • the interaction of the tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof and the immunotherapeutic agent or a pharmaceutically acceptable salt thereof is such that the addition of one compound, results in less of the other compound being required, to achieve the same therapeutic effect.
  • administering results in the need for a smaller dose of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof, results in the need for a smaller dose of the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to pharmaceutical compositions comprising the compounds of the disclosure. That is, a pharmaceutical composition can be provided comprising a therapeutically effective amount of apatinib and a therapeutically effective amount of an immunotherapeutic agent and a pharmaceutically acceptable carrier.
  • the disclosed pharmaceutical compositions comprise the disclosed compounds (such as apatinib and am immunotherapeutic agent) (including
  • compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • a particularly preferred salt is mesylate.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc and the like salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline,
  • ⁇ , ⁇ -dibenzylethylenediamine diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • the compounds of the disclosure, or pharmaceutically acceptable salts thereof, of this disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the disclosure, and/or pharmaceutically acceptable salt(s) thereof can also be administered by controlled release means and/or delivery devices.
  • the compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this disclosure can include a pharmaceutically acceptable carrier, apatinib and an immunotherapeutic agent, or a
  • compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • compositions such as suspensions, elixirs and solutions
  • carriers such as starches, sugars,
  • microcrystalline cellulose diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this disclosure can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present disclosure comprise a compound of the disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • compositions of the present disclosure suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present disclosure suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present disclosure can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.
  • compositions can further comprise other ingredients
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. [00192] In one embodiment of the present disclosure, a composition of a combination therapy of the disclosure may be administered in a single dosage form comprising all the therapeutically active agents together.
  • the combination therapy of the present disclosure comprises more than two compositions contained in separate containers, and these at least two compositions may be administered separately, either simultaneously or sequentially.
  • kits comprising:
  • kits are for treating diseases.
  • kits comprising:
  • kits are for treating diseases.
  • kits comprising:
  • kits are for treating cancer.
  • kits comprising:
  • kits comprising:
  • kits comprising:
  • kits are for treating diseases.
  • kits comprising a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, present in an amount effective to enhance the efficacy of the immunotherapeutic agent to treat diseases.
  • kits comprising an immunotherapeutic agent, or a pharmaceutically acceptable salt thereof, present in an amount effective to enhance the efficacy of the tyrosine kinase inhibitor to treat diseases.
  • kits comprising:
  • kits are for treating diseases
  • packaged pharmaceutical therapies comprising:
  • a kit for treating cancer comprising
  • pembrolizumab for iv administration.
  • a kit for treating cancer comprising i) rivoceranib, or a pharmaceutically acceptable salt thereof, for once daily oral administration;
  • nivolumab for iv administration.
  • mice 40 female C57BL/6 mice purchased from Jackson Laboratories were enrolled on the study. Animals were housed for stabilization period. Animals were housed in individual HEPA ventilated cages (Innocage® IVC, Innovive USA). Fluorescent lighting was provided on a 12-hour cycle. Temperature and humidity was monitored and recorded daily and maintained to the maximum extent possible between 68-74 °F (20-23 °C) and 30-70% humidity, respectively. 2920X.10 18%) soy irradiated rodent feed (Harlan) and autoclaved acidified water (pH 2.5-3) was provided ad libitum.
  • HEPA ventilated cages Innocage® IVC, Innovive USA. Fluorescent lighting was provided on a 12-hour cycle. Temperature and humidity was monitored and recorded daily and maintained to the maximum extent possible between 68-74 °F (20-23 °C) and 30-70% humidity, respectively. 2920X.10 18%) soy irradiated rodent feed (Harlan) and autoclaved
  • LL/2 cell viability was at 98%>.
  • Cryo vials containing LL/2 cells were thawed and prepared for injection into mice.
  • On study day -3 cells were washed in PBS, counted, and re-suspended in cold PBS at concentrations of 250,000 viable cells/100 ⁇ ⁇ .
  • Cell suspensions were mixed with PBS and kept on ice during transport to the vivarium.
  • Cells for injections were prepared by withdrawing the PBS-cell mixture into a chilled 1 mL Lure-lok syringe fitted with a 26 7/8 G (0.5 mm X 22 mm) needle. Animals were shaved prior to injection. One mouse at a time was immobilized and the site of injection was disinfected with an alcohol swab. 100 ⁇ L of the cell suspension was injected subcutaneously into the rear flank.
  • mice Forty mice were enrolled in the study. Ten mice were randomly allocated to each of 4 different study groups: vehicle control, anti-muPD-1 antibody, apatinib mesylate, and apatinib + anti-muPD-1 combination. Randomization was performed in the Study Log software on day 1 when the mean tumor volume was between 73-80 mm 3 . 300 mg/kg of apatinib mesylate formulated by mixing with 0.5% carboxymethylcellulose solution was dosed daily (q.d.) and orally (p.o.), while 10 mg/kg of anti-muPD-1 antibody (RMP1-14) solution was dosed 2 times a week (b.i.w.) and intraperitoneally (i.p).
  • Body weight was measured at least three times a week. All measurements were performed prior to dosing of test articles on day of measurement during the treatment period. If body weight loss of >15% was observed, animal was given a dosing holiday until weight loss was ⁇ 10%. If body weight loss of >20% was observed, animal was sacrificed for humane reasons as per IACUC protocol regulations.
  • Anti-muPD-1 (10 mg/kg) 22 % ⁇ 0.05
  • Apatinib (300 mg/kg) 37 % ⁇ 0.0001
  • Objectives Primary objectives are to evaluate safety & tolerability, efficacy by objective response rate, best overall response, time to response, duration of response, disease control rate, and duration of disease control. Secondary objectives are to evaluate efficacy as measured by overall survival, progression-free survival and event-free survival.
  • Eligible patients have advanced unresectable or metastatic disease, with documented primary diagnosis of solid tumor cancer inclusive of gastric adenocarcinoma, renal cell carcinoma, melanoma, non-small cell lung cancer, and breast or other solid tumor for which anti-VEGFR-2 targeted therapy could be applicable. Patients will have received at least three prior doses of nivolumab treatment and are continuing nivolumab therapy.
  • Rivoceranib 685 mg was studied as a single agent in patients with advanced gastric cancer in Phase 2 and Phase 3 studies and demonstrated efficacy against gastric cancer with manageable toxicity, establishing once daily rivoceranib 685 mg as the recommended dose for gastric cancer.
  • a Phase 3 study is ongoing, using a starting dose of 700 mg rivoceranib. 400 mg was selected as the starting dose.
  • Nivolumab (240 mg, administered once every 2 weeks) forms the primary treatment, supplemented with varying amounts of rivoceranib. The combined use of rivoceranib and nivolumab enhances the antitumor activity of both agents for improved progression -free and overall survival.
  • Study Duration The total duration of the study will be approximately 12 months: 6 months of recruitment plus 6 months of treatment.
  • Dose escalation (Phase I): A sequential evaluation of 3 subjects at each dose level is performed with escalating doses of rivoceranib, starting at 400 mg, escalating up to 700 mg, in combination with nivolumab 240 mg administered IV every 2 weeks, to determine the maximum tolerated dose, as described in Table 4.
  • Expansion (Phase II): Up to 20 patients (with unresectable and metastatic cancer, including subjects with Angiosarcoma, Leiomyosarcoma, and Synovial Sarcoma, and Alveolar Soft Part Sarcoma) begin treatment at the maximum tolerated dose determined in Phase I, in combination with nivolumab 240 mg, administered IV once every 2 weeks.
  • results 300 mg rivoceranib was determined as RP2D for Part 2. 5/13 patients had G2/3 hypertension. Common treatment-related AEs were hypertension, hand and foot syndrome, and nausea and immune-related AEs were hypothyroidism and diarrhea. Notably, in 10 evaluable patients, 3 patients had PD and 4 patients showed tumor shrinkage (5-29%). A patient with Malignant Spindled/Epitheloid Sarcoma, who had PD during previous nivolumab treatment has shown tumor reduction, so far, of 9%. A patient with Gastric Cancer, who had stable disease (a 4% increase) after 2 months of nivolumab showed a reduction of 29%, 2 months after introduction of rivoceranib.
  • Phase I objectives are to determine the recommended phase II dose and establish the toxicity profile of the pembrolizumab - rivoceranib combination.
  • Phase II objectives are to determine the efficacy of the combination, in terms of
  • Phase 1 for a 3+3 dose escalation design with up to 5 escalation dose levels (and 1 de- escalation level) involving 4 - 30 patients.
  • Phase 2 up to 89 patients will be recruited in three cohorts, 25 in the urothelial cohort, 38 in the MSI-H cohort, and 26 in the gastric & GEJ cohort. Eligible patients will have one of the following advanced solid malignancies, which qualifies for standard of care pembrolizumab treatment:
  • pembrolizumab (200 mg, administered once every 3 weeks) forms the primary treatment, supplemented with varying amounts of rivoceranib.
  • the combined use of rivoceranib and pembrolizumab enhances the antitumor activity of both agents for improved progression-free and overall survival.
  • Study Duration The total duration of the study will be up to 6 years. The estimated duration of accrual is 6 months for Phase 1 and 28 months for Phase 2. The study plans for 1 year for enrollment in Phase 1 and first part of Phase 2, 2 years of enrollment for second part of Phase 2 and up to 3 more years of active treatment.
  • Dose escalation Phase I assesses the safety of combining up to 5 increasing dose levels of rivoceranib, administered orally, with a fixed dose of pembrolizumab (200 mg) administered intravenously every three weeks (see Table 5) and will determine the recommended phase II dose.
  • the starting dose is 300 mg oral rivoceranib daily, escalating to 400 mg, 500 mg, 600 mg and 700 mg, or deescalating to 200 mg.
  • a standard 3+3 dose escalation design is used, with a minimum of 3 (and up to 6) evaluable subjects recruited to each dose level (starting with dose level 1).
  • Dose Level 5 700 mg QD PO [00236] The study follows a 3 + 3 dose-escalation scheme until maximum tolerated dose is established; dose escalation, dose de-escalation, or dose level expansion proceeds based on the occurrence of DLTs at each dose level
  • the recommended phase II dose is determined from the 3+3 algorithm or when six patients have been treated at the maximum dose with one or no dose limiting toxicities observed.
  • Phase II assesses the efficacy of the recommended phase II dose of rivoceranib in combination with pembrolizumab and provides additional safety and tolerability data in the three disease-specific cohorts.
  • Rivoceranib is administered as the mesylate salt of its free base.
  • This example refers to the rivoceranib dose strength as the amount of rivoceranib freebase rather than of amount of the rivoceranib mesylate salt.
  • the freebase dosage is approximately 81% of the mesylate dosage with identical formulation. Referring to rivoceranib's dose strength as the freebase aligns with standards for referencing total active product.
  • Rivoceranib is provided as film-coated oral tablets in 200 mg and 100 mg strength (248 mg and 124 mg of rivoceranib mesylate). Components used in the manufacture of the product are listed in Table 6 below. The tablets are packaged in PVDC, heat-sealed foil-laminated blister packs. Table 6.

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WO2021237022A1 (en) * 2020-05-21 2021-11-25 The Regents Of The University Of California Compositions and methods for treating breast cancer
CN111558044A (zh) * 2020-06-01 2020-08-21 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 一种包含舒尼替尼的药物组合物及其制剂和应用

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