Ramucirumab for treatment of cancers in pediatric patients

Abstract

To provide the use of ramucirumab for the treatment of pediatric cancers.SOLUTION: A method of treating cancer in a human patient comprises administering a therapeutically effective amount of ramucirumab to the human patient in need thereof, wherein the human patient has been diagnosed with one of the following cancers: osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, Wilms' tumor, hepatoblastoma, carcinoma NOS, synovial sarcoma, or desmoplastic small round cell tumor. The human patient must be at least 12 months and at most 21 years of age.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of cancer therapy. More specifically, the present invention relates to the treatment of cancer in pediatric patients. Regarding the use of ramucirumab for the treatment of

[0002] Pediatric patients with solid tumors have a poor prognosis if they present with metastatic or recurrent disease Bevacizumab has been studied in pediatric tumors (Gururan gan S,Fangusaro J,Poussaint TY,et al:Eff icacy of bevacizumab plus irinotecan in children with recurrent low-grade glioma s--a Pediatric Brain Tumor Consortium st udy, Neuro Oncol 16:310-7, 2014), ramucirumab is In addition to their specificity, potency, and potential for combination with other therapeutic agents, they also possess different mechanisms of action. This may provide an effective alternative for the patient.

[0003] As used herein, "about" means a deviation of up to or more than 10% from a given value. As a non-limiting example, when used in reference to weight, "about 100 mg" means 90 mg ( The range is from 100mg (inclusive) to 110mg (inclusive).

[0004] As used herein, the term "human VEGFR-2" refers to the amino acid sequence of SEQ ID NO:5. VEGFR-2 is a human vascular endothelial growth factor receptor 2 (VEGFR-2) with a nucleotide sequence. also known as FLK1, and kinase insert domain (KDR).

[0005] As used herein, the term "human VEGF-D" refers to the amino acid sequence of SEQ ID NO: 6. This refers to human vascular endothelial growth factor-D having the sequence

[0006] Ramucirumab is a human immunoglobulin G (IgE) antibody directed against human vascular endothelial growth factor receptor 2 (VEGFR-2). Ramucirumab and its use are Ramucirumab is a fluoropyrimidine or platinum-based For the treatment of advanced gastric or gastroesophageal junction adenocarcinoma with disease progression after the date of chemotherapy containing chemotherapy Platinum-based chemotherapy, either as a single agent or in combination with paclitaxel, is also used. in combination with docetaxel for the treatment of metastatic non-small cell lung cancer with subsequent disease progression and bevacizumab, oxaliplatin, and fluoropyrimidine therapy. FOLFIRI (Irinotecan) for the treatment of metastatic colorectal cancer with disease progression after the date of enactment In combination with cefotaxime, cefotaxime, folinic acid, and 5-fluorouracil, Approved by the Drug Administration.

[0007] A non-limiting example of ramucirumab is CYRAMZA®, CAS Registry Number Ramucirumab has a light chain with each of the amino acids of SEQ ID NO: 3. two light chains having the sequence SEQ ID NO: 4 and two heavy chains, each of the heavy chains having the amino acid sequence SEQ ID NO: 4 The light chain variable region of ramucirumab is represented by SEQ ID NO: The heavy chain variable region of ramucirumab is shown in SEQ ID NO: 2. be.

[0008] As used herein, the terms "treating," "treat," or "treatment" The term "prevents, slows, or attenuates the progression or severity of an existing symptom, disorder, condition, or disease." refers to the reduction, reduction, or reversal of, or the amelioration of, the clinical symptoms of a condition. The desired or anticipated clinical outcome may include the progression of a disease or disorder, whether detectable or undetectable. Mitigation of harm (i.e., if the disease or disorder is not getting worse), progression of the disease or disorder delay or slowing of the progression of a disease or disorder, remission or alleviation of a disease or disorder, and remission of a disease or disorder (part Treatment includes, but is not limited to, It also means prolonging survival compared with the expected survival if the patient does not receive treatment. Those in need of treatment include those who already have the disease. In some embodiments, the present invention can be used as a medicine.

[0009] As used herein, the term "cancer" refers to a cancer caused by a disease typically caused by uncontrolled cell growth. Refers to or describes a physiological condition in mammals characterized by: and malignant cancers.

[0010] In the methods of the invention, a therapeutically effective amount of an anti-VEGFR-2 antibody described herein is administered to In addition, the pharmaceutical compositions of the present invention are administered in a therapeutically effective amount to a mammal or patient in need thereof. The anti-VEGFR-2 antibody may comprise an anti-VEGFR-2 antibody described herein.

[0011] A "therapeutically effective amount" is a dose, at a time, necessary to achieve a desired therapeutic result. A therapeutically effective amount refers to an amount that is obtainable by use of known techniques and under similar circumstances. The results can be readily determined by the attending diagnostician, such as one skilled in the art, by observing the results obtained. In determining a therapeutically effective amount for a patient, factors such as, but not limited to, the patient's species, its size, age, and overall health; the specific disease or disorder involved; the target site; The degree of severity of the disorder, the response of the individual patient, the specific compound administered, the mode of administration, the dosage of the administered compound, The bioavailability characteristics of the formulation being used, the chosen dosage regimen, the use of concomitant medications, and other medications being administered Many factors will be considered by the attending diagnostician, including the nature of the condition, as well as other relevant circumstances. An effective amount also means that any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects. It is also a quantity.

[0012] Generally, dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). In some embodiments, the dose for a pediatric patient may be adjusted to about 6 mg / kg to about 1 6mg / kg, or about 6mg / kg to about 12mg / kg, or about 6mg / kg to About 10 mg / kg, or about 6 mg / kg to about 8 mg / kg, or about 8 mg / kg ~ about 16 mg / kg, or about 8 mg / kg ~ about 12 mg / kg, or about 8 mg / kg to about 10 mg / kg, or about 10 mg / kg to about 16 mg / kg, or about 1 The dose is 0 mg / kg to about 12 mg / kg or about 12 mg / kg to about 16 mg / kg. In some embodiments, doses for pediatric patients are 6 mg / kg, 8 mg / kg, 10 mg / kg, In some embodiments, the dose is 1 mg / kg, 12 mg / kg, or 16 mg / kg. The doses are administered intravenously over 60 minutes every two weeks.

[0013] In some cases, dosing levels below the lower limit of ramucirumab dosing mentioned above may be more than sufficient. In other cases, larger doses may be used with acceptable side effects. Therefore, the dosages set forth above are not intended to limit the scope of the present invention in any way. There is no.

[0014] In the present invention, in order to administer the anti-VEGFR-2 antibodies described herein, any Any suitable method or route may be used, although intravenous (iv) administration is the preferred route. However, the present invention is not limited to any particular method or route of administration. It must be emphasized that this is not a

[0015] Anti-human VEGFR-2 antibodies, including but not limited to ramucirumab, are administered to patients for therapeutic purposes. When used, it is preferably formulated as a pharmaceutical composition. and processes for preparing same are well known in the art. ington:The Science and Practice of Pharm acy (Gennaro A., et al., eds., 19 th ed., Mack Publishing Co., 1995).

[0016] Unless otherwise specified, the term "antibody" refers to antibodies that are inter-connected by disulfide bonds. It refers to an immunoglobulin molecule containing two heavy chains (HC) and two light chains (LC) separated by a single chain. The amino-terminal portion of the chain recognizes antigens via the complementarity-determining regions (CDRs) contained therein. The variable region of each chain consists of approximately 100 to 110 amino acids, which are primarily responsible for The portion defines the constant region primarily responsible for effector function.

[0017] As used herein, the term "light chain variable region" or "LCVR" refers to the CDRs and the amino acid sequence of the framework region (FR).

[0018] As used herein, the term "heavy chain variable region" or "HCVR" refers to the CDRs and It refers to a portion of the heavy chain of an antibody molecule that contains the amino acid sequence of the FR.

[0019] The antibodies described herein can be readily produced in mammalian cells, including, but not limited to, Suitable examples include CHO, NS0, HEK293 or COS cells. , are cultured using techniques well known in the art. Cells were transfected at the optimal predetermined HC:LC vector ratio, or HC (heavy chain) and LC (light chain) ratio. A single vector system encoding both can be used to produce transient or secreted antibodies in an expression system. The polynucleotide sequence of interest (e.g., For example, a vector containing a polynucleotide encoding an antibody polypeptide and an expression control sequence. The vector can be introduced into the host cell by well-known methods, which may vary depending on the type of cellular host. The chemically defined medium into which the antibody is secreted can be prepared using any of a number of commonly used techniques. Various methods of protein purification can be used, such as Methods are known in the art, see, for example, Deutscher, Method s in Enzymology 182:83-89(1990), and Scope s,Protein Purification:Principles and Pr Actice, 3rd Edition, Springer, NY (1994) In some instances, the medium is conveniently loaded onto a column equilibrated with a compatible buffer. The column may be washed to remove non-specifically bound components. The antibody can be eluted, for example, by a pH gradient. The antibody fraction can be analyzed by UV absorbance or SD These may be detected by S-PAGE or the like and then pooled. Therefore, further purification is optional. Antibodies can be concentrated and / or purified using common techniques. Soluble aggregates and multimers can be isolated by size exclusion, hydrophobic interactions, immunoprecipitation, and other methods. General chromatography, including ion-exchange, multimodal, or hydroxyapatite chromatography Antibodies after these chromatography steps can be effectively removed by conventional techniques. The purity of is typically greater than 95%. The product may be immediately frozen at -70°C. Alternatively, it may be freeze-dried.

[0020] The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. The present invention provides a method for treating cancer in a human patient, the method comprising administering to the patient a therapeutically effective amount of ... Cystoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS carcinoma, synovial sarcoma, or desmoplastic small intestine He has been diagnosed with one of the round cell tumors.

[0021] The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. The present invention provides a method for treating cancer in a human patient, the method comprising administering to the patient a therapeutically effective amount of ... Cystoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS carcinoma, synovial sarcoma, or desmoplastic small intestine The human patient must be at least 12 months of age and have been diagnosed with one of the following: However, they are under 21 years old.

[0022] The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. and a method for treating cancer in a human patient, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, ... The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. The present invention provides a method of treating cancer in a human patient, the method comprising: The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. and a method for treating cancer in a human patient, the method comprising: The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. and a method for treating cancer in a human patient, the method comprising administering to the human patient a therapeutically effective amount of ... The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a human patient in need thereof. and a method for treating cancer in a human patient, the method comprising administering to the human patient .... The present disclosure provides a therapeutically effective amount of ramucirumab to a patient in need thereof. and a method of treating cancer in a human patient, the method comprising administering to the human patient a The present disclosure provides a therapeutically effective amount of ramucirumab to a patient in need thereof. and a method for treating cancer in a human patient, the method comprising administering to the human patient a compound ... The present disclosure provides a method for administering a therapeutically effective amount of ramucirumab to a patient in need thereof. and a method for treating cancer in a human patient, the method comprising administering to the human patient a compound ... The patient has been diagnosed with synovial sarcoma. The present disclosure provides a therapeutically effective amount of ramucirumab, and (c) administering to a human patient in need thereof a compound selected from the group consisting of benzodiazepines, ... , a human patient is diagnosed with desmoplastic small round cell tumor.

[0023] In some instances, ramucirumab is administered at a dose of about 6 mg / kg to about 16 mg / kg every 2 weeks. In some cases, ramucirumab is administered intravenously at doses ranging from 6 mg / kg to 16 mg / kg. It is administered intravenously at a dose of 100 mg / kg every 2 weeks. In some instances, ramucirumab is It is administered intravenously every two weeks at a dose of about 8 mg / kg to about 12 mg / kg. In this example, ramucirumab is administered intravenously at a dose of 8 mg / kg to 12 mg / kg every 2 weeks. In some instances, ramucirumab is administered intravenously at a dose of approximately 6 mg / kg every 2 weeks. In some instances, ramucirumab is administered intravenously at a dose of approximately 8 mg / kg every 2 weeks. In some instances, ramucirumab is administered intravenously at a dose of about 10 mg / kg. It is administered intravenously every two weeks. In some instances, ramucirumab is administered at a dose of about 12 mg / kg It is administered intravenously every two weeks at a dose of approximately 16 mg / kg. It is administered intravenously at a dose of g / kg every 2 weeks.

[0024] The present disclosure relates to the treatment of osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS For use in treating human patients with carcinoma, synovial sarcoma, or desmoplastic small round cell tumor The present disclosure provides ramucirumab for the treatment of osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, and ulcerative colitis. Having Films tumor, hepatoblastoma, NOS carcinoma, synovial sarcoma, or desmoplastic small round cell tumor The present invention provides ramucirumab for use in treating a human patient, the human patient being at least one month old. 12 months old but under 21 years old.

[0025] The present disclosure provides ramucirumab for use in treating human patients with osteosarcoma. The present disclosure provides ramucirumab for use in treating human patients with sarcoma. The present disclosure provides ramucirumab for use in treating human patients with pheochromocytoma. The present disclosure provides a method for treating a human patient with paraganglioma, comprising administering to the patient a ramucil agonist. The present disclosure provides mabs for use in treating human patients with Wilms tumor. The present disclosure provides ramucirumab for use in treating human patients with hepatoblastoma. The present disclosure provides ramucirumab for use in treating human patients with NOS cancers. The present disclosure provides ramucirumab for the treatment of human patients with synovial sarcoma. The present disclosure provides ramucirumab for use in treating patients with desmoplastic small round cell tumors. The present invention provides ramucirumab for use in the treatment of rheumatoid arthritis patients.

[0026] The present disclosure relates to the treatment of osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS For use in treating human patients with carcinoma, synovial sarcoma, or desmoplastic small round cell tumor The present disclosure provides a pharmaceutical composition comprising ramucirumab for the treatment of osteosarcoma, sarcoma, and pheochromocytoma. , paraganglioma, Wilms' tumor, hepatoblastoma, NOS carcinoma, synovial sarcoma, or desmoplastic small round tumor A pharmaceutical composition comprising ramucirumab for use in treating human patients with cell tumors. Provided, the human patient is at least 12 months of age but no older than 21 years of age.

[0027] The present disclosure provides a pharmaceutical composition comprising ramucirumab for use in treating human patients with osteosarcoma. The present disclosure provides pharmaceutical compositions for use in treating human patients with sarcoma. The present disclosure provides pharmaceutical compositions comprising sirumab for the treatment of human patients with pheochromocytoma. The present disclosure provides a pharmaceutical composition comprising ramucirumab for use in treating paraganglioma. and a pharmaceutical composition comprising ramucirumab for use in treating a human patient with The present disclosure provides a method for treating a ramucirumab tumor in a human patient with Wilms tumor. The present disclosure provides pharmaceutical compositions containing the antibody. The present disclosure provides a pharmaceutical composition comprising ramucirumab for the treatment of NOS cancer in humans. A pharmaceutical composition comprising ramucirumab for use in treating a patient is provided. COMPOSITION COMPRISING RAMUCIRMAB FOR USE IN THE TREATMENT OF HUMAN PATIENTS WITH SYNOVIAL SARCOMA - Patent application The present disclosure provides a method for treating a human patient with desmoplastic small round cell tumor. The present invention provides a pharmaceutical composition comprising ramucirumab for use in the treatment of rheumatoid arthritis.

[0028] The inclusion criteria for the study were as follows: Patients were aged 12 months or older at the time of study enrollment. Patients must be 21 years of age or younger. Patients must have recurrent or refractory non-CNS solid tumors. Patients had elevated serum tumor markers, including alpha-fetoprotein or beta-HCG. Histologic confirmation of malignancy at time of initial diagnosis or recurrence, except in patients with extracranial germ cell tumors Part A patients must not have CNS metastases. Relapsed or refractory Patients with CNS tumors were eligible, and patients with intrinsic brainstem tumors, visual pathway gliomas, or CN S germ cell tumors and CSF containing alpha-fetoprotein or beta-HCG malignancy at the time of initial diagnosis or recurrence, except in patients with elevated serum tumor markers. Histological confirmation is required. The patient's current medical condition is not related to known definitive therapy or to a treatment that cannot be tolerated. There is no proven therapy that extends survival with a satisfactory quality of life. Performance level: Karnofsky score ≥ 50% for patients over 16 years of age, and If the patient is under 6 years of age, the Lansky score must be 50 or greater. Neurological impairment in patients with CNS tumors is Must be relatively stable for at least 7 days prior to enrollment. Paralysis preventing walking However, patients awake in a wheelchair are considered ambulatory for the purposes of assessing performance scores. Patients must have fully recovered from the acute toxic effects of all previous anticancer therapy. and: a. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (previously 42 days for nitrosoureas; b. Hematopoietic growth factors: long-acting growth factors (e.g., At least 14 days after the last dose of Neulasta or short-acting growth factors For drugs where adverse events are known to occur beyond 7 days after administration, this The period should extend beyond the period during which adverse events are known to occur. The interval period should be discussed with the study representative; c. Biologics (anti-tumor agents): Biologics At least 7 days after the last dose of the drug. There are no known adverse events occurring more than 7 days after administration. For drugs with known adverse events, this period should exceed the period during which the adverse event is known to occur. The duration of this interval should be discussed with the study principal; d. Immunotherapy: At least 42 days after completion of any type of immunotherapy, e.g., tumor vaccine; e.g., monoclonal Monoclonal antibodies: At least three antibody half-lives after the last dose of monoclonal antibodies. See the table on the DVL homepage listing half-lives of monoclonal antibodies. : At least 14 days after local palliative XRT (small port). Previous TBI, craniospinal XRT If you have received 1500 T or more than 50% of your pelvis, If other significant doses of BM irradiation have been administered, at least 42 days have elapsed. g. Stem cell infusion without TBI: evidence of active graft-versus-host disease h. Patients must not have had a previous steroid therapy and at least 84 days have passed since transplantation or stem cell infusion; Patients must have had no prior exposure to ramucirumab. Patients must have adequate bone marrow function, adequate renal function, Adequate liver function, adequate cardiac function, adequate blood pressure control, adequate coagulation, and informed consent are required. providing a consent.

[0029] Exclusion criteria for the study were: pregnant or lactating women, those with a risk of developing a human fetus or teratogenic Unable to enroll in this study as information on sexual toxicity is not yet available; Lloyd, investigational drugs, anti-cancer drugs, anti-GVHD drugs after transplantation, anti-inflammatory drugs, antiplatelet drugs, antihypertensive drugs, Taking concomitant medications including anticoagulants (e.g., heparin), belimumab, and bisphosphonate derivatives Patients who have undergone or are scheduled to undergo the following invasive procedures: Eligible patients: those with evidence of active bleeding, known or known esophageal varices in the past 3 months Patients with a history of stroke, transient ischemic attack (TIA) or cerebrovascular accident within 6 months prior to study enrollment Patients with a history of CNS arterial / venous thromboembolic events, including stroke (CVA), were ineligible; Patients with a history of deep vein thrombosis (including pulmonary embolism) within 3 months prior to study enrollment were excluded. patients with a history of hemoptysis or other signs of pulmonary hemorrhage within 3 months prior to study enrollment were excluded. A history of bleeding disorder of grade 3 or higher, vasculitis, or Patients with severe (grade 3 or greater) attacks from gastrointestinal bleeding were excluded; Petechial foci larger than the size of a puncta on baseline MRI obtained within 14 days prior to the recording and / or >3 evidence of CNS tumor or new CNS hemorrhage are eligible (For patients with CNS tumors, ECHO gradients according to institutional guidelines are used.) MRI sequence required); New York Heart Association Heart disease according to the definition of, e.g., myocardial infarction, severe or unstable angina, peripheral vascular disease , or patients with a known history of congestive heart failure or peripheral vascular disease were ineligible; History of fistula, gastrointestinal ulcer or perforation, or intra-abdominal abscess within 3 months prior to study enrollment Patients with hypertensive crisis or hypertensive encephalopathy within 6 months prior to study enrollment were excluded. Patients with a history of the disease were not eligible; those with non-healing wounds, unhealed or incomplete wounds at the time of enrollment Patients with fully healed or compound (open) fractures were not eligible; Immunocompromised patients, including those known to have patients with uncontrolled infections are not eligible. patients with prior solid organ transplantation are not eligible; in the opinion of the investigator, Patients who may not be able to comply with safety monitoring requirements are excluded.

[0030] Eligible patients will receive a 42-day treatment cycle, which will include Musilumab was administered intravenously over 60 minutes on days 1, 15, and 29, and on day 42, the disease was treated. If the patient's disease is at least stable and the eligibility criteria are met, If ramucirumab is administered, the cycle may be repeated every 42 days. is about 6 mg / kg to about 16 mg / kg.

[0031] Diphenhydramine (1 mg / kg, maximum dose 50 mg) (or alternative antihistamine) Administer this drug to patients within 30-60 minutes before each infusion of ramucirumab. Anaphylactic precautions should be observed during administration. Grade 2 or higher infusion reactions occur. If this occurs, discontinue the infusion and administer supportive care according to institutional guidelines.

[0032] Patients treated with ramucirumab may have any of the following childhood cancers: Osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS cancer (specified separately) in the treatment of human patients with synovial sarcoma, desmoplastic small round cell tumors, or Ramucirumab for use in

[0033] As of April 5, 2018, 16 patents have been registered, with one registered in DL1. The patient was ineligible due to the use of prohibited medications (NSAIDS). 3), other sarcomas (6), pheochromocytoma / paraganglioma (2), Wilms' tumor (1), hepatoblastoma The study included patients diagnosed with rheumatoid arthritis (1), and carcinoma (2). Of the 6 patients receiving the 8 mg / kg dose, One patient had dose-limiting proteinuria (grade 2), and 3 of 5 patients had 50 μg / ml or more C minss Initially, six patients were enrolled on the 12 mg / kg dose. One of the six patients experienced dose-limiting toxicity (DLT), but PK could not be evaluated. Only four patients were enrolled. Two more patients were enrolled. Overall, In the administered patients, DLT (proteinuria, grade 2) was observed in 1 of 8 patients, and DLT in 6 patients Six patients achieved a target concentration of 50 μg / ml or higher. minss DLT was observed. None of the patients completed PK sampling. Enrollment will continue for the 1 kg dose. The median (range) duration of protocol therapy is 1 (1–10) days. 8) Cycle(s) were included. No patient experienced DLT after C1, and no subsequent subcutaneous injections were included. The toxicity profile of Ikuru was similar to that of adults. Response Evaluation Criteria (RECIST) is ongoing. be.

[0034] To date, ramucirumab has been well tolerated with a toxicity profile consistent with class effect. No subjects experienced grade 3 or higher adverse events. Proteinuria (grade 2) occurred at DL1 and DL2, but the MTD was not reached. Toxicity and target trough drug concentrations were used as endpoints for the randomized controlled trial. Sirumab 12 mg / kg IV was identified as the dose for PK expansion. After establishing RP2D in solid tumors, The safety, tolerability, and response of rituximab to children and adolescents with recurrent or refractory brain tumors will be evaluated. Evaluate based on the criteria.

[0035] Sequence Listing SEQ ID NO: 1 (anti-human VEGFR-2 antibody, LCVR) (artificial sequence) DIQMTQSPSSVSASIGDRVTITCRASQGIDNWLGWYQQKP GKAPKLLIYDASNLDTGVPSRFSGSGSGTYFTLTISSLQA EDFAVYFCQQAKAFPPTFGGGTKVDIK

[0036] SEQ ID NO: 2 (anti-human VEGFR-2 antibody, HCVR) (artificial sequence) EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQA PGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARVTDAFDIWGQGTMVTVSS

[0037] SEQ ID NO: 3 (anti-human VEGFR-2 antibody, LC) (artificial sequence) DIQMTQSPSSVSASIGDRVTITCRASQGIDNWLGWYQQKP GKAPKLLIYDASNLDTGVPSRFSGSGSGTYFTLTISSLQA EDFAVYFCQQAKAFPPTFGGGTKVDIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQ ESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC

[0038] SEQ ID NO: 4 (anti-human VEGFR-2 antibody, HC) (artificial sequence) EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQA PGKGLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARVTDAFDIWGQGTMVTVSSASTK GPSVLPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAPIEKTISKAKGQPREPQVYTLPSREEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK

[0039] SEQ ID NO: 5 (Human VEGFR-2) (Homo sapiens) MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDI LTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECS DGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQD YRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVS LCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFC EAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGE KLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQ SGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNST FVRVHEKPFVAFGGSGMESLVEATVGERVRIPAKYLGYPPP EIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVIL TNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTT QTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPY PCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQ AANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQ PTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPT PVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDY VCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSI GESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNR NLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEK TNLEIIILVGTAVIAMFFWLLLVIILRTVKRANGGELKTG YLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPL GRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHR ALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCK FGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLK RRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFL TLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKN VVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDR VYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLK EGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHL GNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVS CMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFE DIPLEEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLSP SFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYS SEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV

Claims

1. A method of treating cancer in a human patient comprising administering a therapeutically effective amount of ramucirumab to a subject in need thereof. and administering to said human patient in need thereof, said human patient being diagnosed with osteosarcoma, sarcoma, pheochromocytoma, tumor, paraganglioma, Wilms' tumor, hepatoblastoma, NOS carcinoma, synovial sarcoma, or desmoplastic angioplasty The patient has been diagnosed with one of the following tumor types:

2. 2. The method of claim 1, wherein the human patient is at least 12 months of age but not more than 21 years of age. The method described.

3. 3. The method of claim 1 or 2, wherein the cancer is osteosarcoma.

4. 3. The method of claim 1 or 2, wherein the cancer is a sarcoma.

5. 3. The method of claim 1 or 2, wherein the cancer is pheochromocytoma.

6. 3. The method of claim 1 or 2, wherein the cancer is paraganglioma.

7. 3. The method of claim 1 or 2, wherein the cancer is Wilms' tumor.

8. 3. The method of claim 1 or 2, wherein the cancer is hepatoblastoma.

9. 3. The method of claim 1, wherein the cancer is a NOS cancer.

10. 3. The method of claim 1 or 2, wherein the cancer is synovial sarcoma.

11. 3. The method of claim 1, wherein the cancer is desmoplastic small round cell tumor. method.

12. Ramucirumab is administered intravenously at a dose of about 6 mg / kg to about 16 mg / kg every two weeks. The method according to any one of claims 1 to 11,

13. Ramucirumab is administered intravenously at a dose of 6 mg / kg to 16 mg / kg every 2 weeks. The method according to any one of claims 1 to 11.

14. Ramucirumab is administered intravenously at a dose of about 8 mg / kg to about 12 mg / kg every two weeks. The method according to any one of claims 1 to 11,

15. Ramucirumab is administered intravenously at a dose of 8 mg / kg to 12 mg / kg every 2 weeks. The method according to any one of claims 1 to 11.

16. 2. The method of claim 1, wherein ramucirumab is administered intravenously at a dose of about 6 mg / kg every two weeks.

12. The method according to any one of claims 11 to 11.

17. 2. The method of claim 1, wherein ramucirumab is administered intravenously at a dose of about 8 mg / kg every two weeks.

12. The method according to any one of claims 11 to 11.

18. 1, wherein ramucirumab is administered intravenously at a dose of about 10 mg / kg every two weeks.

12. The method according to any one of claims 1 to 11.

19. 1, wherein ramucirumab is administered intravenously at a dose of about 12 mg / kg every two weeks.

12. The method according to any one of claims 1 to 11.

20. 1, wherein ramucirumab is administered intravenously at a dose of about 16 mg / kg every two weeks.

12. The method according to any one of claims 1 to 11.

21. Osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS cancer, synovial sarcoma 20060236333 200602352 ... For use in the treatment of human patients with desmoplastic small round cell tumors, Silumab.

22. 21. The human patient is at least 12 months of age but not older than 21 years of age. The use described in.

23. 23. The use according to any one of claims 21 or 22, wherein the cancer is osteosarcoma.

24. 23. The use according to any one of claims 21 or 22, wherein the cancer is a sarcoma.

25. 23. The use according to any one of claims 21 or 22, wherein the cancer is pheochromocytoma.

26. 23. The use according to any one of claims 21 or 22, wherein the cancer is paraganglioma.

27. 23. The use according to any one of claims 21 or 22, wherein the cancer is Wilms' tumor.

28. 23. The use according to any one of claims 21 or 22, wherein the cancer is hepatoblastoma.

29. 23. The use according to any one of claims 21 or 22, wherein the cancer is a NOS cancer.

30. 23. The use according to any one of claims 21 or 22, wherein the cancer is synovial sarcoma.

31. 23. The method of claim 21 or 22, wherein the cancer is desmoplastic small round cell tumor. Use of the above.

32. Ramucirumab is administered intravenously at a dose of 6 mg / kg to 16 mg / kg every 2 weeks. The use according to any one of claims 21 to 31.

33. Ramucirumab is administered intravenously at a dose of 8 mg / kg to 12 mg / kg every 2 weeks. The use according to any one of claims 21 to 31.

34. 21 to 25, wherein ramucirumab is administered intravenously at a dose of 6 mg / kg every two weeks.

31. The use according to any one of claims 31.

35. 21 to 25, wherein ramucirumab is administered intravenously at a dose of 8 mg / kg every two weeks.

31. The use according to any one of claims 31.

36. 21. Ramucirumab is administered intravenously at a dose of 10 mg / kg every two weeks.

32. The use according to any one of claims 1 to 31.

37. 21. Ramucirumab is administered intravenously at a dose of 12 mg / kg every two weeks.

32. The use according to any one of claims 1 to 31.

38. 21. Ramucirumab is administered intravenously at a dose of 16 mg / kg every two weeks.

32. The use according to any one of claims 1 to 31.

39. Osteosarcoma, sarcoma, pheochromocytoma, paraganglioma, Wilms' tumor, hepatoblastoma, NOS cancer, synovial sarcoma 20060236333 200602352 ... For use in the treatment of human patients with desmoplastic small round cell tumors, A pharmaceutical composition comprising sirumab.

40. 39. The human patient is at least 12 months of age but not older than 21 years of age. The use described in.

41. 41. The use according to any one of claims 39 or 40, wherein the cancer is osteosarcoma.

42. 41. The use according to any one of claims 39 or 40, wherein the cancer is a sarcoma.

43. 41. The use according to any one of claims 39 or 40, wherein the cancer is pheochromocytoma.

44. 41. The use according to any one of claims 39 or 40, wherein the cancer is paraganglioma.

45. 41. The use of any one of claims 39 or 40, wherein the cancer is Wilms' tumor.

46. 41. The use according to any one of claims 39 or 40, wherein the cancer is hepatoblastoma.

47. 41. The use of any one of claims 39 or 40, wherein the cancer is a NOS cancer.

48. 41. The use according to any one of claims 39 or 40, wherein the cancer is synovial sarcoma.

49. 41. The method of claim 39 or 40, wherein the cancer is desmoplastic small round cell tumor. Use of the above.

50. Ramucirumab is administered intravenously at a dose of 6 mg / kg to 16 mg / kg every 2 weeks. The use according to any one of claims 39 to 49.

51. Ramucirumab is administered intravenously at a dose of 8 mg / kg to 12 mg / kg every 2 weeks. The use according to any one of claims 39 to 49.

52. 39 to 40, wherein ramucirumab is administered intravenously at a dose of 6 mg / kg every two weeks.

49. The use according to any one of claims 49.

53. 39 to 40, wherein ramucirumab is administered intravenously at a dose of 8 mg / kg every two weeks.

49. The use according to any one of claims 49.

54. 39. Ramucirumab is administered intravenously at a dose of 10 mg / kg every two weeks.

50. The use according to any one of claims 1 to 49.

55. 39. Ramucirumab is administered intravenously at a dose of 12 mg / kg every two weeks.

50. The use according to any one of claims 1 to 49.

56. 39. Ramucirumab is administered intravenously at a dose of 16 mg / kg every two weeks.

50. The use according to any one of claims 1 to 49.