Administration of anti-CD30 antibody-drug conjugates to non-adult humans.

Abstract

To provide methods of treating a disorder characterized by pathological activity of CD30+ cells, such as in certain solid, hematological and lymphoid cancers, in a non-adult human subject by administering an effective amount of an anti-CD30 ADC (antibody drug conjugate), such as, Brentuximab Vedotin, to the subject.SOLUTION: The invention is based, at least in part, on applicant's discovery that a body surface area (BSA)-adjusted dose of an anti-CD30 ADC provides a more consistent exposure to the ADC across non-adult human subjects compared to weight-adjusted doses of an anti-CD30 ADC, as assessed by area under the curve (AUC).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Prior application This application claims priority under U.S. Provisional Patent Application No. 62 / 421,527, filed on November 14, 2016. The entire teachings of the above application are incorporated herein by reference.

[0002] The present invention relates to a method for treating disorders characterized by the pathological activity of CD30+ cells, particularly in certain solid malignancies, hematological malignancies, and lymphoid malignancies in non-adult (child) human subjects. [Background technology]

[0003] Conventional small-molecule drugs are typically dose-adjusted for non-adult human subjects using established methods (methods that adjust for the generally higher metabolism of non-adult human subjects). However, dose adjustment for biomolecules is not easily performed for non-adult subjects, particularly because their pharmacokinetics are considerably more unpredictable than those of small molecules. Antibody-drug conjugates (ADCs), which typically contain both biomolecular and small-molecule components, can exhibit even more unpredictable pharmacokinetics. Anti-CD30 ADCs, such as brentuximab vedotin (BV, trade name ADCETRIS®), offer many benefits to adult subjects when used to treat certain solid tumors, hematological malignancies, and lymphoid cancers. Brentuximab vedotin is currently approved in the United States for the treatment of patients with classical Hodgkin lymphoma (cHL) after autologous hematopoietic stem cell transplantation (auto-HSCT) failure or in patients who are not candidates for auto-HSCT and who have previously failed at least two multi-agent chemotherapy regimens; as consolidation therapy after auto-HSCT in patients at high risk of relapse or progression of classical HL; for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after previously failing at least one multi-agent chemotherapy regimen; and for the treatment of patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have previously received systemic therapy. It is administered by intravenous infusion over 30 minutes every three weeks, at a dose based on body weight in adult human subjects. However, given the unpredictable pharmacokinetics of ADCs like brentuximab vedotin, there is a need for corresponding methods to treat non-adult human subjects. [Overview of the Initiative] [Means for solving the problem]

[0004] The present invention provides, inter alia, methods of treating a disorder characterized by the pathological activity of CD30+ cells, such as in certain solid cancers, hematological cancers and lymphoid cancers, in a non-adult human subject by administering an effective amount of an anti-CD30 ADC to the subject. The present invention is based, at least in part, on the Applicants' discovery that body surface area (BSA)-based doses of anti-CD30 ADC provide a more consistent systemic ADC exposure across non-adult human subjects than weight-based doses of anti-CD30 ADC, as assessed by area under the curve (AUC).

[0005] Accordingly, in one aspect, the present invention provides a method of treating a hematological cancer, lymphoid cancer or solid cancer in a non-adult human subject. The method comprises administering one or more doses of an anti-CD30 antibody-drug conjugate (ADC) at a body surface area-based dose.

[0006] In some embodiments, the anti-CD30 antibody-drug conjugate (ADC) is administered at about 32 to 78 mg / m, for example every 3 weeks 2 , for example, about 64 to 78 mg / m 2 , for example, about 66 to 76 mg / m 2 , 68 to 74 mg / m 2 , 70 to 72 mg / m 2 or about 71.5 mg / m 2 , for example at about 43 to 53 mg / m every 2 weeks 2 , for example, about 45 to 51 mg / m 2 , 47 to 49 mg / m 2 or about 48 mg / m 2 , or for example at about 32 to 40 mg / m about every 2 weeks 2 , for example, about 34 to 38 mg / m 2 , 35 to 37 mg / m 2 or about 36 mg / m 2 . In some specific embodiments, the anti-CD30 antibody-drug conjugate (ADC) is administered at about 70 to 72 mg / m every 3 weeks 2 , 71 to 72 mg / m 2 or about 71.5 mg / m 2Administer in the following dose. In some specific embodiments, the anti-CD30 antibody-drug conjugate (ADC) is administered every two weeks at approximately 45-51 mg / m². 2 , 47-49 mg / m² 2 Or approximately 48 mg / m² 2 Administer in the following dose. In some specific embodiments, the anti-CD30 antibody-drug conjugate (ADC) is administered every two weeks at approximately 34-38 mg / m². 2 , 35-37 mg / m² 2 Or approximately 36 mg / m² 2 Administer in the following dose. In certain specific embodiments, the anti-CD30 antibody-drug conjugate (ADC) is approximately 71.5 mg / m². 2 Or approximately 78 mg / m² 2 Administer in the following dose. In another specific embodiment, the anti-CD30 antibody-drug conjugate (ADC) is approximately 43 mg / m². 2 Or approximately 48 mg / m² 2 It is administered at a dose of approximately 36 mg / m². In yet another specific embodiment, the anti-CD30 antibody-drug conjugate (ADC) is approximately 36 mg / m². 2 Administer in the specified dose.

[0007] In certain embodiments, subjects are receiving AVD (adriamycin, vinblastine, dacarbazine), CHP (doxorubicin, cyclophosphamide, prednisone), RCHOP (doxorubicin, cyclophosphamide, prednisone, vincristine), combination chemotherapy such as rituximab + bendamustine, immunotherapy (including one or more checkpoint inhibitors such as nivolumab), HSC (hematopoietic stem cell) transplantation, radiotherapy, or a combination thereof.

[0008] In some embodiments, the normalized drug exposure of the subject, as measured by the area under the ADC concentration-time curve (AUC), is substantially equivalent to the adult AUC at the indicated adult dose.

[0009] In certain embodiments, the ADC comprises an anti-CD30 antibody containing a complementarity-determining region (CDR) of cAC10. In more specific embodiments, the ADC comprises the anti-CD30 antibody cAC10. In certain specific embodiments, the ADC comprises auristatin. In more specific embodiments, the auristatin is monomethyl auristatin E (MMAE). In some embodiments, the ADC comprises a cathepsin cleavage linker and optionally a spacer. In more specific embodiments, the cathepsin cleavage linker is a valine-citrulline linker. In more specific embodiments, the ADC is brentuximab vedotin.

[0010] In some embodiments of the present invention, the ADC is administered for two or more cycles, for example, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more cycles, for example, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks, for example, once every two or three weeks.

[0011] In a related aspect, the present invention provides an anti-CD30 antibody-drug conjugate (ADC) in a body surface area-based dose suitable for the treatment of non-adult human subjects, such as hematological cancers, lymphoid cancers, or solid tumors.

[0012] In another embodiment, the present invention provides to non-adult human subjects approximately 32-78 mg / m² every three weeks, for example. 2 For example, approximately 64-78 mg / m² 2 For example, approximately 66-76 mg / m² 2 , 68-74 mg / m² 2 70-72 mg / m² 2 Alternatively, approximately 71.5 mg / m² 2 For example, every two weeks, approximately 43-53 mg / m² 2 For example, approximately 45-51 mg / m² 2 , 47-49 mg / m² 2Alternatively, approximately 48 mg / m² 2 Or, for example, every two weeks, approximately 32-40 mg / m² 2 For example, approximately 34-38, 35-37, or 36 mg / m² 2 The present invention provides a method for treating target hematological cancers, lymphoid cancers, or solid tumors by administering one or more doses of brentuximab vedotin at a given dose.

[0013] In yet another embodiment, the present invention relates to brentuximab vedotin for the treatment of hematological or lymphoid cancers in non-adult human subjects, administered, for example, every three weeks, at a dose of approximately 32-78 mg / m². 2 For example, approximately 64-78 mg / m² 2 For example, approximately 66-76 mg / m² 2 , 68-74 mg / m² 2 70-72 mg / m² 2 Alternatively, approximately 71.5 mg / m² 2 For example, every two weeks, for example, approximately 43-53 mg / m² 2 For example, approximately 45-51 mg / m² 2 , 47-49 mg / m² 2 Alternatively, approximately 48 mg / m² 2 Or, for example, every two weeks, approximately 32-40 mg / m² 2 For example, approximately 34-38, 35-37, or 36 mg / m² 2 We offer brentuximab vedotin in the specified dose. In embodiments of the present invention, for example, the following items are provided. (Item 1) A method for treating hematological or lymphoid cancer in non-adult human subjects, comprising administering one or more doses of an anti-CD30 antibody-drug conjugate (ADC) in a dose equivalent to the body surface area. (Item 2) The aforementioned anti-CD30 antibody-drug conjugate (ADC) is administered at approximately 32-78 mg / m². 2 , For example, every three weeks, for example, approximately 64-78 mg / m² 2 For example, approximately 66-76, 68-74, 70-72, or approximately 71.5 mg / m² 2 , For example, every two weeks, for example, approximately 43-53 mg / m² 2 For example, approximately 45-51, 47-49, or 48 mg / m² 2 ,or For example, every two weeks, for example, approximately 32-40 mg / m² 2 For example, approximately 34-38, 35-37, or 36 mg / m² 2 The method described in item 1, administered in the specified dose. (Item 3) The aforementioned anti-CD30 antibody-drug conjugate (ADC) is administered at approximately 71.5 mg / m². 2 , about 48mg / m 2 Or approximately 36 mg / m² 2 The method described in any one of the preceding items, administered in the specified dose. (Item 4) The method described in any one of the preceding items, wherein the subject is receiving combination chemotherapy such as AVD (adriamycin, vinblastine, dacarbazine) or CHP (doxorubicin, cyclophosphamide, prednisone), immunotherapy (such as nivolumab), HSC (hematopoietic stem cell) transplantation, radiotherapy, or a combination thereof. (Item 5) The method according to any one of the preceding items, wherein the normalized drug exposure level of the subject is substantially equivalent to the adult AUC at the indicated adult dose when measured by the area under the ADC concentration-time curve (AUC). (Item 6) The method according to any one of the preceding items, wherein the ADC comprises an anti-CD30 antibody containing the complementarity-determining region (CDR) of cAC10. (Item 7) The method according to any one of the preceding items, wherein the ADC comprises the anti-CD30 antibody cAC10. (Item 8) The method according to any one of the preceding items, wherein the ADC comprises auristatin. (Item 9) The method according to item 8, wherein the auristatin is monomethyl auristatin E (MMAE). (Item 10) The method according to any one of the preceding items, wherein the ADC includes a cathepsin cleavage linker and optionally includes a spacer. (Item 11) The method according to item 10, wherein the cathepsin cleavage linker is a valine-citrulline linker. (Item 12) The method according to any one of the preceding items, wherein the ADC is brentuximab vedotin. (Item 13) The method according to any one of the preceding items, wherein the ADC is administered for two or more cycles, for example, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more cycles, for example, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks, for example, once every two or three weeks. (Item 14) A product containing an anti-CD30 antibody-drug conjugate (ADC) in a body surface area-based dose suitable for the treatment of non-adult human subjects, such as hematological or lymphoid cancers. (Item 15) A method for treating hematological or lymphoid cancers in non-adult human subjects, comprising administering one or more doses of brentuximab vedotin to the subject at approximately 32-78 mg / m². 2 , For example, every three weeks, for example, approximately 64-78 mg / m² 2 For example, approximately 66-76 mg / m² 2 , 68-74 mg / m² 2 70-72 mg / m² 2 Alternatively, approximately 71.5 mg / m² 2 , For example, every two weeks, for example, approximately 43-53 mg / m² 2 For example, approximately 45-51 mg / m² 2 , 47-49 mg / m² 2 Alternatively, approximately 48 mg / m² 2 ,or For example, every two weeks, for example, approximately 32-40 mg / m² 2 For example, approximately 34-38, 35-37, or 36 mg / m² 2 The method comprising administering in the specified dose. (Item 16) Brentuximab vedotin for the treatment of hematological or lymphoid cancers in non-adult human subjects, approximately 32-78 mg / m² 2 , For example, every three weeks, for example, approximately 64-78 mg / m² 2 For example, approximately 66-76 mg / m² 2 , 68-74 mg / m² 2 70-72 mg / m² 2 Alternatively, approximately 71.5 mg / m² 2 , For example, every two weeks, for example, approximately 43-53 mg / m² 2 For example, approximately 45-51 mg / m² 2 , 47-49 mg / m² 2 Alternatively, approximately 48 mg / m² 2 ,or For example, every two weeks, for example, approximately 32-40 mg / m² 2 For example, approximately 34-38, 35-37, or 36 mg / m² 2 The brentuximab vedotin provided in the dose of [amount]. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1A is a scatter plot showing the relationship between the area under the curve (AUC) of BV and the age of the subjects. Figure 1B is a scatter plot showing the relationship between the area under the curve (AUC) of BV and the age of the subjects. The unit of AUC is micrograms / mL × days. [Modes for carrying out the invention]

[0015] The present invention provides, inter alia, methods of treating disorders characterized by the pathological activity of CD30+ cells, such as in certain solid cancers, hematological cancers and lymphoid cancers, in non-adult human subjects. These methods comprise administering to the subject one or more doses of an anti-CD30 antibody-drug conjugate (ADC) at a dose calculated based on body surface area. In a related aspect, the present invention also provides targeted uses (including secondary medical uses) of the anti-CD30 antibody-drug conjugate for providing a dose calculated based on body surface area in the treatment of disorders characterized by the pathological activity of CD30+ cells, such as in certain solid cancers, hematological cancers and lymphoid cancers. These methods, targeted uses and secondary medical uses are collectively referred to as "the methods provided by the present invention" or "the methods of the present invention". In another related aspect, the present invention provides kits and articles of manufacture (such as unit dosage forms or cycle dosage forms) adapted to treat non-adult human subjects, for example, at a dose calculated based on body surface area suitable for treating non-adult human subjects according to the methods provided by the present invention, i.e., for example, with respect to solid cancers, hematological cancers or lymphoid cancers. The kits and articles of manufacture, in some embodiments, comprise instructions and / or labels for use according to any of the methods provided by the present invention. These are collectively referred to as "the kits provided by the present invention", and together with the methods provided by the present invention, are referred to as "the kits and methods provided by the present invention".

[0016] "Anti-CD30" refers to an immunoglobulin (antibody) or a fragment thereof comprising an antigen-binding domain that specifically binds to the antigen CD30. The terms "specific binding" and "specifically binds" mean that the anti-CD30 antibody reacts highly selectively with its corresponding target CD30 and does not react with many other antigens. Typically, the anti-CD30 antibody has at least about 1×10 -7 M, preferably 10 -8 M to 10 -9 M, 10 -10 M, 10 -11 M or 10 -12It binds with affinity for M. One specific antibody useful for ADCs useful in the method provided by the present invention is the chimeric antibody cAC10 (which is the antibody backbone of brentuximab vedotin) or a related antibody. Antibodies that are “related antibodies” (including “related antigen-binding fragments”) of the reference antibody include antibodies (and their antigen-binding fragments) that compete with the reference antibody for binding to a target antigen (for example, in some embodiments, competition for the same epitope, overlapping epitopes, or adjacent epitopes), antibodies having the epitope specificity of the reference antibody, antibodies containing the complementarity-determining region (CDR) of the reference antibody (in some embodiments, there may be up to one, two, three, four, or five conservative amino acid substitutions in the entire CDR, or up to one or two conservative substitutions in each CDR), or antibodies containing the heavy-chain variable domain and light-chain variable domain of the reference antibody (or the amino acid identity to these variable domains may be at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more, in which case any of the amino acid changes may be present in the framework region, and the changes may be conservative or non-conservative). In some embodiments, conservative substitutions are identified by the default parameters of BLASTp, while in other embodiments, conservative mutations are within class substitutions, the classes being aliphatic (glycine, alanine, valine, leucine, isoleucine), hydroxyl or sulfur / selenium-containing classes (serine, cysteine, selenocysteine, threonine, methionine), cyclic (proline), aromatic (phenylalanine, tyrosine, tryptophan), basic (histidine, lysine, arginine), and acidic and amide (aspartate, glutamate, asparagine, glutamine). Generally, those skilled in the art will recognize that a single amino acid substitution in a non-essential region of a polypeptide does not substantially alter its biological activity (e.g., Watson et al. (1987) Molecular Biology of the Gene, The See Benjamin / Cummings Pub.Co., p.224 (4th Ed.). In addition, substitutions of structurally or functionally similar amino acids are unlikely to impair biological activity.

[0017] CD30 (also known as TNFRSF8, human GeneID943; see NP_001234.3 for reference protein sequence and annotated domain, for example; see Homologene949 for homolog description) is a 120 kDa transmembrane glycoprotein of the tumor necrosis factor receptor family and is a tumor marker. This receptor is expressed by activated T cells and activated B cells, but not by resting T cells and resting B cells. CD30 is a positive regulator of apoptosis and has been shown to limit the proliferation of autoreactive CD8 effector T cells and protect the body from autoimmunity. CD30 has been associated with various lymphomas. CD30 has been associated with anaplastic large cell lymphoma. CD30 is also expressed in classical Hodgkin lymphoma Reed-Sternberg cells.

[0018] An "antibody-drug conjugate" or ADC, such as an anti-CD30 antibody-drug conjugate, is a macromolecular complex of a fragment containing an immunoglobulin or antigen-binding domain and a drug such as an antitumor agent, wherein the immunoglobulin portion is linked to the drug by a linker portion, which in certain embodiments may be covalently bound to both the immunoglobulin region and the drug and include a cleavable bond, for example, to release the drug from the ADC at a suitable time. One particular anti-CD30 ADC useful in the methods provided by the present invention is brentuximab vedotin.

[0019] The abbreviation "Body Surface Area Equivalent Dose," and sometimes "BSA Equivalent Dose," such as "Non-Adult (or Child) BSA Equivalent Dose," typically refers to mg / m². 2This drug dosage is expressed as 0.20247 × height (m) and is adjusted according to the approximate surface area of ​​the subject, based on, for example, a standard reference adult dose (such as an approved dosage). It is more accurate than a weight-based dose (expressed as, for example, mg / kg). Body surface area is 0.20247 × height (m) 0.725 ×Weight (kg) 0.425 It can be estimated using the following formula. For example, Du Bois D, Du Bois EF (Jun 1916). "A formula to estimate the approximate surface area if height and See "Weight be known". Archives of Internal Medicine 17 (6):863-71.doi:10.1001 / archinte.1916.00080130010002 and Verbraecken, J; Van de Heyning P; De Backer W; Van Gaal L (Apr 2006). "Body surface area in normal-weight, overweight, and obese adults. A comparison study". Metabolism-Clinical and Experimental 55(4):515-24.

[0020] "Hematological or lymphoid cancers" are non-solid tumors that primarily reside in the blood, bone marrow, lymph, or lymphoid system. In specific embodiments, these cancers include Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), systemic anaplastic large cell lymphoma (sALCL), diffuse large B-cell lymphoma (DLBCL), cutaneous T-cell lymphoma (CTCL), or mantle cell lymphoma (MTCL). In some embodiments, hematological or lymphoid cancers are lymphomas. Non-limiting examples of lymphomas include Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, natural killer (NK) cell tumors, and immunodeficiency-associated lymphoproliferative disorders. Non-limiting examples of Hodgkin lymphoma (HL) include nodular sclerosis HL, mixed cell HL, lymphocyte-rich HL, and lymphopenic or non-lymphopenic HL. Non-specific examples of lymphomas other than Hodgkin lymphoma include, for example, low-grade / follicular non-Hodgkin lymphoma (NHL), follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, T-cell or B-cell prelymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), unspecified PTCL (PTCL-NOS), mantle cell lymphoma, and marginal zone lymphoma. These include lymphoma, mature T-cell lymphoma, B-cell or T-cell lymphoblastic lymphoma, Burkitt lymphoma, primary thyroid lymphoma, Waldenström macroglobulinemia, lymphoplasmacytic lymphoma, mycosis fungoides, adult T-cell leukemia / lymphoma (ATLL), angioimmunoblastic lymphoma (AITL), enteropathy-type T-cell lymphoma (EATL), and anaplastic large cell lymphoma (ALCL). It should be apparent to those skilled in the art that these pathological conditions may often have different names due to differences / changes in classification systems.

[0021] Although the kits and methods provided by the present invention do not address hematological or lymphoid cancers, they can also be used to treat non-adult human subjects with mycosis fungoides or systemic lupus erythematosus (SLE).

[0022] A “solid tumor” is an abnormal mass of tissue that does not typically contain cysts or fluid areas, and in certain embodiments, refers to a tumor as opposed to a benign tumor. In certain embodiments, a solid tumor is a tumor other than hematological or lymphatic cancers as defined above. In some embodiments, cancer is a solid tumor. Non-limiting examples of solid tumors include ovarian cancer (e.g., epithelial or serous ovarian cancer), skin cancer (e.g., melanoma and / or cutaneous squamous cell carcinoma), breast cancer (e.g., triple-negative breast cancer), thyroid cancer (e.g., anaplastic thyroid cancer), pancreatic cancer (e.g., anaplastic or adenocarcinoma), lung cancer (e.g., small cell lung cancer or lung squamous cell carcinoma), thymic cancer (e.g., thymic carcinoma), anal cancer (e.g., anal squamous cell carcinoma), endometrial cancer, uterine cancer, gynecological carcinosarcoma, urethral cancer, urogenital squamous cell carcinoma, cancer of unknown primary origin, Sertoli cell tumor, and Reitig cell tumor. A solid tumor can be a primary tumor or a metastatic tumor.

[0023] In some embodiments, among disorders characterized by the pathological activity of CD30+ cells, disorders treatable by the kits and methods provided by the present invention include cancers such as ovarian cancer, skin cancer, breast cancer, thyroid cancer, pancreatic cancer, lung cancer, squamous cell carcinoma of the lung, anal cancer, uterine cancer, urethral cancer, endometrial cancer, cancer of unknown primary origin, thymic cancer, urogenital squamous cell carcinoma, gynecological carcinosarcoma, Sertoli cell tumor, Reitig cell tumor, and pancreatic adenocarcinoma. In some embodiments, the ovarian cancer is serous ovarian cancer, the skin cancer is melanoma or cutaneous squamous cell carcinoma, the breast cancer is triple-negative breast cancer, the lung cancer is small cell lung cancer or squamous cell carcinoma of the lung, the thyroid cancer is undifferentiated thyroid cancer, the pancreatic cancer is adenocarcinoma or undifferentiated pancreatic cancer, or the anal cancer is anal squamous cell carcinoma.

[0024] "Non-adult human" subjects (sometimes referred to as non-adult subjects or child subjects) are under 18 years of age. In certain embodiments, subjects are 17 years or younger, 2 years or older, for example, 17-4 or 5 years. In some embodiments, subjects are adolescents, i.e., about 17-13 years, for example, about 17-12 years, 16-12 years, 16-13 years, 15-12 years, etc. In other embodiments, subjects are pre-adolescents, for example, under about 13 years, for example, about 12-2 years, 12-6 years, 11-2 years, 11-6 years, 10-2 years, 10-6 years, etc. In some embodiments, subjects are 6 years or younger, for example, about 6-2 years, 6-3 years, 6-4 years, 6-5 years, 5-2 years, 4-2 years, or 3-2 years. In certain embodiments, the weight of a non-adult human subject is less than approximately 50 kg, for example, less than approximately 50 kg, less than approximately 49 kg, less than approximately 48 kg, less than approximately 47 kg, less than approximately 46 kg, or less than approximately 45 kg. In some embodiments, the weight of a non-adult human subject is approximately 50-12.5 kg, 50-16 kg, 45-12.5 kg, 45-16 kg, etc.

[0025] The methods provided by the present invention can be implemented using an ADC as a frontline therapy, alone or in combination with another treatment or treatment regimen, or as a subsequent therapy (e.g., as a second-line therapy, third-line therapy, re-treatment therapy, consolidation therapy or salvage therapy) after a subject has been treated with at least one treatment or treatment regimen, where the prior treatment or treatment regimen may or may not have been successful (e.g., where there may be a relapse, refractoriness, or no significant initial response). In the methods provided by the present invention, when the ADC is administered as a frontline therapy, second-line therapy, third-line therapy, re-treatment therapy, consolidation therapy, salvage therapy or re-treatment therapy, it can be used as either monotherapy or combination therapy (e.g., in combination with 1, 2, 3, 4, 5 or more additional agents). In some embodiments, the subject to be treated by the methods provided by the present invention may have also received treatment with a composition comprising hematopoietic stem cells (HSCs, either autologous or allogeneic), such as bone marrow or a fraction thereof (which may or may not have undergone expansion culture and / or enrichment culture). In certain embodiments, the subject may have previously received HSC therapy.

[0026] In the methods provided by the present invention, the anti-CD30 antibody-drug conjugate (ADC) can be administered to a non-adult human subject at a body surface area-based dose relative to any effective adult dose (e.g., a weight-based dose). In some embodiments, the normalized drug exposure of the non-adult subject, as measured by the area under the ADC concentration-time curve (AUC), is substantially comparable to the adult AUC at the indicated adult dose. In certain embodiments, the ADC is administered at about 32 to 78 mg / m 2 In certain specific embodiments, this dose is about 64 to 78 mg / m 2 , for example, about 66 to 76 mg / m 2 , 68 to 74 mg / m 2 , 70 to 72 mg / m 2 or about 71.5 mg / m 2 . In a more specific embodiment, the ADC is about 70 to 72 mg / m 271-72 mg / m² 2 Or approximately 71.5 mg / m² 2 Administer in the following dose. In another specific embodiment, the ADC is approximately 43-53 mg / m². 2 For example, approximately 45-51 mg / m² 2 , 47-49 mg / m² 2 Or approximately 48 mg / m² 2 Administer in the following dose. In yet another specific embodiment, the ADC is approximately 32-40 mg / m². 2 For example, approximately 34-38 mg / m² 2 , 35-37 mg / m² 2 Or approximately 36 mg / m² 2 Administer in the following doses. Many regimens using these doses are included in the methods provided by the present invention and are described, among other things, below. For example, in some embodiments, these doses are administered every two weeks (for example, every two weeks, about 43-53 mg / m²). 2 (For example, approximately 45-51 mg / m²) 2 , 47-49 mg / m² 2 Alternatively, approximately 48 mg / m² 2 ) or approximately 32-40 mg / m² 2 (For example, approximately 34-38 mg / m²) 2 , 35-37 mg / m² 2 Alternatively, approximately 36 mg / m² 2 )), or every three weeks (for example, every three weeks, approximately 64-78 mg / m²) 2 (For example, approximately 66-76 mg / m²) 2 , 68-74 mg / m² 2 70-72 mg / m² 2 Or approximately 71.5 mg / m² 2 )) May be administered.

[0027] In some embodiments, the subjects treated by the methods provided by the present invention are receiving combination chemotherapy (AVD (adriamycin, vinblastine, dacarbazine), CHP (doxorubicin, cyclophosphamide, prednisone), RCHOP (doxorubicin, cyclophosphamide, prednisone, vincristine), rituximab + bendamustine, etc.), nivolumab, radiotherapy, HSC therapy, or a combination of any of the above. These combination therapies may be substantially simultaneous or sequential, and in the case of sequential therapy, ADC therapy may be administered before or after additional therapy. AVD chemotherapy regimens are known in the art, and in some embodiments, adriamycin (e.g., 25 mg / m² by intravenous bolus) is used. 2 ), vinblastine (for example, 6 mg / m² by intravenous infusion) 2 ), dacarbazine (for example, 375 mg / m² by intravenous infusion) 2 This includes a dosage such as CHP (doxorubicin, for example, 50 mg / m²). 2 The drug is administered intravenously every three weeks for 6-8 cycles, with prednisone, for example, 100 mg, orally for 6-8 cycles on days 1-5 of each three-week cycle, and cyclophosphamide, for example, 750 mg / m². 2 (Administered intravenously every three weeks for 6-8 cycles), RCHOP (doxorubicin, for example, 50 mg / m²) 2 The drug is administered intravenously every three weeks for 6-8 cycles, with prednisone, for example, 100 mg, orally for 6-8 cycles on days 1-5 of each three-week cycle, and vincristine, for example, 1.4 mg / m². 2 (Maximum 2 mg), administered intravenously every 3 weeks for 6-8 cycles, with cyclophosphamide, for example, 750 mg / m². 2Treatment with brentuximab vedotin (e.g., administered intravenously every three weeks for 6-8 cycles), rituximab + bendamustine (e.g., rituximab administered intravenously on day 1 or day 2 of each 21-day cycle, and bendamustine administered on both day 1 and day 2 of each 21-day cycle; for example, brentuximab vedotin is administered intravenously on day 1 of each 21-day cycle, followed by bendamustine, and rituximab is administered on day 2 of each 21-day cycle, followed by bendamustine), and nivolumab (e.g., 3 mg / kg administered intravenously (IV) every 14 days, for example, for a maximum of 4, 10, 14, 15, 20, 25, or 30 cycles) is known (the above doses are illustrative only). These doses are administered, in some embodiments, every week, every two weeks, or every three weeks (in specific embodiments, every two weeks), for example, in two treatments per 28-day cycle. For example, subjects treated with AVD, CHP, RCHOP, rituximab + bendamustine, or nivolumab therapy may be given one, two, three, four, five, six, seven, eight, nine, ten, or eleven or more cycles. Additional combination therapies that can be adapted to the methods provided by the present invention, i.e., to BSA-equivalent doses, include combinations of anti-CD30 ADCs and aurora kinase inhibitors, as described in WO / 2015 / 085289 (which is incorporated herein by reference in its entirety).

[0028] In certain embodiments, as described above, the ADC for the kits and methods provided by the present invention comprises an anti-CD30 antibody which is substantially similar to cAC10 (an antibody backbone of brentuximab vedotin) or an associated antibody of cAC10. cAC10 is a chimeric antibody that conjugates to the CD30 protein (human GeneID943, protein reference sequence NP_001234.3). cAC10 is described in WO2002 / 043661 (see also U.S. Patent No. 7,090,843), and certain specific conjugates that can be made with cAC10 are described in WO2004 / 010957 (see also U.S. Patent No. 7,659,241). The structure of brentuximab vedotin and its specific administration regimen are described in WO2010081004 (also published as US20110268751A1, see claim 17; see also US9211319). The above references are incorporated by reference, in particular, for descriptions of cAC10, ADCs containing cAC10 (e.g., ADCs containing auristatin, as in brentuximab vedotin), and their formulations and methods of administration. In certain embodiments, the anti-CD30 antibody comprises the complementarity-determining region (CDR) of cAC10, and in some even more specific embodiments, the anti-CD30 antibody is cAC10. While various toxic payloads may exist for the ADCs used in the kits and methods provided by the present invention, in some embodiments, the ADC contains auristatin. In some even more specific embodiments, the auristatin is monomethyl auristatin E (MMAE). In another embodiment, the drug portion is dovalin-valine-dry soloin-dlaproin-phenylalanine (MMAF). The drug and the anti-CD30 antibody can be conjugated by any preferred means. In certain embodiments, the ADC includes a cathepsin cleavage linker and optionally a spacer. In a more specific embodiment, the cathepsin cleavage linker is a valine-citrulline linker. In a more specific embodiment, the ADC is brentuximab vedotin.

[0029] The kits and methods provided by the present invention are adapted for treating non-adult human subjects in BSA-equivalent doses according to a treatment schedule for adult subjects. Accordingly, in some embodiments of the methods provided by the present invention, the ADC is administered in two or more cycles (doses), for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more cycles, for example, once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks, for example, once every 2 or 3 weeks. Accordingly, in certain embodiments, a treatment cycle includes administering a certain dose every 14 days, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 or more cycles. In another embodiment, the treatment cycle includes administering a certain dose every 21 days, for example, for cycle 1, cycle 2, cycle 3, cycle 4, cycle 5, cycle 6, cycle 7, cycle 8, cycle 9, cycle 10, or cycle 11 or more.

[0030] The present invention assumes that ADCs are administered over one or more treatment cycles, for example, 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st or more treatment cycles. In some embodiments, there will be a rest period between one or more treatment cycles. For example, in some embodiments, there will be a rest period between the second and third treatment cycles, but not between the first and second treatment cycles. In another embodiment, there may be a rest period between the first and second treatment cycles, but not between the second and third treatment cycles. The administration schedule may include, for example, administering the antibody-drug conjugate once during the treatment schedule, for example on day 1 of a 21-day cycle; twice during the treatment cycle, for example on days 1 and 15 of a 21-day cycle or on days 1 and 15 of a 28-day cycle; and three times during the treatment cycle, for example on days 1, 8 and 15 of a 21-day cycle or on days 1, 8 and 15 of a 28-day cycle. Other administration schedules are also included in the present invention.

[0031] The present invention includes a treatment schedule in which an antibody-drug conjugate is administered once during a treatment cycle, for example, over a period of one, two, three, or four weeks. For example, in some embodiments, the antibody-drug conjugate would be administered on the first day of a two-week, three-week, or four-week treatment cycle, for example, on day one of a three-week or four-week cycle. In some embodiments, the antibody-drug conjugate would be administered on day one of a three-week or four-week treatment cycle, or on any other date within a two-week, three-week, or four-week treatment cycle.

[0032] In other embodiments, the antibody-drug conjugate will be administered more than once during a treatment cycle. For example, in some embodiments, the antibody-drug conjugate will be administered once a week for three consecutive weeks in a three-week or four-week treatment cycle. For example, in some embodiments, the antibody-drug conjugate will be administered on days 1, 8, and 15 of each 21-day treatment cycle. In some embodiments, the antibody-drug conjugate will be administered on days 1, 8, and 15 of each 28-day treatment cycle.

[0033] In yet another embodiment, the antibody-drug conjugate would be administered every two weeks during a four-week treatment cycle. For example, in some embodiments, the antibody-drug conjugate compound would be administered on day 1 and day 15 of each 28-day treatment cycle.

[0034] The dose of antibody-drug conjugate administered to a patient will also depend on the frequency of administration. This invention envisions the delivery of the antibody-drug conjugate in a single dose or by fractional delivery during a treatment cycle.

[0035] The present invention includes embodiments in which the antibody-drug conjugate compound is administered at a BSA-equivalent dose for non-adult humans (children) relative to adult dose ranges of 0.1 mg to 2.7 mg per kg of body weight per dose, 0.5 mg to 2.0 mg per kg of body weight per dose, 0.9 mg to 2.0 mg per kg of body weight per dose, and 0.9 mg to 1.8 mg per kg of body weight per dose. Other ranges are also included in the present invention, as long as the desired results are obtained. In one embodiment, the antibody-drug conjugate is administered at a BSA-equivalent dose for non-adult humans relative to an adult dose range of approximately 1.2 mg per kg of body weight per dose. In another embodiment, the antibody-drug conjugate compound is administered at a BSA-equivalent dose for non-adult humans relative to an adult dose range of approximately 1.8 mg per kg of body weight per dose. In yet another embodiment, the antibody-drug conjugate compound is administered in a BSA equivalent dose for non-adult humans, relative to an adult dose range of approximately 0.9 mg per kg of body weight per administration.

[0036] The present invention includes a treatment schedule in which the total dose of the antibody-drug conjugate is administered over a treatment cycle, for example, over a period of 3 or 4 weeks, in a non-adult human BSA equivalent dose to an adult dose range, for example, 0.1 mg to 5 mg, 0.1 mg to 4 mg, 0.1 mg to 3.2 mg, or 0.1 mg to 2.7 mg per kg of body weight. In some embodiments, the total dose of the antibody-drug conjugate administered in a non-adult human BSA equivalent dose over a treatment cycle, for example, over a period of 3 or 4 weeks, is for an adult dose range, for example, about 0.6 mg / kg to about 5 mg / kg, about 0.6 mg / kg to about 4 mg / kg, about 0.6 mg / kg to about 3.2 mg / kg, about 0.6 mg / kg to about 2.7 mg / kg, or even about 0.9 mg / kg to about 3.0 mg / kg. In some embodiments, the dose in non-adult human BSA equivalents corresponds to the adult dose range of approximately 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, or 3.8 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks. In some embodiments, the total dose of the antibody-drug conjugate administered in non-adult human BSA equivalent doses corresponds to an adult dose range of 1.8 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks. In some embodiments, the total dose of the antibody-drug conjugate compound administered to the patient is 2.4 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks.In some embodiments, the total dose of the antibody-drug conjugate compound administered at a non-adult human BSA equivalent dose is relative to an adult dose range of 3.6 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks. In some embodiments, the antibody-drug conjugate is administered at a non-adult human BSA equivalent dose relative to an adult dose range of 1.2 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks. In some embodiments, the antibody-drug conjugate compound is administered at a non-adult human BSA equivalent dose relative to an adult dose range of 1.8 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks. In some embodiments, the antibody-drug conjugate compound is administered at a non-adult human BSA equivalent dose relative to an adult dose range of 0.9 mg per kg of body weight over a treatment cycle, e.g., 3 or 4 weeks.

[0037] The above adult dose is 0.9 mg / kg (36 mg / m²). 2 ), 1.2 mg / kg (48 mg / m²) 2 ) or 1.8 mg / kg (71.5 mg / m²) 2 Using one or both of the following reference values, it can be easily converted to human pediatric doses in BSA equivalent using interpolation.

[0038] The antibody-drug conjugate of the present invention can be administered by any method known to those skilled in the art. For example, the antibody-drug conjugate of the present invention can be administered in the form of a composition, and in some embodiments, in the form of a pharmaceutical composition of the antibody-drug conjugate and a pharmaceutically acceptable carrier (such as those described herein). In some embodiments, the pharmaceutical composition, when reconstituted, is a lyophilized powder that can be administered via an intravenous route (such as intravenous injection or intravenous infusion). In some embodiments, the antibody-drug conjugate is administered via intravenous injection. In some embodiments, the antibody-drug conjugate is administered via intravenous infusion. In another embodiment, brentuximab vedotin is administered via intravenous infusion.

[0039] The term “pharmaceutically acceptable carrier” is used herein to refer to a substance that is suitable for a recipient, preferably a mammal, more preferably a human, and that is suitable for delivering the active drug to a target site without causing loss of activity. Where the carrier has associated toxicity or adverse effects, it is preferable that such toxicity or adverse effects are balanced by a reasonable risk-benefit ratio with respect to the intended use of the active drug.

[0040] The terms “carrier,” “adjuvant,” and “vehicle” are used synonymously herein and include any solvent, diluent, and other liquid vehicle, dispersing aid, suspension aid, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, lubricant, etc., suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000, discloses various carriers used in the preparation of pharmaceutically acceptable compositions and known techniques for preparing such compositions. Any conventional carrier medium is intended to be used within the scope of the present invention unless it is incompatible with the compounds of the present invention, for example, by producing any undesirable biological effect or otherwise interacting in an adverse manner with any other component(s) of the pharmaceutically acceptable composition.Some examples of substances that can function as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as disodium hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium hydroxide and aluminum hydroxide, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, pyrogen-free water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin fat, and sugars (lactose, glucose, sucrose). Examples of ingredients include, but are not limited to, corn starch (corn starch and potato starch, etc.), cellulose and its derivatives (sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, etc.), tragacanth powder, malt, gelatin, talc, excipients (cocoa butter and suppository wax, etc.), oils (peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, etc.), glycols (propylene glycol and polyethylene glycol, etc.), esters (ethyl oleate and ethyl laurate, etc.), agar, alginic acid, isotonic saline, Ringer's solution, alcohols (ethanol, isopropyl alcohol, hexadecyl alcohol and glycerol, etc.), cyclodextrin, lubricants (sodium lauryl sulfate and magnesium stearate, etc.), and petroleum hydrocarbons (mineral oil and petrolatum, etc.). The composition of the present invention may also contain, at the discretion of the formulation, colorants, release agents, coating agents, sweeteners, flavoring agents, odoring agents, preservatives and antioxidants.

[0041] The preparation of the antibody or fragment to be administered will vary depending on the chosen route of administration and formulation (e.g., liquid, emulsion, capsule). A suitable pharmaceutical composition containing the antibody or functional fragment to be administered can be prepared in a physiologically acceptable vehicle or carrier. A mixture of the antibody and / or fragment may also be used. For liquid or emulsion formulations, suitable carriers include aqueous solutions or alcohol / aqueous solutions, emulsions or suspensions, including physiological saline and buffering media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, Ringer's lactate, or fixative oil. Various suitable aqueous carriers are known to those skilled in the art and include water, buffered water, buffered physiological saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), dextrose solution, and glycine. Intravenous vehicles can include a variety of additives, preservatives, fluids, nutritional supplements, or electrolyte solutions (see, for general, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980). The compositions of the present invention may optionally contain pharmaceutically acceptable auxiliary substances (pH adjusters, buffers, and toxicity modifiers, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate) as needed to approximate physiological conditions. The antibodies and fragments of the present invention can be lyophilized for storage according to lyophilization and reconstitution techniques known in the art and reconstituted on a suitable carrier before use. The optimal concentration of the active ingredient(s) in the selected medium can be determined experimentally according to procedures well known to those skilled in the art, and the concentration will be determined by the desired final pharmaceutical formulation. For inhalation, the antibodies or fragments of the present invention can be solubilized and filled into a suitable dispenser for administration (e.g., atomizer, nebulizer, or pressurized aerosol dispenser). [Examples]

[0042] Example 1: Phase 1 / 2 trial of brentuximab vedotin in pediatric patients with relapsed or refractory (R / R) Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL) We designed a pediatric trial as a phase 1 / 2 open-label, multicenter, dose-escalation study of brentuximab vedotin (BV) in pediatric patients with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) or Hodgkin lymphoma (HL) for whom standard, curative, life-sustaining, or palliative treatments are unavailable or ineffective. One of the objectives of this trial was to evaluate the pharmacokinetics of BV in pediatric patients.

[0043] The objective of the Phase 1 portion of this study was to establish the safety of brentuximab vedotin in pediatric hematological malignancies with high CD30 expression and to define its MTD (maximum tolerated dose), including both HL and ALCL in its Phase 1 study population. The Phase 2 study was designed to administer brentuximab vedotin at the RP2D (recommended dose for Phase 2), which was determined as the MTD in the Phase 1 portion of this study.

[0044] During treatment with BV at a dose of 1.4 mg or 1.8 mg per kg of body weight every three weeks, blood samples were taken at several time points to determine BV levels from serum. These doses were within the range previously determined to be safe and effective in adult populations in previous studies (Younes, et al., N.Engl J Med 363;19, Nov, 2010). The pharmacokinetic analyses described herein included pharmacokinetic data obtained from 30 pediatric patients for the initial analysis.

[0045] Analysis of systemic exposure to BV in this pediatric population, measured by the area under the concentration-time curve (AUC) (micrograms / mL × days), revealed that systemic exposure to BV decreased with age below approximately 18 years. (See Figure 1A.) This relationship was weaker and improved compared to that with body weight. The original dosing schedule was based on body weight and had normalized exposure levels across a range of pediatric body sizes. Therefore, further analysis based on population pharmacokinetics was performed to determine how pediatric patients should be administered to achieve exposure levels comparable to those seen in adults.

[0046] Population PK (pharmacokinetic) modeling used PK data from the C25002 pediatric and adult patient studies (N.Engl.J.Med 363;19,Nov,2010). In the analysis, body surface area was a significant covariate of brentuximab vedotin exposure. The BSA-based dose established by the simulation procedure normalizes systemic exposure to BV in children of various body weights, i.e., different age groups (Figure 1B). For example, the simulation analysis showed that 71.5 mg / m² 2 When brentuximab vedotin was administered, the AUC was closer to that observed in the adult population administered BV at 1.8 mg / kg, especially in pediatric patients in the lower body weight range. Since linear pharmacokinetics have been observed with BV, the AUC at 1.8 mg / kg and 71.5 mg / m² were similar. 2 In relation to mg / m 2 It is reasonable to estimate various conversion quantities for units.

[0047] Example 2: Treatment of pediatric patients with relapsed or refractory (R / R) Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL) with brentuximab vedotin using a body surface area-based dosing regimen. In this study, we will obtain pediatric (non-adult human) patients with relapsed or refractory (R / R) Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL) for whom standard treatment, curative treatment, life-sustaining treatment, or palliative treatment is unavailable or ineffective, and administer brentuximab vedotin (BV). The dose will be adjusted according to body surface area (BSA), not body weight. In the pediatric study, BV will be administered at a dose of 71.5 mg / m². 2 The drug is administered at the specified dose (intravenous infusion, once every 3 weeks (21 days)). Each 21-day treatment cycle consists of day 1 of the study drug treatment followed by a 20-day monitoring period. Patients may receive BV for up to 16 cycles. An independent evaluation committee (IRF) will determine the objective response rate (ORR, complete remission (CR) + partial remission (PR)) using PET, CT, MRI and clinical evaluations in accordance with the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma. The following will also be evaluated: progression-free survival (time from the first dose of the study treatment to the first documented date of progressive disease), time to response (time from the first dose of the study treatment to the first documented date of complete or partial response), duration of response (time from the first documented date of response to the date of progressive disease), event-free survival (time from the first dose to treatment failure), progression-free survival (PFS, time from the first dose of the study treatment to disease progression or death), and overall survival (OS, time from the first dose of the study treatment to death). For 12 months from the end of treatment (EOT) consultation, patients' progression-free survival (PFS) and overall survival (OS) will be followed up every 12 weeks. Thereafter, OS will be evaluated every 6 months until the earlier of death or end of the study, or up to 2 years after the enrollment of the last patient. Compared to treatment without BV, pediatric patients treated with BV will show improvement in one or more of the following: CR, PR, PFS, or OS. In pediatric patients treated with BSA-equivalent dose BV, one or more of the following improved: CR, PR, PFS, or OS, compared to pediatric patients treated with body weight-based dose BV of 1.8 mg / kb.

[0048] Example 3: Treatment of pediatric patients with advanced classical Hodgkin lymphoma using a body surface area-based dosing regimen with brentuximab vedotin + AVD. Obtain a pediatric (non-adult human) patient diagnosed with progressive classical Hodgkin lymphoma. 1) Administer brentuximab vedotin (BV) at 48 mg / m². 2 The following dosage is administered intravenously on days 1 and 15 of each 28-day cycle, along with AVD (Adriamycin 25 mg / m²). 2 Vinblastine 6 mg / m² 2 and dacarbazine (DTIC) 375 mg / m² 2 Treatment involves either 1) administering the drugs intravenously on days 1 and 15 of each 28-day cycle, or 2) treatment with ABVD (doxorubicin 25 mg / m²). 2 bleomycin 10 units / m 2 Vinblastine 6 mg / m² 2 and dacarbazine (DTIC) 375 mg / m² 2 Participants will be randomly assigned to receive one of the following treatments (administered intravenously on days 1 and 15 of each 28-day cycle):

[0049] An independent evaluation committee (IRF) calculates the modified progression-free survival (mPFS) (approximately 3-5 years from the randomization date to the mPFS event). Overall survival (OS) is also evaluated (approximately 5-7 years from the randomization date to the death date). Compared to treatment with ABVD alone, pediatric patients treated with BV+AVD show improvement in one or more of either mPFS or OS.

[0050] Example 4: Treatment of pediatric patients with CD30-positive mature T-cell lymphoma using a body surface area-based dosing regimen with brentuximab vedotin + CHP. Obtain pediatric (non-adult human) patients with CD30-positive mature T-cell lymphoma (anaplastic large cell lymphoma, non-Hodgkin lymphoma, T-cell lymphoma). 1) Administer BV (IV once every 3 weeks (21 days)) at a dose of 71.5 mg / m². 2 6-8 cycles at this dose, and CHP (cyclophosphamide 750 mg / m²)2 6-8 cycles of intravenous infusion every 3 weeks, doxorubicin 50 mg / m² 2 1) Combination chemotherapy with (1) Chemotherapy with CHOP (doxorubicin 50 mg / m²) administered intravenously every three weeks for 6-8 cycles, and prednisone 100 mg administered orally on days 1-5 of each three-week cycle for 6-8 cycles, or 2) Chemotherapy with CHOP (doxorubicin 50 mg / m²) 2 This medication is administered intravenously every three weeks for 6-8 cycles, prednisone 100 mg is taken orally on days 1-5 of each three-week cycle for 6-8 cycles, and vincristine 1.4 mg / m² is administered. 2 (Maximum 2 mg) administered intravenously every 3 weeks for 6-8 cycles, and cyclophosphamide 750 mg / m². 2 Participants will be randomly assigned to receive one of the treatments: intravenous infusion every three weeks for 6-8 cycles.

[0051] An independent evaluation committee (IRF) determines progression-free survival (up to 5 years from treatment, including disease progression, subsequent chemotherapy, death, or termination of the trial). Complete remission (CR), overall survival (OS), and objective response rate (ORR) are also evaluated by the IRF.

[0052] Compared to treatment with CHOP alone, patients treated with BV+CHP show improvement in one or more of the following: PFS, OS, or ORR.

[0053] Example 5: Treatment of pediatric patients with CD30-positive cutaneous T-cell lymphoma with brentuximab vedotin using a body surface area-based dosing regimen. Obtain pediatric (non-adult human) patients with CD30-positive cutaneous T-cell lymphoma (primary cutaneous anaplastic large cell lymphoma, mycosis fungoides, cutaneous T-cell lymphoma). 1) Administer BV (IV once every 3 weeks (21 days)) at a dose of 71.5 mg / m². 2 At this dose, as monotherapy, for a total of up to 16 cycles, or 2) at the physician's discretion, methotrexate or bexarotene (methotrexate orally once weekly (5-50 mg), adjusting the dose according to the patient's response and toxicity, or bexarotene orally once daily with food or drink (300 mg / m²)2 One of the treatments involves randomly assigning subjects to the study.

[0054] We evaluate the proportion of patients who maintain an objective response (ORR, complete remission (CR) + partial remission (PR)) for at least four months. We also evaluate the proportion of patients who achieve complete response (CR) and progression-free survival (PFS).

[0055] Compared to treatment with either methotrexate or besarotene, patients treated with BV show improvement in one or more of the following: ORR, CR, or PFS.

[0056] Example 6: Treatment of a newly diagnosed pediatric participant with advanced Hodgkin lymphoma using a body surface area-based dosing regimen of brentuximab vedotin in combination with adriamycin, vinblastine, and dacarbazine. This trial will evaluate the safety and availability of a combination of brentuximab vedotin (BV) with a multi-agent chemotherapy regimen based on the latest standard of care (SOC) first-line treatment regimen for newly diagnosed HL, and will also evaluate the antitumor activity of this combination, by selecting newly diagnosed children with advanced (stage III and stage IV) Hodgkin lymphoma (HL, histologically confirmed CD30+ classical HL, untreated).

[0057] This trial will be conducted in two phases (Phase 1 and Phase 2). In Phase 1, brentuximab vedotin (BV) will be administered at a dose of 48 milligrams per square meter (48 mg / m²). 2 ) or 36 mg / m² 2 The drug is administered intravenously at the dose specified, once on day 1 and day 15 of each 28-day cycle. This dose is doxorubicin 25 mg / m². 2 Vinblastine 6 mg / m² 2 and dacarbazine 375 mg / m² 2 Approximately one hour later, the drug is administered intravenously to the subject once on day 1 and day 15 of each 28-day cycle, for a maximum of six cycles.

[0058] If, after observing dose-limiting toxicity (DLT) in the first six subjects, DLT is observed in 0 or 1 subject, then 48 mg / m² 2 This will be the recommended BV dose for Phase 2 of this trial. If DLT is observed in two or more of the up to six subjects for which DLT can be evaluated at any point in time, the BV dose will be increased to 36 mg / m² using the same dosing schedule as above. 2 The dose is reduced to [a certain level]. In Phase 2, BV is administered using the same dosing schedule as in Phase 1, at the prescribed Phase 2 recommended dose.

[0059] Evaluate the subjects, and in particular in the pediatric population, determine the recommended BV dose in combination with doxorubicin, vinblastine, and dacarbazine; the proportion of subjects experiencing adverse events (AEs) (e.g., from the first dose of protocol therapy to 30 days after the final dose of protocol therapy); the proportion of subjects experiencing serious adverse events (SAEs) (e.g., from the first dose of protocol therapy to 30 days after the final dose of protocol therapy); and the proportion of subjects achieving complete remission (CR) (e.g., International Working Group). In accordance with the Group (IWG) criteria, determine at least one of the following (based on evaluations by an Independent Review Foundation (IRF) at the end of treatment (EOT): the proportion of subjects whose disease is negative on positron emission tomography (PET) after two cycles of protocol therapy (e.g., based on IRF evaluation); the proportion of subjects showing partial remission (PR) (e.g., based on IRF evaluation at EOT according to IWG criteria); the proportion of subjects showing overall response (OR) (e.g., based on IRF evaluation at EOT according to IWG criteria); or the proportion of subjects in the evaluable response population who can complete six 28-day treatment cycles at the recommended dose.

[0060] In patients treated with BV in combination with adriamycin, vinblastine, and dacarbazine, one or more of the following were observed: an acceptable proportion of patients experiencing AEs and SAEs, and a significant proportion of patients achieving CR, PET-negative disease, PR, OR, and completion of 6 treatment cycles.

[0061] In this application, all boundary values ​​(such as "approximately," "at least," "less than," and "greater than") used to describe certain parameters should be understood to necessarily include any range that has the indicated value as its boundary. Therefore, for example, the statement "at least 1, at least 2, at least 3, at least 4, or at least 5" also includes ranges such as 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, and 4-5.

[0062] All patents, applications, or other references cited herein (including non-patent literature and reference sequence information) are incorporated herein by reference in their entirety for all purposes and with respect to any statements made herein. In the event of any conflict between the documents incorporated herein and this application, this application shall prevail. All information related to the reference gene sequence disclosed herein, including GeneID or other accession numbers (typically referring to National Center for Biotechnology Information (NCBI) accession numbers), such as genomic loci, genomic sequences, functional annotations, allele variants and reference mRNA (including, for example, exon boundaries or response elements), protein sequences (including conserved domain structures), Homologene, OMIM, and chemical references (e.g., PubChem Compound, PubChem Substance, or PubChem Bioassay entries, including their annotations such as structure and assay), are incorporated herein by reference in their entirety.

[0063] The headings used in this application are for convenience only and do not affect the interpretation of this application.

[0064] The preferred features of each aspect provided by the present invention are applicable mutatis mutandis to all other aspects of the present invention, without limitation, and include, but are not limited to, those illustrated by the dependent claims, including combinations and substitutions of specific features (e.g., elements (including numerical ranges and exemplary embodiments)) of specific embodiments and aspects (including examples) of the present invention. For example, specific experimental parameters illustrated in examples can be adapted, in part, to use in the claimed invention without departing from the present invention. For example, with respect to the disclosed materials, even if specific references to each of various combinations of these compounds individually and collectively are not explicitly disclosed, they are specifically envisioned and described herein. Thus, if groups A, B, and C and groups D, E, and F are disclosed, and examples of combinations of elements A-D are disclosed, each is envisioned individually and collectively, even if not shown individually. Therefore, in this example, the disclosure of examples of A, B and C, D, E and F, and combinations of A-D shall be deemed to specifically envision and disclose combinations of A-E, A-F, B-D, B-E, B-F, C-D, C-E and C-F. Similarly, any subset or combination of these shall be specifically envisioned and disclosed. Therefore, for example, the disclosure of examples of A, B and C, D, E and F, and combinations of A-D shall be deemed to specifically envision and disclose the subgroups A-E, B-F and C-E. This concept applies to all aspects of the present application, including elements of a composition and steps of a method for preparing or using the composition.

[0065] The above aspects of the present invention can be claimed in any combination or substitution, as can be recognized by those skilled in the art according to the teachings herein, unless the combination or substitution is novel and not obvious to the prior art; that is, any element described in one or more references known to those skilled in the art can be excluded from the claimed invention, in particular by a negative proviso or waiver of a feature or combination of features.

Claims

1. A composition comprising brentuximab vedotin for the treatment of hematological or lymphoid cancer in non-adult human subjects, wherein the composition contains brentuximab vedotin at a dose of 71.5 mg / m² to the subject. ２ A composition characterized by being used to be administered in a dose equivalent to the body surface area, wherein the hematological or lymphoid cancer expresses CD30.

2. The composition according to claim 1, characterized in that the composition is administered once every three weeks.

3. The composition according to claim 1 or 2, wherein the cancer is Hodgkin lymphoma, anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), or mantle cell lymphoma (MTCL).

4. The composition according to claim 3, wherein the cancer is recurrent or refractory Hodgkin lymphoma.

5. The composition according to claim 3, wherein the cancer is systemic anaplastic large cell lymphoma (sALCL).

6. The composition according to any one of claims 1 to 5, characterized in that the composition is administered on the first day of a 21-day cycle, and the non-adult human subject is about 5 to about 17 years of age.

7. The composition according to any one of claims 1 to 6, characterized in that the subject is receiving combination chemotherapy.

8. The composition according to claim 7, wherein the combination chemotherapy comprises adriamycin-vinblastine-dacarbazine (AVD), doxorubicin-cyclophosphamide-prednisone (CHP), immunotherapy, hematopoietic stem cell transplantation, radiotherapy, or any combination thereof.

9. The composition according to claim 7, wherein the combination chemotherapy comprises AVD and / or CHP.

10. The composition according to any one of claims 1 to 9, wherein the non-adult human subject is approximately 5 to approximately 17 years old.

11. The composition according to any one of claims 1 to 10, characterized in that the composition is administered for two or more treatment cycles.

12. The composition according to claim 11, characterized in that the composition is administered for a maximum of 16 treatment cycles.

13. The composition according to claim 12, characterized in that the composition is administered for 16 treatment cycles.

14. The composition according to claim 11, characterized in that the composition is administered for nine treatment cycles.

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