Non-adult human dosing of Anti-CD30 antibody-drug conjugates

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 to U.S. Provisional Patent Application No. 62 / 421,527, filed November 14, 2016, the entire teachings of which are incorporated herein by reference.

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

[0003] Conventional small molecule drugs are typically dosed for non-adult human subjects using established methods (adjusted for the generally higher metabolism of non-adult human subjects). However, biomolecules cannot be dosed as easily for non-adult subjects, especially because their pharmacokinetics are much less predictable than small molecules. Antibody-drug conjugates (ADCs) are therapeutic agents that typically contain both biomolecule and small molecule components, and therefore may exhibit even more unpredictable pharmacokinetics. Anti-CD30 ADCs such as brentuximab vedotin (BV, trade name ADCETRIS®) offer many benefits to adult subjects, for example, when treating certain solid, hematological and lymphatic cancers. Brentuximab vedotin is currently approved in the United States for the treatment of patients with classical Hodgkin lymphoma (cHL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two previous multiagent chemotherapy regimens in patients who are not auto-HSCT candidates, 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 failure of at least one previous multiagent chemotherapy regimen, and for the treatment of patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, administered by intravenous infusion over 30 minutes every 3 weeks at weight-based doses in adult human subjects. However, given the unpredictable pharmacokinetics of ADCs such as brentuximab vedotin, there is a need for corresponding methods of treating non-adult human subjects. Summary of the Invention [Means for solving the problem]

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

[0005] Thus, in one aspect, the invention provides a method of treating a hematological, lymphatic or solid cancer in a non-adult human subject, the method comprising administering one or more doses of an anti-CD30 antibody-drug conjugate (ADC) in a body surface area equivalent dose.

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

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

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

[0009] In certain embodiments, the ADC comprises an anti-CD30 antibody comprising the complementarity determining regions (CDRs) of cAC10. In more specific embodiments, the ADC comprises the anti-CD30 antibody cAC10. In certain specific embodiments, the ADC comprises an auristatin. In more specific embodiments, the auristatin is monomethylauristatin E (MMAE). In some embodiments, the ADC comprises a cathepsin-cleavable linker, optionally including a spacer. In more specific embodiments, the cathepsin-cleavable linker is a valine-citrulline linker. In more specific embodiments, the ADC is brentuximab vedotin.

[0010] In some embodiments of the invention, the ADC is administered for two or more cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more cycles, e.g., once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks or once per six weeks, e.g., once every two or three weeks.

[0011] In a related aspect, the invention provides anti-CD30 antibody-drug conjugates (ADCs) in body surface area-equivalent doses suitable for treatment of non-adult human subjects, e.g., for treatment of hematological, lymphatic or solid cancers.

[0012] In another aspect, the present invention provides a method for administering 1,2-diazepam to a non-adult human subject, e.g., at a dose of about 32-78 mg / m every 3 weeks. 2 , for example, about 64 to 78 mg / m 2 , for example, about 66 to 76 mg / m 2 , 68-74mg / m 2 , 70-72mg / m 2 or about 71.5 mg / m 2 , for example, about 43-53 mg / m2 every 2 weeks 2 , for example, about 45 to 51 mg / m 2 , 47-49 mg / m 2or about 48 mg / m 2 , or, for example, about 32-40 mg / m every 2 weeks. 2 , for example, about 34 to 38, 35 to 37, or about 36 mg / m 2 The present invention provides a method for treating a blood cancer, lymphatic cancer, or solid cancer in a subject by administering one or more doses of brentuximab vedotin at a dose of

[0013] In yet another embodiment, the present invention provides brentuximab vedotin for treating a blood or lymphatic cancer in a non-adult human subject, e.g., at about 32-78 mg / m every 3 weeks. 2 , for example, about 64 to 78 mg / m 2 , for example, about 66 to 76 mg / m 2 , 68-74mg / m 2 , 70-72mg / m 2 or about 71.5 mg / m 2 , for example, about 43-53 mg / m2 every 2 weeks 2 , for example, about 45 to 51 mg / m 2 , 47-49 mg / m 2 or about 48 mg / m 2 , or, for example, about 32-40 mg / m every 2 weeks. 2 , for example, about 34 to 38, 35 to 37, or about 36 mg / m 2 The present invention provides brentuximab vedotin, which is provided in a dose of In an embodiment of the present invention, for example, the following items are provided: (Item 1) A method for treating a blood or lymphatic cancer in a non-adult human subject, comprising administering one or more doses of an anti-CD30 antibody-drug conjugate (ADC) in a body surface area equivalent dose. (Item 2) The anti-CD30 antibody-drug conjugate (ADC) is administered in a dose of about 32 to 78 mg / m 2 , For example, about 64 to 78 mg / m2 every 3 weeks. 2 , for example, about 66 to 76, 68 to 74, 70 to 72, or about 71.5 mg / m 2 , For example, about 43-53 mg / m2 every 2 weeks. 2 , for example, about 45 to 51, 47 to 49, or about 48 mg / m 2 ,or For example, about 32-40 mg / m2 every 2 weeks. 2 , for example about 34 to 38, 35 to 37, or about 36 mg / m 2 The method according to item 1, wherein the dose is (Item 3) The anti-CD30 antibody-drug conjugate (ADC) was administered at about 71.5 mg / m 2 , about 48mg / m 2 or about 36 mg / m 2 The method of any one of the preceding items, wherein the dose is (Item 4) The method of 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 therapy, radiation therapy, or a combination thereof. (Item 5) The method of any one of the preceding items, wherein the subject's normalized drug exposure, as measured by the area under the ADC concentration-time curve (AUC), is substantially similar to the adult AUC at the indicated adult dose. (Item 6) The method of any one of the preceding items, wherein the ADC comprises an anti-CD30 antibody comprising the complementarity determining regions (CDRs) of cAC10. (Item 7) The method of any one of the preceding items, wherein the ADC comprises the anti-CD30 antibody cAC10. (Item 8) The method of any one of the preceding items, wherein the ADC comprises an auristatin. (Item 9) 9. The method of claim 8, wherein the auristatin is monomethylauristatin E (MMAE). (Item 10) The method of any one of the preceding items, wherein the ADC comprises a cathepsin-cleavable linker and optionally a spacer. (Item 11) 11. The method of claim 10, wherein the cathepsin-cleavable linker is a valine-citrulline linker. (Item 12) The method of any one of the preceding items, wherein the ADC is brentuximab vedotin. (Item 13) The method of any one of the preceding items, wherein the ADC is administered for two or more cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more cycles, e.g., once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks or once per six weeks, e.g., once every two or three weeks. (Item 14) A product comprising an anti-CD30 antibody-drug conjugate (ADC) in a body surface area equivalent dose suitable for treatment of a non-adult human subject, for example, for treatment of a blood or lymphatic cancer. (Item 15) A method for treating a blood or lymphatic cancer in a non-adult human subject, comprising administering one or more doses of brentuximab vedotin to the subject at a dose of about 32 to 78 mg / m 2 , For example, about 64-78 mg / m every 3 weeks 2 , for example, about 66 to 76 mg / m 2 , 68-74mg / m 2 , 70-72mg / m 2 or about 71.5 mg / m 2 , For example, about 43-53 mg / m every 2 weeks 2 , for example, about 45 to 51 mg / m 2 , 47-49 mg / m 2 or about 48 mg / m 2 ,or For example, about 32-40 mg / m2 every 2 weeks. 2 , for example about 34 to 38, 35 to 37, or about 36 mg / m 2 The method comprises administering at a dose of (Item 16) Brentuximab vedotin for treating hematological or lymphatic cancers in non-adult human subjects, comprising a dose of about 32 to 78 mg / m 2 , For example, about 64-78 mg / m every 3 weeks 2 , for example, about 66 to 76 mg / m 2 , 68-74mg / m 2 , 70-72mg / m 2 or about 71.5 mg / m 2 , For example, about 43-53 mg / m every 2 weeks 2 , for example, about 45 to 51 mg / m 2 , 47-49 mg / m 2 or about 48 mg / m 2 ,or For example, about 32-40 mg / m2 every 2 weeks. 2 , for example about 34 to 38, 35 to 37, or about 36 mg / m 2 The brentuximab vedotin is provided in a dose of [Brief description of the drawings]

[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 subject. Figure 1B is a scatter plot showing the relationship between the area under the curve (AUC) of BV and the age of the subject. The unit of AUC is micrograms / mL x days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present invention provides, inter alia, methods of treating disorders characterized by pathological activity of CD30+ cells, such as in certain solid, hematological and lymphatic cancers, in a non-adult human subject. These methods comprise administering to the subject one or more doses of an anti-CD30 antibody-drug conjugate (ADC) in a body surface area equivalent dose. In a related aspect, the present invention also provides targeted uses (including secondary medical uses) of anti-CD30 antibody-drug conjugates to provide a body surface area equivalent dose in the treatment of disorders characterized by pathological activity of CD30+ cells, such as in certain solid, hematological and lymphatic cancers. These methods, targeted uses and secondary medical uses are collectively referred to as "methods provided by the present invention" or "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, e.g., according to the methods provided by the present invention, i.e., for solid, hematological or lymphatic cancers, in a body surface area equivalent dose suitable for treating the non-adult human subject. The kits and articles of manufacture, in some embodiments, include instructions and / or labels for use in accordance with any of the methods provided herein, and together they are "kits provided herein," and together with the methods provided herein they are "kits and methods provided by the invention."

[0016] "Anti-CD30" refers to an immunoglobulin (antibody) or a fragment thereof that contains the antigen-binding domain that specifically binds to the antigen CD30. The terms "specific binding" and "specifically bind" mean that an anti-CD30 antibody reacts with high selectivity with its corresponding target CD30 and does not react with many other antigens. Typically, an anti-CD30 antibody has a specific binding affinity of at least about 1×10 -7 M, preferably 10 -8 M~10 -9 M, 10 -10 M, 10 -11 M or 10 -12One particular antibody that is useful in an ADC useful in the methods provided herein 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 a reference antibody include antibodies (and antigen-binding fragments thereof) that compete with the reference antibody for binding to a target antigen (e.g., in some embodiments, compete for the same, overlapping or adjacent epitopes), antibodies that have the epitopic specificity of the reference antibody, antibodies that comprise the complementarity determining regions (CDRs) of the reference antibody (in some embodiments, there may be up to 1, 2, 3, 4 or 5 conservative amino acid substitutions across the CDRs, or up to 1 or 2 conservative substitutions in each CDR), or antibodies that comprise the heavy and light chain variable domains of the reference antibody (or may have at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more amino acid identity to the variable domains, in which case any amino acid changes are in the framework regions, which may be conservative or non-conservative). In some embodiments, conservative substitutions are determined by 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). In general, those skilled in the art will recognize that single amino acid substitutions in non-essential regions of a polypeptide will not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The (See Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)) In addition, substitution of structurally or functionally similar amino acids is unlikely to destroy biological activity.

[0017] CD30 (TNFRSF8, also known as human GeneID943; see e.g. NP_001234.3 for reference protein sequence and annotated domains; see Homologene949 for description of homologues) is a 120 kDa transmembrane glycoprotein of the tumor necrosis factor receptor family and a tumor marker. The receptor is expressed by activated T cells and activated B cells, but not by resting T cells or B cells. CD30 is a positive regulator of apoptosis and has been shown to limit the proliferative capacity of autoreactive CD8 effector T cells as well as protect the body from autoimmunity. CD30 has been associated with a variety of 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 an immunoglobulin or a fragment thereof that contains an antigen-binding domain, and a drug, such as an anti-tumor drug, in which the immunoglobulin portion is linked to the drug by a linker moiety that, in certain embodiments, may be covalently attached to both the immunoglobulin region and the drug, and includes, for example, a cleavable bond, so as to release the drug from the ADC at a suitable time. One particular anti-CD30 ADC useful in the methods provided herein is brentuximab vedotin.

[0019] The abbreviations "body surface area equivalent dose" and, in some cases, "BSA equivalent dose" such as non-adult (or pediatric) BSA equivalent dose, are typically expressed in mg / m 2A drug dose expressed as 0.20247 × height (m) is a drug dose based, for example, on a standard reference adult dose (such as an approved dose) and adjusted for the approximate surface area of ​​the subject, and is more accurate than a weight-based dose (e.g., expressed in mg / kg). Body surface area is calculated as 0.20247 × height (m) 0.725 ×Weight (kg) 0.425 For example, Du Bois D, Du Bois EF (Jun 1916). “A formula to estimate the approximate surface area if height and See, e.g., "Body surface area in normal-weight, overweight, and obese adults. A comparative study". Metabolism-Clinical and Experimental 55(4):515-24.

[0020] A "blood or lymphatic cancer" is a non-solid tumor that is present primarily in the blood, bone marrow, lymph, or lymphatic system. In particular embodiments, the cancer is Hodgkin's 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, the blood or lymphatic cancer is a lymphoma. Non-limiting examples of lymphomas include Hodgkin's lymphoma, B cell lymphoma, T cell lymphoma, natural killer (NK) cell neoplasms, and immunodeficiency-associated lymphoproliferative disorders. Non-limiting examples of Hodgkin's lymphoma (HL) include nodular sclerosis HL, mixed cell HL, lymphocyte-rich HL, and lymphopenic or non-reduced HL. Non-limiting examples of lymphomas other than Hodgkin's lymphoma include, for example, low-grade / follicular non-Hodgkin's lymphoma (NHL), follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL, T-cell or B-cell prolymphocytic leukemia, diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), PTCL not otherwise specified (PTCL-NOS), mantle cell lymphoma, marginal zone lymphoma, These include lymphoma, mature T-cell lymphoma, B-cell or T-cell lymphoblastic lymphoma, Burkitt's lymphoma, primary thyroid lymphoma, Waldenstrom's macroglobulinemia, lymphoplasmacytic lymphoma, mycosis fungoides, adult T-cell leukemia / lymphoma (ATLL), angioimmunoblastic lymphoma (AITL), enteropathic T-cell lymphoma (EATL), and anaplastic large cell lymphoma (ALCL). It should be clear to one skilled in the art that these pathological conditions may often be referred to differently due to differences / changes in classification systems.

[0021] The kits and methods provided by the present invention do not contemplate hematological or lymphatic cancers, but may also be used to treat non-adult human subjects with mycosis fungoides or systemic lupus erythematosus (SLE).

[0022] A "solid tumor" refers to an abnormal mass of tissue that does not usually contain cysts or liquid areas, and in particular embodiments, as opposed to a benign tumor. In certain embodiments, a solid tumor is a tumor other than a blood cancer or lymphatic cancer as defined above. In some embodiments, the cancer is a solid tumor. Non-limiting examples of solid tumors include ovarian cancer (e.g., epithelial ovarian cancer or ovarian serous carcinoma), 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 pancreatic carcinoma or pancreatic adenocarcinoma), lung cancer (e.g., small cell lung carcinoma or lung squamous cell carcinoma), thymic carcinoma (e.g., thymic carcinoma), anal cancer (e.g., anal squamous cell carcinoma), endometrial cancer, uterine cancer, gynecological carcinosarcoma, urethral cancer, genitourinary squamous cell carcinoma, carcinoma of unknown primary, Sertoli cell tumor, and Leittig cell tumor. A solid tumor can be a primary tumor or a metastatic tumor.

[0023] In some embodiments, disorders characterized by pathological activity of CD30+ cells that can be treated by the kits and methods provided herein include cancers such as ovarian cancer, skin cancer, breast cancer, thyroid cancer, pancreatic cancer, lung cancer, lung squamous cell carcinoma, anal cancer, uterine cancer, urethral cancer, uterine cancer, cancer of unknown primary site, thymic cancer, genitourinary squamous cell carcinoma, gynecological carcinosarcoma, Sertoli cell tumor, Leittig cell tumor, and pancreatic adenocarcinoma. In some embodiments, the ovarian cancer is ovarian serous carcinoma, 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 lung squamous cell carcinoma, the thyroid cancer is anaplastic thyroid cancer, the pancreatic cancer is adenocarcinoma or undifferentiated pancreatic cancer, or the anal cancer is anal squamous cell carcinoma.

[0024] A "non-adult human" subject (sometimes referred to as a non-adult subject or a pediatric subject) is under 18 years of age. In particular embodiments, the subject is 17 years of age or younger, 2 years of age or older, e.g., 17-4 or 5 years of age. In some embodiments, the subject is an adolescent, i.e., about 17-13 years of age, e.g., about 17-12 years of age, 16-12 years of age, 16-13 years of age, 15-12 years of age, etc. In other embodiments, the subject is pre-adolescent, e.g., less than about 13 years of age, e.g., about 12-2 years of age, 12-6 years of age, 11-2 years of age, 11-6 years of age, 10-2 years of age, 10-6 years of age, etc. In some embodiments, the subject is 6 years of age or younger, e.g., about 6-2 years of age, 6-3 years of age, 6-4 years of age, 6-5 years of age, 5-2 years of age, 4-2 years of age, or 3-2 years of age. In certain embodiments, the non-adult human subject weighs less than about 50 kg, e.g., less than about 50 kg, less than about 49 kg, less than about 48 kg, less than about 47 kg, less than about 46 kg, or less than about 45 kg. In some embodiments, the non-adult human subject weighs between about 50 and 12.5 kg, between about 50 and 16 kg, between about 45 and 12.5 kg, between about 45 and 16 kg, etc.

[0025] The methods provided by the present invention can be performed using ADCs alone or in combination with another treatment or therapeutic regimen as a frontline therapy, or as a subsequent therapy (e.g., as a second-line, third-line, retreatment, consolidation, or salvage therapy) after a subject has been treated with at least one treatment or therapeutic regimen where the prior treatment or therapeutic regimen may or may not be successful (e.g., relapsed, refractory, or may not have a significant initial response). In the methods provided by the present invention, when performed as a frontline, second-line, third-line, retreatment, consolidation, salvage, or retreatment therapy, ADCs can be used either as a monotherapy or in combination (e.g., in combination with one, two, three, four, or five or more additional agents). The subject treated by the methods provided by the present invention can, in some embodiments, have been treated with a composition comprising hematopoietic stem cells (HSCs, either autologous or allogeneic cells), such as bone marrow or a fraction thereof (which may or may not have been expanded and / or enriched). In certain embodiments, the subject may have previously undergone HSC therapy.

[0026] In the methods provided herein, anti-CD30 antibody-drug conjugates (ADCs) can be administered to non-adult human subjects at any effective adult dose (e.g., body weight equivalent dose) in a body surface area equivalent dose. In some embodiments, the normalized drug exposure of the non-adult subject, as measured by area under the ADC concentration-time curve (AUC), is substantially similar to the adult AUC at the indicated adult dose. In certain embodiments, the ADC is administered at a dose of about 32-78 mg / m 2 In certain specific embodiments, the dose is about 64-78 mg / m 2 , for example, about 66 to 76 mg / m 2 , 68-74mg / m 2 , 70-72mg / m 2 or about 71.5 mg / m 2 In a more specific embodiment, the ADC is about 70-72 mg / m 2, 71-72mg / m 2 or about 71.5 mg / m 2 In another specific embodiment, the ADC is administered at a dose of about 43-53 mg / m 2 , for example, about 45 to 51 mg / m 2 , 47-49 mg / m 2 or about 48 mg / m 2 In yet another specific embodiment, the ADC is administered at a dose of about 32-40 mg / m 2 , for example, about 34 to 38 mg / m 2 , 35-37mg / m 2 or about 36 mg / m 2 Many regimens using these doses are encompassed by the methods provided herein, and are described, among others, below. For example, in some embodiments, these doses are administered every 2 weeks (e.g., about 43-53 mg / m every 2 weeks). 2 (For example, about 45 to 51 mg / m 2 , 47-49 mg / m 2 or about 48 mg / m 2 ) or about 32-40 mg / m 2 (For example, about 34 to 38 mg / m 2 , 35-37mg / m 2 or about 36 mg / m 2 ) or every 3 weeks (e.g., about 64–78 mg / m 2 (For example, about 66 to 76 mg / m 2 , 68-74mg / m 2 , 70-72mg / m 2 or about 71.5 mg / m 2 )) may be administered.

[0027] In some embodiments, the subject treated by the methods provided herein is receiving combination chemotherapy (such as AVD (adriamycin, vinblastine, dacarbazine), CHP (doxorubicin, cyclophosphamide, prednisone), RCHOP (doxorubicin, cyclophosphamide, prednisone, vincristine), rituximab + bendamustine), nivolumab, radiation therapy, HSC therapy, or any combination of the above. These combination therapies may be substantially simultaneous or sequential, and if sequential, the ADC treatment may precede or follow the additional therapy. AVD chemotherapy regimens are known in the art, and in some embodiments, include adriamycin (e.g., 25 mg / m2 by intravenous bolus). 2 ), vinblastine (e.g., 6 mg / m 2 ), dacarbazine (e.g., 375 mg / m by intravenous infusion) 2 Similarly, CHP (doxorubicin at 50 mg / m 2 , administered by intravenous infusion every 3 weeks for 6-8 cycles; prednisone, e.g., 100 mg, administered orally on days 1-5 of each 3-week cycle for 6-8 cycles; cyclophosphamide, e.g., 750 mg / m 2 , administered by intravenous infusion every 3 weeks for 6–8 cycles), RCHOP (doxorubicin at 50 mg / m 2 , administered by intravenous infusion every 3 weeks for 6-8 cycles; prednisone, e.g., 100 mg, administered orally on days 1-5 of each 3-week cycle for 6-8 cycles; vincristine, e.g., 1.4 mg / m 2 (maximum 2 mg), given by intravenous infusion every 3 weeks for 6 to 8 cycles, and cyclophosphamide, e.g., 750 mg / m 2, administered by intravenous infusion every 3 weeks for 6-8 cycles), rituximab plus bendamustine (e.g., rituximab is administered intravenously on day 1 or 2 of each 21-day cycle, and bendamustine is administered on both days 1 and 2 of each 21-day cycle, e.g., brentuximab vedotin is administered intravenously followed by bendamustine on day 1 of each 21-day cycle, and rituximab is administered followed by bendamustine on day 2 of each 21-day cycle) and nivolumab (e.g., 3 mg / kg administered by intravenous (IV) infusion, e.g., every 14 days, for up to, e.g., 4, 10, 14, 15, 20, 25 or 30 cycles) are known treatments (the above doses are merely exemplary). These doses are administered in some embodiments every other week, every other week, or every three weeks (in particular embodiments, every two weeks), for example, two treatments per 28-day cycle. For example, subjects treated with AVD, CHP, RCHOP, rituximab + bendamustine, or nivolumab therapy may receive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 or more cycles. Additional combination therapies that can be adapted according to the methods provided herein, i.e., 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 ADCs for use in the kits and methods provided herein comprise an anti-CD30 antibody that is substantially similar to cAC10 (the antibody backbone of brentuximab vedotin) or a related antibody of cAC10. cAC10 is a chimeric antibody that binds 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 dosing regimen are described in WO2010081004 (also published as US20110268751A1, see claim 17; see also US9211319). The above references are incorporated by reference, inter alia, for their description of cAC10, ADCs comprising cAC10 (e.g., ADCs comprising with an auristatin, as in brentuximab vedotin), and methods of formulation and administration thereof. In specific embodiments, the anti-CD30 antibody comprises the complementarity determining regions (CDRs) of cAC10, and in some more specific embodiments, the anti-CD30 antibody is cAC10. ADCs for use in the kits and methods provided herein can have a variety of toxic payloads, but in some embodiments, the ADC comprises an auristatin. In some more specific embodiments, the auristatin is monomethyl auristatin E (MMAE). In another embodiment, the drug moiety is dovaline-valine-dolaisoloin-dolaproine-phenylalanine (MMAF). The drug and anti-CD30 antibody can be conjugated by any suitable means. In certain embodiments, the ADC comprises a cathepsin-cleavable linker, and optionally a spacer. In a more specific embodiment, the cathepsin-cleavable 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 to treat non-adult human subjects at BSA equivalent doses according to treatment schedules for adult subjects.Thus, in some embodiments of the methods provided by the present invention, the ADC is administered for 2 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 a 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 weeks or once every 3 weeks.Thus, in certain embodiments, a treatment cycle includes administering a dose every 14 days, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 or more cycles. In another embodiment, a treatment cycle includes administering a dose every 21 days, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 or more cycles.

[0030] The invention contemplates administering the ADC for one or more treatment cycles, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 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 other embodiments, there may be a rest period between the first and second treatment cycles, but not between the second and third treatment cycles. Dosing schedules include, for example, administering the antibody-drug conjugate once during a treatment cycle, e.g., on day 1 of a 21 day cycle, twice during a treatment cycle, e.g., on days 1 and 15 of a 21 day cycle or days 1 and 15 of a 28 day cycle, and three times during a treatment cycle, e.g., on days 1, 8 and 15 of a 21 day cycle or days 1, 8 and 15 of a 28 day cycle. Other dosing schedules are encompassed by the invention.

[0031] The present invention includes treatment schedules in which the antibody-drug conjugate is administered once during a treatment cycle, for example, during a period of 1 week, 2 weeks, 3 weeks or 4 weeks.For example, in some embodiments, the antibody-drug conjugate will be administered on the first day of a 2-week, 3-week or 4-week treatment cycle, for example, on the first day of a 3-week or 4-week cycle.In some embodiments, the antibody-drug conjugate will be administered on the first day of a 3-week or 4-week treatment cycle, or on any other date during a 2-week, 3-week or 4-week treatment cycle.

[0032] In another embodiment, 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 will be administered every two weeks in a four week treatment cycle, for example, in some embodiments, the antibody-drug conjugate compound will be administered on days 1 and 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. The present invention contemplates delivering the antibody-drug conjugate once or in divided deliveries during a treatment cycle.

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

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

[0037] The adult dose is 0.9 mg / kg (36 mg / m 2 ), 1.2 mg / kg (48 mg / m 2 ) or 1.8 mg / kg (71.5 mg / m 2 ) can be readily converted to a BSA-equivalent human pediatric dose by 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, in some embodiments, a pharmaceutical composition of the antibody-drug conjugate and a pharma- ceutically acceptable carrier (such as those described herein). In some embodiments, the pharmaceutical composition is a lyophilized powder that, upon reconstitution, can be administered via an intravenous route (such as intravenous injection or 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 "pharmaceutical acceptable carrier" is used herein to refer to a substance that is compatible with a recipient subject, preferably a mammal, more preferably a human, and that is suitable for delivering an active agent to a target site without loss of activity of the agent. Any toxicity or adverse effects associated with the carrier, if any, are preferably commensurate with a reasonable risk-benefit ratio with respect to the intended use of the active agent.

[0040] The terms "carrier", "adjuvant" or "vehicle" are used interchangeably herein and include any solvent, diluent and other liquid vehicle, dispersion aid, suspension aid, surface active agent, tonicity agent, thickener, emulsifier, preservative, solid binder, lubricant, etc., as appropriate for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000, discloses various carriers for use in formulating pharmaceutically acceptable compositions and known techniques for preparing said compositions. The use of any conventional carrier medium is contemplated within the scope of the present invention, except insofar as it is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition.Some examples of substances which can function as pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as disodium hydrogen phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium and aluminum hydroxides, 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, wool fat, sugars (lactose, glucose, sucrose, glyceryl stearate ... Examples of suitable cellulose derivatives include, but are not limited to, starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, alginic acid, isotonic saline, Ringer's solution, alcohols (such as ethanol, isopropyl alcohol, hexadecyl alcohol and glycerol), cyclodextrins, lubricants (such as sodium lauryl sulfate and magnesium stearate), and petroleum hydrocarbons (such as mineral oil and petrolatum). Coloring agents, release agents, coating agents, sweeteners, flavoring agents, odorants, preservatives and antioxidants can also be present in the compositions of the present invention, according to the discretion of the formulator.

[0041] The formulation of the antibody or fragment to be administered will vary depending on the route of administration and formulation (e.g., solution, emulsion, capsule) selected. 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 can also be used. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. A variety of suitable aqueous carriers are known to those skilled in the art and include water, buffered water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), dextrose solution and glycine. Intravenous vehicles may include various additives, preservatives, fluids, nutritional replenishers, or electrolyte replenishers (see generally Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980). The compositions of the invention may optionally include pharma- ceutically acceptable auxiliary substances as required to approximate physiological conditions (such as pH adjusters, buffers, and toxicity adjusters, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate). The antibodies and fragments of the invention may be lyophilized for storage and reconstituted in a suitable carrier prior to use, according to lyophilization and reconstitution techniques known in the art. The optimal concentration of the active ingredient(s) in the selected vehicle may be empirically determined according to procedures well known to those skilled in the art, and the concentration will depend on the desired final pharmaceutical formulation. For inhalation, the antibodies or fragments of the invention may be solubilized and loaded into a suitable dispenser for administration (e.g., an atomizer, nebulizer, or pressurized aerosol dispenser). EXAMPLES

[0042] Example 1: A Phase 1 / 2 Study of Brentuximab Vedotin in Pediatric Patients with Relapsed or Refractory (R / R) Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL) The pediatric study was designed as a phase 1 / 2 open-label, single-agent, 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 which standard, curative, life-prolonging, or palliative therapies do not exist or are no longer effective. One of the objectives of the study is to evaluate the pharmacokinetics of BV in pediatric patients.

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

[0044] Blood samples for serum BV levels were obtained at several time points during treatment with BV every 3 weeks at doses of 1.4 or 1.8 mg / kg body weight, within the range of doses 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 analysis described herein included pharmacokinetic data from 30 pediatric patients for the initial analysis.

[0045] Analysis of systemic exposure to BV in this pediatric population showed that age below approximately 18 years decreased systemic exposure to BV as measured by area under the concentration-time curve (AUC) (micrograms / mL x days). See Figure 1A. This relationship was found to be weaker and more favorable than for weight. Because the original dosing schedule was based on weight and had normalized exposure across the pediatric size range, further analysis based on population pharmacokinetics was performed to determine how pediatric patients should be dosed to achieve exposures similar to those seen in adults.

[0046] Population PK modeling used PK data from the above C25002 pediatric study and adult patient study (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 the total body exposure to BV in children of various weights, i.e., different age groups (Figure 1B). That is, as an example, the simulation analysis showed that 71.5 mg / m 2 When brentuximab vedotin was administered at 71.5 mg / m 2, the AUC in pediatric patients with a lower body weight range was shown to be closer to that seen in the adult population when BV was administered at 1.8 mg / kg. Linear pharmacokinetics were observed for BV, with the AUCs at 1.8 mg / kg and 71.5 mg / m 2 being the most common. 2 From the relationship, mg / m 2 It is reasonable to estimate various equivalents of 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 Pediatric (non-adult human) patients with relapsed or refractory (R / R) Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL) for which standard, curative, life-prolonging, or palliative treatments do not exist or are no longer effective are obtained and administered brentuximab vedotin (BV), with the dose adjusted for body surface area (BSA) rather than weight. Pediatric study subjects are administered BV at 71.5 mg / m 2 (administered by intravenous infusion once every 3 weeks (21 days)). Each 21-day treatment cycle consists of study drug treatment on day 1 followed by a 20-day monitoring period. Patients may receive up to 16 cycles of BV. An Independent Review Facility (IRF) will determine the objective response rate (ORR, complete response (CR) + partial response (PR)) using PET, CT, MRI, and clinical assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma. Time to progression (time from first dose of study treatment to first documented progressive disease), time to response (time from first dose of study treatment to first documented complete or partial response), duration of response (time from first documented response to date of progressive disease), event-free survival (time from first dose to treatment failure), progression-free survival (PFS, time from first dose of study treatment to disease progression or death), and overall survival (OS, time from first dose of study treatment to death) will also be assessed. Patients will be followed for progression-free survival (PFS) and overall survival (OS) every 12 weeks for 12 months from the end-of-treatment (EOT) visit. OS will then continue to be assessed every 6 months until death or end of study, whichever occurs first, or up to 2 years after the last patient enrolled. Pediatric patients treated with BV will have improved CR, PR, PFS, or OS compared to treatment without BV. Pediatric patients treated with a BSA-equivalent dose of BV also have improved CR, PR, PFS, or OS compared with pediatric subjects treated with a body weight-equivalent dose of 1.8 mg / kb BV.

[0048] Example 3: Treatment of Pediatric Patients with Advanced Classical Hodgkin Lymphoma with Brentuximab Vedotin + AVD Using a Body Surface Area-Based Dosing Regimen Obtain pediatric (non-adult human) patients diagnosed with progressive classical Hodgkin lymphoma. 1) Administer brentuximab vedotin (BV) at 48 mg / m 2 is administered by intravenous infusion on days 1 and 15 of each 28-day cycle, along with AVD (adriamycin 25 mg / m 2 , vinblastine 6 mg / m 2 and dacarbazine (DTIC) 375 mg / m 2 ) treatment with ABVD (doxorubicin 25 mg / m 2 , bleomycin 10 units / m 2 , vinblastine 6 mg / m 2 and dacarbazine (DTIC) 375 mg / m 2 Subjects will be randomly assigned to receive one of two treatments:

[0049] Modified progression-free survival (mPFS) will be determined by an independent review facility (IRF) (approximately 3-5 years from date of randomization to date of mPFS event). Overall survival (OS) will also be assessed (approximately 5-7 years from date of randomization to date of death). Compared to treatment with ABVD, pediatric patients treated with BV+AVD have improved mPFS or OS.

[0050] Example 4: Treatment of Pediatric Patients with CD30-Positive Mature T-Cell Lymphoma with Brentuximab Vedotin + CHP Using a Body Surface Area-Based Dosing Regimen Obtain pediatric (non-adult human) patients with CD30-positive mature T-cell lymphoma (anaplastic large cell lymphoma, non-Hodgkin's lymphoma, T-cell lymphoma). 1) Administer BV (IV once every 3 weeks (21 days)) at 71.5 mg / m 2 and CHP (cyclophosphamide 750 mg / m2 6–8 cycles of doxorubicin 50 mg / m 2 by intravenous infusion every 3 weeks for 6–8 cycles, followed by prednisone 100 mg orally on days 1–5 of each 3-week cycle for 6–8 cycles); or 2) chemotherapy with CHOP (doxorubicin 50 mg / m 2 by intravenous infusion every 3 weeks for 6–8 cycles, prednisone 100 mg orally on days 1–5 of each 3-week cycle for 6–8 cycles, and vincristine 1.4 mg / m 2 (maximum 2 mg) by intravenous infusion every 3 weeks for 6 to 8 cycles, and cyclophosphamide 750 mg / m 2 Study subjects will be randomly assigned to one of two treatments:

[0051] An Independent Review Facility (IRF) will determine progression-free survival (PFS) (until disease progression, subsequent anticancer chemotherapy, death, or end of study, up to a maximum of 5 years after treatment). Complete response (CR), overall survival (OS), and objective response rate (ORR) will also be assessed by the IRF.

[0052] Compared with CHOP, patients treated with BV+CHP have improved 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 71.5 mg / m 2 as monotherapy for a total of up to 16 cycles, or 2) physician's choice of methotrexate or bexarotene (methotrexate orally once weekly (5-50 mg) with dose adjustments based on patient response and toxicity, or bexarotene orally once daily with food or drink (300 mg / m2 )) treatments.

[0054] The proportion of patients experiencing an objective response (ORR, complete response (CR) + partial response (PR)) lasting at least 4 months will be assessed. The proportion of patients experiencing a complete response (CR) and progression-free survival (PFS) will also be assessed.

[0055] Compared with treatment with either methotrexate or bexarotene, patients treated with BV have improved ORR, CR, or PFS.

[0056] Example 6: Treatment of Pediatric Participants Newly Diagnosed with Advanced Hodgkin Lymphoma with Brentuximab Vedotin in a Body Surface Area-Based Dosing Regimen in Combination with Adriamycin, Vinblastine, and Dacarbazine To acquire pediatric subjects newly diagnosed with advanced stage (stage III and stage IV disease) Hodgkin lymphoma (HL, histologically confirmed CD30+ classical HL, previously untreated) in a study to evaluate the safety and feasibility of combining brentuximab vedotin (BV) with a multiagent chemotherapy regimen based on current standard of care (SOC) first-line treatment regimens for newly diagnosed HL, as well as to evaluate the antitumor activity of this combination.

[0057] The trial will be conducted in two phases (Phase 1 and Phase 2). Phase 1 will evaluate brentuximab vedotin (BV) at a dose of 48 milligrams per square meter (48 mg / m 2 ) or 36 mg / m 2 Doxorubicin is administered by intravenous infusion at a dose of 25 mg / m once on days 1 and 15 of each 28-day cycle. 2 , vinblastine 6 mg / m 2 and dacarbazine 375 mg / m 2 Approximately one hour after administration, subjects will receive the treatment via intravenous infusion once on days 1 and 15 of each 28-day cycle for up to six cycles.

[0058] After completing observation for dose-limiting toxicity (DLT) in the first 6 subjects, if 0 or 1 subject experienced DLT, 2 is the recommended BV dose for Phase 2 of this study. If at any time point, DLT occurs in 2 or more of the maximum 6 subjects evaluable for DLT, the BV dose will be increased to 36 mg / m using the same dosing schedule as above. 2 In Phase 2, BV will be administered at the recommended Phase 2 dose using the same dosing schedule as in Phase 1.

[0059] Subjects will be evaluated to determine, among other things, the recommended dose of BV in combination with doxorubicin, vinblastine, and dacarbazine in the pediatric population; the proportion of subjects experiencing an adverse event (AE) (e.g., from the time of first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy); the proportion of subjects experiencing a serious adverse event (SAE) (e.g., from the time of first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy); the proportion of subjects experiencing a complete response (CR) (e.g., from the time of first dose of protocol therapy through 30 days after administration of the last dose of protocol therapy); The study will determine one or more of the following: proportion of subjects whose disease is positron emission tomography (PET) negative after two cycles of protocol therapy (e.g., as assessed by an IRF according to IWG criteria); proportion of subjects who experience a partial response (PR) (e.g., as assessed by an IRF at EOT according to IWG criteria); proportion of subjects who experience an overall response (OR) (e.g., as assessed by an IRF at EOT according to IWG criteria); and proportion of subjects in the response-evaluable population who complete six 28-day treatment cycles at the recommended dose.

[0060] Subjects treated with BV in combination with adriamycin, vinblastine and dacarbazine experienced one or more of the following: acceptable rates of subjects experiencing AEs and SAEs, and significant rates of subjects experiencing CR, PET-negative disease, PR, OR and completion of 6 treatment cycles.

[0061] It is to be understood that all numerical boundaries (such as "about," "at least," "less than," and "greater than") describing certain parameters in this application necessarily include any range bounded by the recited values. Thus, for example, a description of "at least 1, at least 2, at least 3, at least 4, or at least 5" also denotes ranges such as 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, and 4 to 5, among others.

[0062] With respect to all patents, applications or other references cited herein (such as non-patent literature and reference sequence information), it is understood that they are incorporated by reference in their entirety for all purposes and for the statements made. In the event of any inconsistency between the documents incorporated herein and this application, this application will take precedence. All information related to the reference gene sequences disclosed herein, such as GeneID or other accession numbers (typically referencing National Center for Biotechnology Information (NCBI) accession numbers), including, for example, genomic loci, genomic sequences, functional annotations, allelic variants and reference mRNAs (including, for example, exon boundaries or response elements), protein sequences (including conserved domain structures), Homologene, OMIM, chemical references (such as PubChem Compound, PubChem Substance or PubChem Bioassay entries (including their annotations such as structures and assays), etc.), are incorporated by reference in their entirety.

[0063] The headings used in this application are for convenience only and have no effect on the interpretation of this application.

[0064] Preferred features of each aspect provided by the present invention are applicable mutatis mutandis to all other aspects of the present invention and are illustrated by the dependent claims without limitation, including combinations and permutations of individual 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 the examples can be adapted for use in the claimed invention in a piecemeal manner without departing from the present invention. For example, with respect to the disclosed materials, even if specific reference to each of the various combinations and permutations of these compounds individually and collectively is not explicitly disclosed, each is specifically contemplated and described herein. Thus, if a group of elements A, B, and C and a group of D, E, and F are disclosed, and an example of a combination of elements A-D is disclosed, each is individually and collectively contemplated, even if not individually shown. Thus, in this example, from the disclosure of examples of combinations A, B and C, D, E and F, and A-D, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F is specifically contemplated and each of the combinations is considered to be disclosed. Similarly, any subset or combination of these is specifically contemplated and disclosed. Thus, for example, from the disclosure of examples of combinations A, B and C, D, E and F, and A-D, the subgroups A-E, B-F, and C-E are specifically contemplated and each of the subgroups is considered to be disclosed. This concept applies to all aspects of this application, including the elements of the composition and the steps of the method of making or using the composition.

[0065] The above aspects of the invention may be claimed in any combination or permutation, so long as such combination or permutation is novel and non-obvious over the prior art, as would be recognized by one of skill in the art following the teachings herein; i.e., to the extent that certain elements are described in one or more references known to those of skill in the art, they may be excluded from the claimed invention by, inter alia, a negative disclaimer or disclaimer of the feature or combination of features.

Claims

1. A composition for treating blood or lymphatic cancer in a non-adult human subject comprising brentuximab vedotin, wherein the brentuximab vedotin is administered to the subject at a body surface area equivalent dose of 71.5 mg / m2, and the blood or lymphatic cancer expresses CD30.

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

3. The composition described in claim 1 or claim 2, wherein the cancer is Hodgkin's lymphoma, anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL) or mantle cell lymphoma (MTCL).

4. The composition described in claim 3, wherein the cancer is recurrent or refractory Hodgkin's lymphoma.

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

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

7. The composition of claim 1, wherein the subject is undergoing combination chemotherapy.

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

9. The composition of claim 7, wherein the combination chemotherapy includes AVD and / or CHP.

10. A composition described in any one of claims 1 to 9, wherein the non-adult human subject is from about 5 to about 17 years of age.

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

12. The composition of claim 11, wherein the composition is administered for up to 16 treatment cycles.

13. The composition of claim 12, wherein the composition is administered for 16 treatment cycles.

14. The composition of claim 11, wherein the composition is administered for nine treatment cycles.

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