Method for reducing side effects of Anti- CD30 antibody-drug conjugate therapy

Abstract

To provide a method for ameliorating adverse event peripheral neuropathies in a subject undergoing treatment with an anti- CD30 antibody-drug conjugate and optionally also receiving concomitant chemotherapies.SOLUTION: 1. Provided is a method of treating a subject who has exhibited peripheral neuropathy of Grade 2 or greater after initiating treatment with an anti- 2mg antibody-drug conjugate therapy at a dose of CD30 / kg or greater, comprising administering the anti- 9mg antibody-drug conjugate therapy at a dose of 0. CD30 / kg.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 570,901, filed October 11, 2017, U.S. Provisional Patent Application No. 62 / 580,267, filed November 1, 2017, U.S. Provisional Patent Application No. 62 / 639,308, filed March 6, 2018, and U.S. Provisional Patent Application No. 62 / 764,805, filed August 16, 2018, each of which is incorporated herein by reference.

[0002] The present disclosure relates generally to methods of reducing neutropenia and peripheral neuropathy in subjects receiving anti-CD30 antibody drug conjugate therapy, optionally in combination with a chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine. [Background technology]

[0003] Outcomes for patients with advanced-stage Hodgkin lymphoma have improved dramatically over the past half century. 1 Although there are regional variations, the most commonly used frontline treatment regimen, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), has remained unchanged since its first description in 1975.

[0004] Up to 30% of patients with stage III / IV Hodgkin lymphoma have refractory disease or relapse after frontline ABVD. 2~4 Bleomycin is considered the least active of the four components of ABVD, is associated with unpredictable and sometimes fatal pulmonary toxicity, and is often withdrawn from later cycles of chemotherapy due to pulmonary symptoms. 5、6 Recent studies suggest that interim positron emission tomography (PET)-guided response-adaptive therapy using 18F-fluorodeoxyglucose may offer a more personalized treatment approach, with escalating reduction / intensification of treatment intensity depending on early response to treatment. 7、8Efforts are also being made to incorporate new drugs into established scaffolds to improve efficacy and reduce toxicity. 9

[0005] CD30 is a characteristic surface antigen expressed on Reed-Sternberg cells of classical Hodgkin's lymphoma. 10 Brentuximab vedotin is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E. Brentuximab vedotin is approved for the treatment of patients with classical Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or after failure of at least two prior multiagent chemotherapy treatment regimens in patients who are not ASCT candidates, and as post-ASCT consolidation therapy for Hodgkin lymphoma patients at high risk of relapse / progression. 11、12 It is also approved for systemic anaplastic large cell lymphoma after failure of at least one multiagent chemotherapy regimen.

[0006] A previous phase 1, dose-escalation study in advanced Hodgkin lymphoma evaluated frontline brentuximab vedotin in combination with either ABVD or AVD (doxorubicin, vinblastine, dacarbazine) [Younes A, Connors JM, Park SI, et al. Patients with newly diagnosed Hodgkin lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 2013;14:1348-56]. Summary of the Invention

[0007] The present disclosure provides improved methods for administering anti-CD30 antibody-drug conjugates and reducing adverse events in subjects undergoing anti-CD30 antibody-drug conjugate therapy. In some embodiments, adjusting the amount and / or timing of the anti-CD30 antibody-drug conjugate can be used to reduce adverse events. In another embodiment, side effects including neutropenia, febrile neutropenia, or infections are reduced by co-administration of an anti-CD30 antibody-drug conjugate with a granulopoiesis-stimulating factor.

[0008] In one aspect, the present disclosure provides a method of administering an anti-CD30 drug conjugate, e.g., brentuximab vedotin, to a subject in need thereof, e.g., at a dose of 0.9 mg / kg administered every two weeks. The subject in need thereof may have a hematological cancer, e.g., classical Hodgkin's lymphoma. In various embodiments, the present disclosure provides a method of treating a subject who exhibits grade 2 or higher peripheral neuropathy after initiating anti-CD30 antibody-drug conjugate therapy at a dose of 1.2 mg / kg or higher, the method comprising administering the anti-CD30 antibody-drug conjugate at a dose of 0.9 mg / kg. In various embodiments, the subject exhibits grade 2 or grade 3 peripheral neuropathy. In various embodiments, if the subject exhibits grade 3 neuropathy, administration of the anti-CD30 antibody-drug conjugate is withheld until the peripheral neuropathy decreases to grade 2 or lower, after which 0.9 mg / kg of the anti-CD30 antibody-drug conjugate is administered.

[0009] In various embodiments, if the subject exhibits Grade 3 neuropathy, administration of the anti-CD30 antibody drug conjugate is reduced, for example to 0.9 mg / kg, until peripheral neuropathy is reduced to Grade 2 or less, after which 0.9 mg / kg of the anti-CD30 antibody drug conjugate is administered or maintained.

[0010] In various embodiments, the subject exhibited grade 2 or 3 peripheral neuropathy after initiating brentuximab vedotin at a dose of 1.8 mg / kg every 3 weeks.

[0011] In various embodiments, the subject exhibited grade 2 or 3 peripheral neuropathy after initiating anti-CD30 antibody-drug conjugate therapy at a dose of 1.2 mg / kg every two weeks, optionally in combination with a chemotherapy treatment regimen. It is contemplated that the treatment regimen may include chemotherapeutic agents known in the field of cancer treatment. Exemplary chemotherapeutic agents are disclosed in more detail in the detailed description. In various embodiments, the methods herein include treatment comprising chemotherapy consisting essentially of doxorubicin (A), vinblastine (V), and / or dacarbazine (D) therapy. Preferably, the anti-CD30 antibody-drug conjugate and AVD therapy are administered every two weeks.

[0012] In various embodiments, the dose of the anti-CD30 antibody drug conjugate is increased from 0.9 mg / kg to 1.8 mg / kg or 1.2 mg / kg after improvement of Grade 2 or Grade 3 peripheral neuropathy to Grade 1 or less, and upon increase to 1.2 mg / kg, administration is optionally combined with chemotherapy consisting essentially of doxorubicin, vinblastine, and / or dacarbazine therapy. Preferably, the anti-CD30 antibody drug conjugate and AVD therapy are administered every two weeks.

[0013] In various embodiments, neuropathy is measured periodically using standard assays known in the art.

[0014] In various embodiments, if a patient experiences renal or hepatic impairment, the dose of the anti-CD30 antibody-drug conjugate can be reduced. In various embodiments, if a subject experiences mild hepatic impairment (Child-Pugh A), the dose is reduced to approximately 0.9 mg / kg administered every two weeks, up to a maximum of 90 mg (depending on the patient's weight) administered every two weeks. In various embodiments, if a subject experiences mild (CrCl greater than 50-80 mL / min) or moderate (CrCl If renal impairment occurs (30-50 mL / min), the dose of anti-CD30 antibody-drug conjugate is maintained at 1.2 mg / kg up to a maximum of 120 mg every 2 weeks.

[0015] In various embodiments, when the anti-CD30 antibody drug conjugate is administered at 1.2 mg / kg with AVD combination therapy, the combination therapy is administered every two weeks. In various embodiments, the combination therapy is administered on days 1 and 15 of a 28-day cycle. In various embodiments, the anti-CD30 antibody drug conjugate + AVD combination therapy is administered for six cycles or less. In various embodiments, the anti-CD30 antibody drug conjugate + AVD combination therapy is administered for four to six cycles. In various embodiments, the anti-CD30 antibody drug conjugate + AVD therapy is administered for four, five, or six cycles.

[0016] In various embodiments, therapy is administered until a PET scan determines there is no tumor or tumor progression.

[0017] In various embodiments, the neuropathy is peripheral motor neuropathy or peripheral sensory neuropathy. In various embodiments, the treatment alleviates one or more symptoms of peripheral neuropathy selected from the group consisting of paresthesia, hypoesthesia, polyneuropathy, muscle weakness, and demyelinating polyneuropathy.

[0018] In various embodiments, if peripheral neuropathy appears, the dose of the anti-CD30 antibody drug conjugate is delayed for one or two weeks, and therapy is continued if the neuropathy is determined to resolve or be Grade 2 or less, or Grade 1 or less.

[0019] In a second aspect, the present disclosure provides methods for treating hematological cancer in a subject, comprising co-administering an anti-CD30 antibody-drug conjugate and a granulopoiesis stimulating factor, e.g., as primary prevention, beginning with cycle 1 of administration of the anti-CD30 antibody-drug conjugate or the first administration of anti-CD30 antibody-drug conjugate therapy. In various embodiments, the granulopoiesis stimulating factor can also be used in combination with any standard or modified chemotherapy treatment regimen, e.g., as frontline therapy. For example, treatment beginning with cycle 1 of administration of the anti-CD30 antibody-drug conjugate, e.g., as primary prevention, includes administering the granulopoiesis stimulating factor within one day to seven days after initiating cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered within one or two days to five days after initiating cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In some embodiments, the granulopoiesis stimulating factor is administered on the same day as the antibody-drug conjugate treatment. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration or dose of the anti-CD30 antibody drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration or dose of the anti-CD30 antibody drug conjugate.

[0020] In various embodiments of this second aspect, the method is for reducing the incidence of neutropenia or febrile neutropenia in a subject receiving an anti-CD30 antibody-drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy or before the subject experiences treatment-emergent neutropenia. In various embodiments, the subject does not experience treatment-emergent Grade 3-4 neutropenia after administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the subject has febrile neutropenia and is 60 years of age or older.

[0021] In various embodiments of this second aspect, the method is for reducing the incidence of infection or other adverse events in a subject receiving an anti-CD30 antibody-drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy or to the subject before the subject experiences treatment-emergent neutropenia. In various embodiments, the subject does not experience treatment-emergent Grade 3-4 neutropenia after administration of the anti-CD30 antibody-drug conjugate.

[0022] In various embodiments, the granulopoiesis stimulating factor is administered 1 to 7 days, or 1 to 5 days, or 2 to 5 days after the second or subsequent administration of the anti-CD30 antibody drug conjugate. In some embodiments, the granulopoiesis stimulating factor is administered on the same day as the second or subsequent antibody drug conjugate treatment. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate, or about 24 hours to about 36 hours after each dose of the anti-CD30 antibody drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered 24 hours to about 36 hours after each administration, i.e., each dose, of the anti-CD30 antibody drug conjugate.

[0023] In various embodiments, the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy or before the subject experiences treatment-emergent neutropenia. In various embodiments, the subject does not experience treatment-emergent Grade 3-4 neutropenia after administration of the anti-CD30 antibody-drug conjugate.

[0024] In various embodiments, the granulopoiesis stimulating factor is granulocyte colony-stimulating factor (GCSF). In various embodiments, the GCSF is long-acting GCSF or is not long-acting GCSF. In various embodiments, the granulopoiesis stimulating factor is granulocyte-monocyte colony-stimulating factor (GM-CSF). In various embodiments, the GCSF is long-acting and is administered in a single dose 1, 2, or 3 days after administration of the anti-CD30 antibody-drug conjugate. In various embodiments, G-CSF is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate. In various embodiments, G-CSF is administered 24 hours to 36 hours after each administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the stimulating agent is GMCSF or GCSF, which is not long-acting and is administered multiple times (e.g., several times daily) for a period of at least 3, 4, 5, 6, or more days, beginning 1, 2, 3, 4, 5, 6, or 7 days after administration of the anti-CD30 antibody drug conjugate. In various embodiments, the granulopoiesis stimulating agent is pegfilgrastim or filgrastim.

[0025] In various embodiments, the anti-CD30 antibody drug conjugate is administered every three weeks.

[0026] In various embodiments, the anti-CD30 antibody drug conjugate is administered every two weeks. In various embodiments, the anti-CD30 antibody drug conjugate is administered on days 1 and 15 of a 28-day cycle. In various embodiments, the anti-CD30 antibody drug conjugate is administered for six cycles or less. In various embodiments, the anti-CD30 antibody drug conjugate is administered for four to six cycles. In various embodiments, the method further comprises administering chemotherapy consisting essentially of doxorubicin, vinblastine, and / or dacarbazine as a combination therapy, preferably an A+AVD therapy, on the same day as the anti-CD30 antibody drug conjugate therapy.

[0027] In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate comprises i) a heavy chain CDR1 set forth in SEQ ID NO: 4, a heavy chain CDR2 set forth in SEQ ID NO: 6, a heavy chain CDR3 set forth in SEQ ID NO: 8, and ii) a light chain CDR1 set forth in SEQ ID NO: 12, a light chain CDR2 set forth in SEQ ID NO: 14, and a light chain CDR13 set forth in SEQ ID NO: 16.

[0028] In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate also comprises i) an amino acid sequence at least 85% identical to the heavy chain variable region set forth in SEQ ID NO: 2, and ii) an amino acid sequence at least 85% identical to the light chain variable region set forth in SEQ ID NO: 10. It is contemplated that the amino acid variable region sequence may be 90%, 95%, 96%, 97%, 98%, or 99% identical to either SEQ ID NO: 2 or SEQ ID NO: 10.

[0029] In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a monoclonal antibody. Anti-CD30 Antibody In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a chimeric AC10 antibody.

[0030] In various embodiments, the antibody-drug conjugate comprises monomethyl auristatin E and a protease-cleavable linker. In various embodiments, the protease-cleavable linker comprises a thiol-reactive spacer and a dipeptide. In various embodiments, the protease-cleavable linker consists of a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer.

[0031] In various embodiments, the antibody is an IgG antibody, preferably an IgG1 antibody.

[0032] In various embodiments, the anti-CD30 antibody drug conjugate is brentuximab vedotin.

[0033] In various embodiments, the subject is also receiving chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as combination therapy.

[0034] In various embodiments, the anti-CD30 antibody drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg and doxorubicin is administered at 25 mg / m 2 and vinblastine at 6 mg / m 2 and dacarbazine 375 mg / m 2 It is administered at .

[0035] In various embodiments, the granulopoiesis stimulating factor, e.g., G-CSF, is administered at a dose range of 5-10 mcg / kg / day, or 300-600 mcg / day. In various embodiments, the granulopoiesis stimulating factor is administered at a dose of 6 mg / dose. In various embodiments, the G-CSF is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate, and the subject is also undergoing AVD therapy.

[0036] In various embodiments, the granulopoiesis stimulating factor is administered intravenously or subcutaneously. In various embodiments, the granulopoiesis stimulating factor is administered in a single dose or multiple doses, for example, long-acting GCSF may be administered in a single dose or multiple doses on the same day, and non-long-acting GCSF may be administered multiple times over multiple days.

[0037] In any of the aspects disclosed herein, the subject has a hematological cancer. In various embodiments, the hematological cancer is selected from the group consisting of classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL).

[0038] In various embodiments, the hematological cancer is classical Hodgkin's lymphoma. In various embodiments, the hematological cancer is stage III or IV classical Hodgkin's lymphoma. In various embodiments, the subject's hematological cancer has not been treated.

[0039] In various embodiments, the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL).

[0040] In various embodiments, the cutaneous T-cell lymphoma (CTCL) is mycosis fungoides (MF). In various embodiments, the mycosis fungoides (MF) is CD30-positive mycosis fungoides (MF).

[0041] In various embodiments, the cutaneous T-cell lymphoma (CTCL) is primary cutaneous anaplastic large cell lymphoma (pcALCL).

[0042] In various embodiments, the subject has previously received systemic therapy.

[0043] In a third aspect, the disclosure provides a method of treating a subject with advanced classical Hodgkin lymphoma, the method comprising administering as frontline treatment an effective amount of a composition comprising bretuximab vedotin in combination with an AVD regimen consisting of doxorubicin, vinblastine, and dacarbazine, wherein the brentuximab vedotin is administered at 1.2 mg / kg every two weeks and the doxorubicin is administered at 25 mg / m every two weeks. 2 and vinblastine at 6 mg / m every 2 weeks. 2 and dacarbazine 375 mg / m every 2 weeks. 2The AVD therapy is administered at 100 mg / kg / day, preferably on days 1 and 15 of a 28-day cycle, for up to six cycles, and brentuximab vedotin is administered within about one hour of administration of the AVD therapy. Optionally, the subject is characterized by one or more of the following: (1) Stage 4 Hodgkin lymphoma, (2) HL involving at least one extranodal site, e.g., at least one, two, or three extranodal sites, (3) age less than 60 years or less than 65 years, (4) an International Prognostic Score of 4-7 [4, 5, 6, 7], or (5) a pre-therapy Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The methods herein further provide that the subject's progression-free survival (PFS) after therapy is maintained for more than one year. In various embodiments, the subject's progression-free survival (PFS) after therapy is maintained for about two years. In certain embodiments, after four to six cycles of the A+AVD therapy, the subject has a Deauville score of 3 or less, or 2 or less.

[0044] In another aspect, the disclosure provides an anti-CD30 antibody drug conjugate for use in treating a subject who has exhibited Grade 2 or greater peripheral neuropathy after initiating anti-CD30 antibody drug conjugate therapy at a dose of 1.2 mg / kg or greater, wherein the patient is administered the anti-CD30 antibody drug conjugate at a dose of 0.9 mg / kg.

[0045] In a further aspect, contemplated herein is an anti-CD30 antibody drug conjugate for use in treating a hematological cancer in a subject, comprising administering the anti-CD30 antibody drug conjugate and prophylactically administering a granulopoiesis stimulating factor, wherein the stimulating factor is administered 1 to 7 days after starting cycle 1 of administration of the anti-CD30 antibody drug conjugate.

[0046] In a related aspect, an anti-CD30 antibody-drug conjugate for use in reducing the incidence of neutropenia, infection, or other adverse events in a subject receiving treatment with the anti-CD30 antibody-drug conjugate is also contemplated, comprising prophylactically administering to the subject a granulopoiesis stimulating factor, the stimulating factor being administered 1 to 7 days after starting cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered about 24 to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate, optionally in combination with a chemotherapy treatment regimen described herein. In various embodiments, the granulopoiesis stimulating factor is long-acting G-CSF. In various embodiments, the G-CSF is administered 24 to 36 hours after each administration of the anti-CD30 antibody-drug conjugate.

[0047] It is specifically provided herein that all aspects of the above disclosure involving methods of treatment are applicable to anti-CD30 antibody drug conjugates for use in any of the above indications.

[0048] It is understood that each feature or embodiment, or combination, described herein is intended to be a non-limiting, illustrative example of any of the aspects of the invention, and as such, be combinable with any other feature or embodiment, or combination, described herein, e.g., "one embodiment," "some embodiments," "particular embodiments," "further embodiments," "particular exemplary embodiments," and / or "another embodiment," etc. When features are described in this language, each of these embodiment types is a non-limiting example of the feature that is intended to be combined with any other feature or combination of features described herein, without listing all possible combinations. Such features or combinations of features are provided for any of the aspects of the invention. When example values ​​within ranges are disclosed, all of these examples are contemplated as possible endpoints of the range, and all numerical values ​​between such endpoints are contemplated, with all combinations of upper and lower endpoints being envisioned. [Brief explanation of the drawings]

[0049] [Figure 1A] Modified progression-free survival in the intention-to-treat population. Figure 1A shows Kaplan-Meier estimates of modified progression-free survival by treatment group based on central review committee assessment. [Figure 1B] Figure 1B shows investigator-generated Kaplan-Meier estimates of modified progression-free survival by treatment group. [Figure 1C] Figure 1C shows a forest plot analysis of modified progression-free survival based on central review committee assessment for key prespecified subgroups. The intention-to-treat population included all patients who underwent randomization. [Figure 2] (Table 1). Baseline patient demographics and clinical characteristics (intention-to-treat population). [Figure 3] (Table 2). Summary of subsequent therapy and end-of-treatment Deauville scores for events recorded in modified progression-free survival as assessed by the central review committee, and correlation with investigator-recorded events (intention-to-treat population). [Figure 4] (Table 3). Summary of responses in the intention-to-treat population. [Figure 5-1] (Table 4). Summary of adverse events in the safety data analysis population. [Figure 5-2] (Table 4). Summary of adverse events in the safety data analysis population. [Figure 6] Kaplan-Meier analysis of overall survival in the intention-to-treat population. [Figure 7] Brentuximab vedotin dose adjustment details. [Figure 8] Summary of first subsequent chemotherapy for patients who did not achieve a complete response at the completion of frontline therapy. [Figure 9] Summary of reasons for switching to alternative chemotherapy during frontline treatment (safety data analysis population). [Figure 10] Exposure to individual treatment plan components and their dosage adjustments. [Figure 11]Overview of peripheral neuropathy (SMQ) (safety data analysis set). DETAILED DESCRIPTION OF THE INVENTION

[0050] The present disclosure provides methods for ameliorating adverse events associated with the treatment of cancer with anti-CD30 antibody-drug conjugates. The treatment regimens described herein are effective in reducing peripheral neuropathy and ameliorating neutropenia, febrile neutropenia, and / or therapy-related infections in treated patients.

[0051] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following references provide those skilled in the art with general definitions of many of the terms used in this invention: DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (Singleton et al., 2nd ed., 1994), CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker, ed., 1988), THE GLOSSARY OF GENETICS, 5th ed., R. Rieger et al., ed., Springer Verlag (1991), and Hale and Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991).

[0052] Each publication, patent application, patent, and other reference cited herein is incorporated by reference in its entirety, to the extent not inconsistent with this disclosure.

[0053] As used in this specification and the appended claims, the singular forms "a," "the," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "derivative" includes a plurality of such derivatives, reference to "the object" includes a reference to one or more objects, and so forth.

[0054] Where the descriptions of various embodiments use the term "comprising," those skilled in the art will further understand that in some specific instances, the embodiments may alternatively be described using the phrase "consisting essentially of" or "consisting of."

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, exemplary methods, devices, and materials are described herein.

[0056] As used herein, a "therapeutically effective amount" refers to an amount of an agent effective to produce an intended beneficial effect on health.

[0057] As used herein, "antibody+AVD therapy" or "A+AVD therapy" refers to treatment of a subject with an anti-CD30 antibody-drug conjugate described herein in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD therapy).

[0058] As used herein, "lymphoma" refers to a hematological malignancy that typically arises from hyperproliferative cells of lymphoid origin. Lymphomas can be classified into two major types: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Lymphomas can also be classified according to the normal cell type that most closely resembles the cancer cells, according to phenotypic, molecular, or cytogenetic markers. Lymphoma subtypes based on this classification include, but are not limited to, mature B-cell neoplasms, mature T-cell and natural killer (NK)-cell neoplasms, Hodgkin's lymphoma, and immunodeficiency-associated lymphoproliferative disorders. Subtypes of lymphoma include precursor T-cell lymphoblastic lymphoma (sometimes called lymphoblastic leukemia because T-cell lymphoblasts are produced in the bone marrow), follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic lymphoma (sometimes called leukemia because of peripheral blood involvement), MALT lymphoma, Burkitt lymphoma, mycosis fungoides and its more aggressive variant Sézary disease, peripheral T-cell lymphoma not otherwise specified, nodular sclerosis of Hodgkin lymphoma, and mixed cellularity subtype Hodgkin lymphoma.

[0059] The term "leukemia," as used herein, refers to a hematological malignancy that typically arises from hyperproliferative cells derived from the bone marrow, and includes, but is not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and acute monocytic leukemia (AMoL). Other leukemias include hairy cell leukemia (HCL), T-cell lymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and adult T-cell leukemia.

[0060] As used herein, "prophylactic" or "primary prevention" refers to the prevention of neutropenia or refers to administration of an agent such as a colony-stimulating factor or granulopoiesis-stimulating factor prior to the onset of neutropenic symptoms. Prophylaxis is contemplated to include administration of a granulopoiesis-stimulating factor at the beginning of cycle 1 of administration of an anti-CD30 conjugate therapy, or the first administration of an anti-CD30 antibody-drug conjugate therapy, optionally in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and / or dacarbazine (AVD therapy). The terms "beginning with cycle 1 of administration of an anti-CD30 antibody-drug conjugate" and "first administration of an anti-CD30 antibody-drug conjugate" are used interchangeably herein with respect to treatment with a granulopoiesis-stimulating factor.

[0061] As used herein, "granulopoiesis stimulating factor" refers to agents such as cytokines or other growth factors that can induce the production of neutrophils and other granulocytes.Exemplary granulopoiesis stimulating factors include, but are not limited to, granulocyte colony-stimulating factor (GCSF) and its derivatives, such as filgrastim and long-acting GCSF PEG-filgrastim, or granulocyte-monocyte colony-stimulating factor (GMCSF).

[0062] As used herein, "neutropenia" refers to abnormally low neutrophil concentrations in the blood. "Reducing the incidence of neutropenia in a subject" refers to reducing the number of neutropenic episodes in a treated subject and / or reducing the severity of neutropenic episodes in a subject. "Preventing neutropenia" refers to preventing or inhibiting the onset of neutropenia, for example, as a result of prophylactic treatment with a granulopoiesis-stimulating factor. The normal reference range for absolute neutrophil count (ANC) in adults is 1,500 to 8,000 cells per microliter (μl) of blood. Neutropenia can be classified as follows: mild neutropenia (1,000≦ANC<1,500), moderate neutropenia (500≦ANC<1,000), and severe neutropenia (ANC<500). Hsieh et al., Ann.Intern.Med.146, 486-92, 2007.

[0063] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The term "pharmaceutically compatible ingredient" refers to a pharmaceutically acceptable diluent, adjuvant, excipient, or vehicle with which an antibody-drug conjugate is administered.

[0064] 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.

[0065] The term "monoclonal antibody" refers to an antibody that is derived from a single cell clone, including any eukaryotic or prokaryotic cell clone, or a phage clone, and not the method by which it is produced. Thus, the term "monoclonal antibody" as used herein is not limited to antibodies produced through hybridoma technology.

[0066] The terms "identical" or "percent identity," in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that, when compared and aligned for maximum correspondence, are identical or have a certain percentage of identical nucleotides or amino acid residues. To determine percent identity, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between two sequences is The percent identity is a function of the number of identical positions shared by the sequences (i.e., % identity = # of identical positions / total # of positions (e.g., overlapping positions) x 100). In certain embodiments, the two sequences are the same length.

[0067] The term "substantially identical," with respect to two nucleic acids or polypeptides, refers to two or more sequences or subsequences that have at least 70% or at least 75% identity, more typically at least 80% or at least 85% identity, and even more typically at least 90%, at least 95%, or at least 98% identity (e.g., as determined using one of the methods described below).

[0068] The percent identity between two sequences can be determined using a mathematical algorithm.A preferred, non-limiting example of a mathematical algorithm used to compare two sequences is the algorithm of Karlin and Altschul, 1990, Proc.Natl.Acad.Sci.USA 87:2264-2268, modified as in Karlin and Altschul 1993, Proc.Natl.Acad.Sci.USA 90:5873-5877.Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J.Mol.Biol.215:403-410.BLAST nucleotide searches can be performed using the NBLAST program, score=100, word length=12, to obtain nucleotide sequences homologous to the nucleic acid encoding the target protein. BLAST protein searches can be performed using the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences homologous to the protein of interest. To obtain gapped alignments for comparison purposes, gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search that detects distant relationships between molecules (Id). Another preferred, non-limiting example of a mathematical algorithm utilized for sequence comparison is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. Additional algorithms for sequence analysis are known in the art and are described in Torellis and Robotti, 1994, Comput. Appl. Biosci. 10:3-5; FASTA, Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. 85:2444-8.Alternatively, protein sequence alignments can be performed using the CLUSTAL W algorithm as described in Higgins et al., 1996, Methods Enzymol. 266:383-402.

[0069] The abbreviation "MMAE" refers to monomethylauristatin E.

[0070] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0071] The abbreviation "PAB" refers to a self-immolative spacer. [ka]

[0072] The abbreviation "MC" refers to the stretcher maleimidocaproyl. [ka]

[0073] cAC10-MC-vc-PAB-MMAE refers to the chimeric AC10 antibody conjugated to the drug MMAE via the MC-vc-PAB linker.

[0074] An anti-CD30 MC-vc-PAB-MMAE antibody-drug conjugate refers to an anti-CD30 antibody linked to the drug MMAE via a linker comprising the dipeptide valine citrulline and the self-immolative spacer PAB, as shown in formula (I) of U.S. Pat. No. 9,211,319.

[0075] antibody Murine anti-CD30 mAbs known in the art have been generated by immunizing mice with Hodgkin's disease (HD) cell lines or purified CD30 antigen. Originally designated C10 (Bowen et al., 1993, J. Immunol., 151:5896-5906), AC10 differs in that this anti-CD30 mAb was prepared against the human NK-like cell line YT (Bowen et al., 1993, J. Immunol., 151:5896-5906). Initially, the signaling activity of this mAb was demonstrated by downregulating the cell surface expression of CD28 and CD45 molecules, upregulating cell surface CD25 expression, and inducing homotypic adhesion after C10 binding to YT cells. The sequence of the AC10 antibody is shown in SEQ ID NOs: 1-16 and in Table A below. See also US Pat. No. 7,090,843, which is incorporated herein by reference, which discloses chimeric AC10 antibodies.

[0076] In general, the antibodies of the present disclosure immunospecifically bind to CD30 and exert cytostatic and cytotoxic effects against malignant cells of Hodgkin's disease. The antibodies of the present disclosure are preferably monoclonal and may be multispecific, human, humanized, or chimeric antibodies, single-chain antibodies, Fab fragments, F(ab') fragments, fragments produced by an Fab expression library, and CD30-binding fragments of any of the above. As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that immunospecifically binds to CD30. The immunoglobulin molecules of the present disclosure may be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecule.

[0077] In certain embodiments of the present disclosure, the antibody is a human antigen-binding antibody fragment of the present disclosure, including, but not limited to, Fab, Fab' and F(ab'), Fd, single-chain Fv (scFv), single-chain antibodies, disulfide-linked Fv (sdFv), and V L or V HAntigen-binding antibody fragments, including single-chain antibodies, can comprise the variable region(s) alone or in combination with all or a portion of the following: hinge region, CH1, CH2, CH3, and CL domains. Also included in the disclosure are antigen-binding fragments comprising any combination of the variable region(s) and hinge region, CH1, CH2, CH3, and CL domains. Preferably, the antibody is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, "human" antibodies include antibodies having the amino acid sequence of a human immunoglobulin, and are described below and, for example, in U.S. Patent No. 5,939,598 to Kucherlapati et al. As described, these include antibodies isolated from human immunoglobulin libraries, human B cells, or animals transgenic for one or more human immunoglobulins.

[0078] The antibodies of the present disclosure may be monospecific, bispecific, trispecific, or of higher multispecificity. Multispecific antibodies may be specific for different epitopes of CD30, or may be specific for both CD30 and a heterologous protein. See, for example, PCT Publication Nos. WO93 / 17715, WO92 / 08802, WO91 / 00360, and WO92 / 05793; Tutt et al., 1991, J. Immunol. 147:60-69; U.S. Patent Nos. 4,474,893, 4,714,681, 4,925,648, 5,573,920, and 5,601,819; and Kostelny et al., 1992, J. Immunol. 148:1547-1553.

[0079] Antibodies of the present disclosure may be described or specified in terms of the particular CDRs they contain. In certain embodiments, antibodies of the present disclosure comprise one or more CDRs of AC10. The present disclosure encompasses antibodies or derivatives thereof comprising a heavy or light chain variable domain, the variable domain comprising (a) and (b): (a) a set of three CDRs derived from monoclonal antibody AC10, and (b) a set of four framework regions distinct from the set of framework regions of monoclonal antibody AC10, such that the antibody or derivative thereof immunospecifically binds to CD30.

[0080] In certain embodiments, the present disclosure encompasses an antibody or derivative thereof comprising a heavy chain variable domain, wherein the variable domain comprises (a) and (b): (a) a set of three CDRs, the set of CDRs comprising SEQ ID NO: 4, 6, or 8, and (b) a set of four framework regions, the set of framework regions differing from the set of framework regions of monoclonal antibody AC10, wherein the antibody or derivative thereof immunospecifically binds to CD30.

[0081] In various embodiments, the present invention encompasses an antibody or derivative thereof comprising a light chain variable domain, the variable domain comprising: (a) a set of three CDRs, the set of three CDRs comprising SEQ ID NO: 12, 14, or 16; and (b) a set of four framework regions, the set of four framework regions differing from the set of framework regions of monoclonal antibody AC10, such that the antibody or derivative thereof immunospecifically binds to CD30.

[0082] Furthermore, the antibodies of the present disclosure may also be described or specified in terms of their primary structure. Antibodies having at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, and most preferably 98% identity (calculated using methods known in the art and described herein) with the variable region of AC10 are also included in the present invention, preferably comprising the CDRs of AC10. The antibodies of the present invention may also be described or specified in terms of their binding affinity to CD30. Preferred binding affinities are those with a dissociation constant or Kd of 5×10 2 Under M, 10 -2 Less than M, 5 x 10 -3 Under M, 10 -3 Less than M, 5 x 10 -4 Under M, 10 -4 Less than M, 5 x 10 -5 Under M, 10 -5 Less than M, 5 x 10 -6 Under M, 10 -6 Less than M, 5 x 10 -7 Under M, 10 -7 Less than M, 5 x 10 -8 Under M, 10 -8 Less than M, 5 x 10 -9 Under M, 10 -9 Less than M, 5 x 10 -10 Under M, 10 -10 Under M, 5x10 -11 Under M, 10 -11 Under M, 5x10 -12 Under M, 10 -12 Under M, 5x10 -13 Under M, 10 -13 Under M, 5x10 -14 Under M, 10 -14 Under M, 5x10 -15 Less than M or 10 -15 Includes items under M.

[0083] Antibodies also include derivatives modified by the covalent attachment of any type of molecule to the antibody, i.e., such that the covalent attachment does not prevent the antibody from binding to CD30 or from exerting a cytostatic or cytotoxic effect on Hodgkin's disease cells. For example, without limitation, antibody derivatives include antibodies modified by, for example, glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, conjugation to cellular ligands or other proteins, and the like. Any of a number of chemical modifications can be performed using known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, and the like. Furthermore, derivatives may contain one or more non-classical amino acids.

[0084] The antibodies of the present invention can be generated by any suitable method known in the art.

[0085] The present invention further provides nucleic acids comprising a nucleotide sequence encoding a protein of the invention, including, but not limited to, a protein and fragments thereof. The nucleic acids of the invention preferably encode one or more CDRs of an antibody that binds to CD30 and exerts a cytotoxic or cytostatic effect on HD cells. Exemplary nucleic acids of the invention include SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:11, SEQ ID NO:13, or SEQ ID NO:15. Variable region nucleic acids of the invention include SEQ ID NO:1 or SEQ ID NO:9. (See Table A). [Table 1]

[0086] In various embodiments, the antibody is an IgG antibody, eg, an IgG1, IgG2, IgG3, or IgG4 antibody, preferably an IgG1 antibody.

[0087] antibody-drug conjugates The present invention contemplates the use of an antibody-drug conjugate comprising an anti-CD30 antibody covalently linked to MMAE via an MC-vc-PAB linker. The antibody-drug conjugate is delivered to a subject as a pharmaceutical composition. Anti-CD30 antibody-drug conjugates are described in U.S. Patent No. 9,211,319, which is incorporated herein by reference.

[0088] In various embodiments, the anti-CD30 antibody-drug conjugates of the invention have the following formula: [ka] or a pharmaceutically acceptable salt thereof, wherein mAb is an anti-CD30 antibody, S is a sulfur atom of the antibody, A- is a Stretcher unit, and p is about 3 to about 5.

[0089] Drug loading is represented by p, the average number of drug molecules per antibody in a pharmaceutical composition. For example, if p is about 4, the average drug loading, considering all antibodies present in the pharmaceutical composition, is about 4. P ranges from about 3 to about 5, more preferably from about 3.6 to about 4.4, and even more preferably from about 3.8 to about 4.2. P can be about 3, about 4, or about 5. The average number of drugs per antibody in a conjugate reactant preparation can be characterized by conventional means, such as mass spectrometry, ELISA assay, and HPLC. The quantitative distribution of antibody-drug conjugates with respect to p can also be determined. In some instances, separation, purification, and characterization of homogeneous antibody-drug conjugates with a certain p from antibody-drug conjugates with other drug loads can be achieved by means such as reverse-phase HPLC or electrophoresis.

[0090] The Stretcher unit (A) can link the antibody unit to the valine-citrulline amino acid unit via a sulfhydryl group of the antibody. The sulfhydryl group can be generated, for example, by reduction of the interchain disulfide bond of the anti-CD30 antibody. For example, the Stretcher unit can be linked to the antibody via the sulfur atom generated from the reduction of the interchain disulfide bond of the antibody. In some embodiments, the Stretcher unit is linked to the antibody solely via the sulfur atom generated from the reduction of the interchain disulfide bond of the antibody. In some embodiments, the sulfhydryl group can be generated by reacting the amino group of the lysine moiety of the anti-CD30 antibody with 2-iminothiolane (Traut's reagent) or other sulfhydryl-generating reagent. In certain embodiments, the anti-CD30 antibody is a recombinant antibody and is engineered to carry one or more lysines. In certain other embodiments, the recombinant anti-CD30 antibody is engineered to carry additional sulfhydryl groups, for example, additional cysteines.

[0091] The synthesis and structure of MMAE are described in U.S. Patent No. 6,884,869, which is incorporated herein by reference in its entirety for all purposes. The synthesis and structure of exemplary Stretcher units and methods for making antibody-drug conjugates are described, for example, in U.S. Patent Publication Nos. 2006 / 0074008 and 2009 / 0010945, each of which is incorporated herein by reference in its entirety.

[0092] Representative Stretcher units are set forth within the brackets of Formulas IIIa and IIIb of US Pat. No. 9,211,319, incorporated herein by reference.

[0093] In various embodiments, the anti-CD30 antibody-drug conjugate comprises monomethyl auristatin E and a protease-cleavable linker. The protease-cleavable linker is contemplated to include a thiol-reactive spacer and a dipeptide. In various embodiments, the protease-cleavable linker consists of a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer.

[0094] In a preferred embodiment, the anti-CD30 antibody drug conjugate is a Brentzki molecule having the structure: It is cimab vedotin. [ka]

[0095] Brentuximab vedotin is an antibody-drug conjugate directed against CD30, consisting of three components: (i) the chimeric IgG1 antibody cAC10 specific for human CD30, (ii) the microtubule-disrupting agent MMAE, and (iii) a protease-cleavable linker covalently attaching MMAE to cAC10. The drug-to-antibody ratio, or drug loading, is represented by "p" in the structure of brentuximab vedotin and ranges from an integer value of 1 to 8. The average drug loading of brentuximab vedotin in pharmaceutical compositions is approximately 4.

[0096] How to use Provided herein are improved methods for administering anti-CD30 antibody-drug conjugates. Disclosed herein are methods for reducing adverse events in subjects with hematological cancers during administration of anti-CD30 antibody-drug conjugates, optionally in combination with a chemotherapy regimen. In various embodiments, the chemotherapy regimen consists essentially of doxorubicin, vinblastine, and / or dacarbazine, preferably as A+AVD therapy.

[0097] Additional chemotherapeutic agents are disclosed in the table below and can be used alone or in combination with one or more additional chemotherapeutic agents, which can also be administered in combination with the anti-CD30 antibody drug conjugate. [Table 2-1] [Table 2-2] [Table 2-3]

[0098] Hematologic cancer refers to cancer that arises in blood-forming tissues or cells of the immune system. CD30-expressing hematologic cancer refers to a hematologic cancer that expresses the CD30 antigen. The CD30 antigen is expressed in high numbers on tumor cells of select lymphomas and leukemias. Hematologic cancers such as classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, anaplastic large cell lymphoma, and cutaneous T-cell lymphoma (CTCL) are examples of hematologic cancers that can be treated with this method.

[0099] In any of the aspects or embodiments herein, the methods herein are provided for treating a subject who is newly diagnosed and has not been previously treated for a hematological cancer, or a subject who has relapsed. It is contemplated that the subject has advanced classical Hodgkin's lymphoma (e.g., stage III or stage IV).

[0100] In various embodiments, the present disclosure provides brentuximab vedotin in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD therapy). (A) is provided, wherein brentuximab vedotin is administered at 1.2 mg / kg and doxorubicin is administered at 25 mg / m 2 and vinblastine at 6 mg / m 2and dacarbazine 375 mg / m 2 and the brentuximab vedotin is administered within one hour of administering AVD therapy. It has been shown herein that the above treatment appears to have increased efficacy in subjects characterized by one or more of the following: (1) stage 4 Hodgkin lymphoma, (2) HL involving at least one extranodal site, e.g., at least one, two, or three extranodal sites, (3) an International Prognostic Score of 4-7 [4, 5, 6, 7], (4) an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less before therapy, and (5) age less than 60 or 65. The methods herein further provide the subject's progression-free survival (PFS) after therapy is maintained for more than one year. In various embodiments, the subject's progression-free survival (PFS) after therapy is maintained for approximately two years. In certain embodiments, after four to six cycles of A+AVD therapy, the subject has a Deauville score of 3 or less, or 2 or less. In certain embodiments, after two cycles of therapy (ie, four administrations), the subject has a Deauville score of 1 or 2.

[0101] peripheral neuropathy Peripheral neuropathy occurs as a result of damage to the peripheral nervous system during treatment with anti-CD30 antibody-drug conjugates. Symptoms include numbness or tingling, pins-and-needles sensations (paresthesia), and muscle weakness. Damage to motor nerves is most commonly associated with muscle weakness.

[0102] Provided herein are methods of treatment that include administering an anti-CD30 antibody-drug conjugate, e.g., brentuximab vedotin, at a dose of 1.2 mg / kg or greater to a subject who exhibits peripheral neuropathy of Grade 2 or greater, followed by administering the anti-CD30 antibody-drug conjugate at a dose of 0.9 mg / kg. In various embodiments, if the subject exhibits Grade 3 neuropathy, administration of the anti-CD30 antibody-drug conjugate, e.g., brentuximab vedotin, is withheld until the peripheral neuropathy is reduced to Grade 2 or less, after which 0.9 mg / kg of the anti-CD30 antibody-drug conjugate is administered. In some embodiments, the reduced dose of 0.9 mg / kg is given every two weeks up to a maximum dose of 90 mg.

[0103] In various embodiments, if the subject exhibits Grade 3 neuropathy, administration of the anti-CD30 antibody drug conjugate is reduced, for example to 0.9 mg / kg, until peripheral neuropathy is reduced to Grade 2 or less, after which 0.9 mg / kg of the anti-CD30 antibody drug conjugate is administered or maintained.

[0104] In certain embodiments, the subject exhibited grade 2 or 3 peripheral neuropathy after initiating anti-CD30 antibody drug conjugate administration at a dose of 1.8 mg / kg. In various embodiments, the subject exhibited grade 2 or 3 peripheral neuropathy after initiating anti-CD30 antibody drug conjugate administration at a dose of 1.2 mg / kg, optionally in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as concomitant therapy.

[0105] In certain embodiments, after improvement of Grade 2 or Grade 3 peripheral neuropathy to Grade 1 or less, the dose of the anti-CD30 antibody-drug conjugate is increased to 1.8 mg / kg or 1.2 mg / kg, and when the dose is increased to 1.2 mg / kg, administration is optionally in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as a combination therapy. In certain embodiments, if the peripheral neuropathy is Grade 2, a reduced dose of 0.9 mg / kg is given every two weeks up to a maximum dose of 90 mg.

[0106] Methods for measuring neuropathy are known in the art and are utilized by treating physicians to monitor and diagnose neuropathy in subjects receiving anti-CD30 antibody-drug conjugate therapy. For example, the National Cancer Information Center-Common Toxicity Criteria (NCIC-CCT) describes Grade 1 PN as characterized by mild paresthesia and / or loss of deep tendon flexion. Grade 2 PN is characterized by miles or moderate objective sensory loss and / or moderate paresthesia, while Grade 3 PN is characterized by sensory loss and / or paresthesia that interferes with function. Grade 4 PN is characterized by paralysis.

[0107] In various embodiments, when the anti-CD30 antibody drug conjugate is administered at 1.2 mg / kg with the AVD combination therapy, the combination therapy is administered every two weeks, e.g., on days 1 and 15 of a 28-day cycle.

[0108] In various embodiments, the anti-CD30 antibody drug conjugate+AVD combination therapy is administered for six cycles or less, for example, four to six cycles, or four, five, or six cycles.

[0109] It is contemplated that therapy will be administered until a PET scan reveals no tumor or tumor progression. If a tumor is still visible on a PET scan after treatment is completed, for example, after 4-6 cycles, the course of treatment will be repeated as needed until the PET scan becomes negative, tumor progression slows, or no tumor progression is observed. Repeated cycles may begin without a break or after 1, 2, 3, 4, 5, 6, or more weeks after the initial treatment with A+AVD therapy.

[0110] In various embodiments, the anti-CD30 antibody-drug conjugate, e.g., brentuximab vedotin therapy, is administered by intravenous infusion over 30 minutes. In certain embodiments, the anti-CD30 antibody-drug conjugate, in combination with AVD therapy, is administered at 1.2 mg / kg up to 120 mg.

[0111] The treatment is useful for treating peripheral motor neuropathy or peripheral sensory neuropathy. The treatment relieves one or more symptoms of peripheral neuropathy, including, but not limited to, paresthesia, hypoesthesia, polyneuropathy, muscle weakness, and demyelinating polyneuropathy.

[0112] In various embodiments, if peripheral neuropathy appears, the dose of the anti-CD30 antibody drug conjugate is delayed for one or two weeks, and therapy is continued if the neuropathy resolves or is determined to be Grade 2 or less or Grade 1 or less.

[0113] Neutropenia Neutropenia is a common side effect of chemotherapy treatment regimens and results from the depletion of neutrophils in the blood of patients receiving chemotherapy. Neutropenia has also been observed with brentuximab vedotin treatment. Neutropenia is generally diagnosed based on the level of neutrophils in the blood. For example, grade 3 neutropenia is defined as an absolute neutrophil count [ANC] <1.0 × 10 9 / L, and grade 4 neutropenia was defined as an absolute neutrophil count [ANC] <0.5 × 10 9 / L, and febrile neutropenia refers to neutropenia accompanied by fever, with a single oral temperature of 38.3°C or higher or 38.0°C or higher for more than 1 hour, and grade 3 / 4 neutropenia.

[0114] It is contemplated herein that a subject receiving an anti-CD30 antibody drug conjugate, e.g., brentuximab vedotin, or an anti-CD30 antibody drug conjugate in combination with chemotherapy, such as AVD combination therapy, will receive a granulopoiesis stimulating agent prophylactically beginning with cycle 1 of administration of the anti-CD30 antibody drug conjugate, e.g., as primary prevention. Exemplary granulopoiesis stimulating agents include granulopoiesis stimulating agents, such as granulopoiesis stimulating agents, and granulopoiesis stimulating agents. Included are granulocyte colony-stimulating factors (GCSF), derivatives of GCSF, or granulocyte-monocyte colony-stimulating factors (GMCSF). Commercially available GCSFs contemplated for use herein are filgrastim (NEUPOGEN®) and pegfilgrastim (NEULASTA®). Commercially available GMCSF is available as sargramostim (LEUKINE®).

[0115] Provided herein are methods of treating hematological cancer in a subject, the methods comprising administering an anti-CD30 antibody-drug conjugate and prophylactically administering a granulopoiesis stimulating factor beginning with cycle 1 of administration of the anti-CD30 antibody-drug conjugate, wherein the granulopoiesis stimulating factor is administered within 1 to 7 days after initiating cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In further embodiments, the granulopoiesis stimulating factor is administered within 1, 2, or 5 days after initiating cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate, optionally in combination with a chemotherapy treatment regimen described herein. In various embodiments, the granulopoiesis stimulating factor is administered after each administration of the anti-CD30 antibody-drug conjugate, i.e., 24 hours to 36 hours after each dose.

[0116] In some embodiments, the method is a method for reducing adverse events associated with administration of an anti-CD30 antibody-drug conjugate, such as neutropenia, febrile neutropenia, the occurrence of infections, fever, gastrointestinal disorders such as constipation, vomiting, diarrhea, stomatitis, abdominal pain, nervous system disorders such as peripheral sensory neuropathy and peripheral motor neuropathy, musculoskeletal disorders such as bone pain and back pain, respiratory disorders such as dyspnea, and other adverse events such as weight loss, increased alanine aminotransferase, decreased appetite, and / or insomnia. In some embodiments, the method is a method for reducing the incidence of neutropenia and / or febrile neutropenia and / or infections associated with administration of an anti-CD30 antibody-drug conjugate.

[0117] Also provided are methods for reducing the incidence of infection in a subject receiving an anti-CD30 antibody-drug conjugate, comprising administering to the subject an amount of a granulopoiesis stimulating factor effective to reduce infection, wherein the granulopoiesis stimulating factor is administered 1 to 7 days after the start of cycle 1 of administration of the anti-CD30 antibody-drug conjugate. The granulopoiesis stimulating factor may also be administered 1 to 7 days, or 1 day, or 2 to 5 days after the start of cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate, optionally in combination with a chemotherapy treatment regimen described herein. In various embodiments, the granulopoiesis stimulating factor is administered 24 hours to 36 hours after each administration of the anti-CD30 antibody-drug conjugate.

[0118] Methods for reducing the incidence of neutropenia and / or febrile neutropenia in a subject receiving treatment with an anti-CD30 antibody-drug conjugate are also contemplated, comprising administering a granulopoiesis stimulating factor to the subject, the stimulating factor being administered 1 to 7 days beginning with cycle 1 of administration of the anti-CD30 antibody-drug conjugate, and optionally 1 day or 2 to 5 days after beginning cycle 1 of administration of the anti-CD30 antibody-drug conjugate. In various embodiments, the subject has febrile neutropenia and is 60 years of age or older. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate, optionally in combination with a chemotherapy treatment regimen described herein. In various embodiments, the granulopoiesis stimulating factor is administered 24 hours to 36 hours after each administration of the anti-CD30 antibody-drug conjugate.

[0119] Further contemplated are methods in which the granulopoiesis stimulating factor is administered 1 to 7 days after the second or subsequent administration of the anti-CD30 antibody drug conjugate. The granulopoiesis stimulating factor is administered one day or two to five days after the second or subsequent administration of the anti-CD30 antibody drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate, optionally in combination with a chemotherapy treatment regimen described herein. In various embodiments, the granulopoiesis stimulating factor is administered 24 hours to 36 hours after each administration of the anti-CD30 antibody drug conjugate.

[0120] In various embodiments, the subject has not received prior anti-CD30 antibody-drug conjugate therapy, hi various embodiments, the subject has not experienced treatment-emergent Grade 3-4 neutropenia following administration of the anti-CD30 antibody-drug conjugate.

[0121] The granulopoiesis stimulating factor is contemplated to be granulocyte colony stimulating factor (GCSF). It is contemplated that the GCSF may or may not be a long-acting GCSF.

[0122] In various embodiments, if the stimulatory agent is not a long-acting GCSF, e.g., filgrastim, the stimulatory agent can be administered starting 1 to 7 days, 1 to 5 days, or 1 to 3 days after the start of cycle 1 of administration of the anti-CD30 antibody drug conjugate, e.g., daily doses. In certain embodiments, GCSF is administered after days 2, 3, 4, 5, 6, and / or 7 of the anti-CD30 antibody drug conjugate or A+AVD therapy. In various embodiments, filgrastim is administered at a dose of 5 μg / kg / day to 10 μg / kg / day for a period of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0123] Pegfilgrastim is a long-acting pegylated form of filgrastim with a longer half-life in vivo. In various embodiments, pegfilgrastim is administered at 6 mg / dose on days 1 to 5 after anti-CD30 antibody-drug conjugate treatment or, optionally, A+AVD therapy. In certain embodiments, GCSF is administered in a single dose or multiple doses on the same day, or on days 2, 3, 4, or 5 after anti-CD30 antibody-drug conjugate or A+AVD therapy. In various embodiments, GCSF is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate, optionally in combination with a chemotherapy treatment regimen described herein. In various embodiments, G-CSF is administered 24 hours to 36 hours after each administration of the anti-CD30 antibody-drug conjugate.

[0124] In various embodiments, the granulopoiesis stimulating factor is given intravenously or subcutaneously. It is contemplated that the granulopoiesis stimulating factor may be given in a single dose or multiple doses, e.g., multiple daily doses.

[0125] It is contemplated that subjects receiving the granulopoiesis stimulating factor and anti-CD30 antibody-drug conjugate may also be administered antibiotics to address febrile neutropenia and / or infection issues. Exemplary antibiotics contemplated include those known in the art, such as cephalosporins, sulfamethoxazole-trimethoprim, ACYCOLOVIR®, FLUCANOZOLE®, or INTRACONAZOLE®.

[0126] In various embodiments, the anti-CD30 antibody drug conjugate is administered every three weeks. In various embodiments, if a subject receives 1.8 mg / kg of the anti-CD30 antibody drug conjugate every three weeks, the dose may be reduced from 1.2 mg / kg to a maximum of 120 mg every two weeks to improve neutropenia, e.g., Grade 4 neutropenia.

[0127] In various embodiments, the anti-CD30 antibody drug conjugate is administered every two weeks, e.g., every 28 days. In various embodiments, the anti-CD30 antibody-drug conjugate is administered on days 1 and 15 of the cycle. In various embodiments, the anti-CD30 antibody-drug conjugate is administered for six cycles or less. In various embodiments, the anti-CD30 antibody-drug conjugate is administered for four to six cycles. Optionally, when the anti-CD30 antibody-drug conjugate is administered every two weeks, the treatment regimen further comprises administering chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as a combination therapy on the same days as the anti-CD30 antibody therapy.

[0128] In various embodiments, the hematological cancer is selected from the group consisting of classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL).

[0129] In various embodiments, the hematological cancer is classical Hodgkin's lymphoma. In various embodiments, the hematological cancer is stage III or IV classical Hodgkin's lymphoma. In various embodiments, the subject's hematological cancer has not been treated.

[0130] In various embodiments, the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL).

[0131] In various embodiments, the cutaneous T-cell lymphoma (CTCL) is mycosis fungoides (MF). In various embodiments, the mycosis fungoides (MF) is CD30-positive mycosis fungoides (MF). In various embodiments, the cutaneous T-cell lymphoma (CTCL) is primary cutaneous anaplastic large cell lymphoma (pcALCL).

[0132] In various embodiments, the subject has received prior systemic therapy or prior radiation.

[0133] In various embodiments, subjects with mycosis fungoides or primary cutaneous anaplastic large cell lymphoma receive a therapy comprising an anti-CD30 antibody drug conjugate at a dose of 1.8 mg / kg every three weeks.

[0134] It is further contemplated that upon completion of therapy with the anti-CD30 antibody-drug conjugates described herein, optionally in combination with a chemotherapy regimen, the subject may undergo additional therapy to address one or more symptoms of the cancer that remain at the end of treatment or that may be refractory to the therapy herein. Such therapy may include, but is not limited to, surgery, radiation therapy, proton therapy, stem cell transplant, and / or additional chemotherapy regimens.

[0135] formulation A variety of delivery systems can be used to administer the antibody-drug conjugate. In certain preferred embodiments of the present invention, the antibody-drug conjugate compound is administered by intravenous infusion. In some embodiments, administration is by 30-minute, 1-hour, or 2-hour intravenous infusion.

[0136] Antibody-drug conjugate compounds can be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable components.For example, pharmaceutical compositions typically contain one or more pharmaceutically acceptable carriers, such as water-based carriers (e.g., sterile liquids).When pharmaceutical compositions are administered intravenously, water is the more typical carrier.

[0137] The composition can also contain, as needed, for example, physiological saline, buffer, salt, non-ionic surfactant, and / or sugar. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. The formulation corresponds to the method of administration.

[0138] The present disclosure provides, for example, pharmaceutical compositions comprising a therapeutically effective amount of an antibody-drug conjugate, a buffer, an optional cryoprotectant, an optional bulking agent, an optional salt, and an optional surfactant. Additional agents can be added to the composition. In some cases, a single agent can provide multiple functions. For example, a sugar such as trehalose can act as both a cryoprotectant and a bulking agent. Any suitable pharmaceutically acceptable buffer, surfactant, cryoprotectant, and bulking agent can be used in accordance with the present invention.

[0139] In addition to providing methods for treating hematological cancers, the present invention provides antibody-drug conjugate formulations, including drug conjugate formulations that have undergone lyophilization or other protein preservation methods, as well as antibody-drug formulations that have not undergone lyophilization.

[0140] In some embodiments, the antibody-drug conjugate formulation comprises: (i) about 1 to 25 mg / ml, about 3 to about 10 mg / ml, or about 5 mg / ml of the antibody-drug conjugate (e.g., an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof); (ii) about 5 to 50 mM, preferably about 10 mM to about 25 mM, of a buffer selected from a citrate, phosphate, or histidine buffer or a combination thereof, preferably sodium citrate, potassium phosphate, histidine, histidine hydrochloride, or a combination thereof; (iii) about 3% to about 10% of sucrose or trehalose or a combination thereof; optionally, (iv) about 0.05 to 2 mg / ml of a surfactant selected from polysorbate 20 or polysorbate 80 or a combination thereof; and (v) water, wherein the pH of the composition is about 5.3 to about 7, preferably about 6.6.

[0141] In some embodiments, the antibody-drug conjugate formulation comprises about 1 to 25 mg / ml, about 3 to about 10 mg / ml, and preferably about 5 mg / ml of the antibody-drug conjugate; (ii) about 10 mM to about 25 mM of a buffer selected from sodium citrate, potassium phosphate, histidine, histidine hydrochloride, or a combination thereof; (iii) about 3% to about 7% of trehalose or sucrose, or a combination thereof; optionally, (iv) about 0.05 to about 1 mg / ml of a surfactant selected from polysorbate 20 or polysorbate 80; and (v) water, wherein the pH of the composition is about 5.3 to about 7, and preferably about 6.6.

[0142] In some embodiments, the antibody-drug conjugate formulation comprises about 5 mg / ml of the antibody-drug conjugate, (ii) about 10 mM to about 25 mM of a buffer selected from sodium citrate, potassium phosphate, histidine, histidine hydrochloride, or a combination thereof, (iii) about 3% to about 7% trehalose, optionally (iv) about 0.05 to about 1 mg / ml of a surfactant selected from polysorbate 20 or polysorbate 80, and (v) water, wherein the pH of the composition is about 5.3 to about 7, preferably about 6.6.

[0143] Any of the above formulations can be stored in liquid or frozen form, and can be optionally subjected to a preservation process.In some embodiments, the above formulations are lyophilized, i.e., they are subjected to freeze-drying.In some embodiments, the above formulations are subjected to a preservation process, for example, freeze-drying, and then reconstituted with a suitable liquid, for example, water.Lyophilization means that the composition is freeze-dried under vacuum.Lyophilization is typically achieved by freezing a particular formulation so that the solute is separated from the solvent.The solvent is then removed by sublimation (i.e., primary drying), and then by desorption (i.e., secondary drying).

[0144] The formulations of the present invention can be used in conjunction with the methods described herein or other methods for treating diseases. The antibody-drug conjugate formulations can be further diluted before administration to a subject. In some embodiments, the formulations are diluted with saline and administered via IV bolus prior to administration to a subject. Thus, in some embodiments, the method of treating a hematological cancer in a subject comprises administering to a subject in need thereof a weekly dose of a pharmaceutical composition comprising an antibody-drug conjugate having Formula I, wherein the administered dose of the antibody-drug conjugate is about 1.8 mg / kg or 1.2 mg / kg to 0.9 mg / kg of the subject's body weight, and wherein the pharmaceutical composition is administered for at least 3 weeks, and wherein the antibody drug is conjugated prior to administration to the subject and is present in a formulation comprising: (i) about 1 to 25 mg / ml, preferably about 3 to about 10 mg / ml, of the antibody drug; (ii) about 5 to 50 mM, preferably about 10 mM to about 25 mM, of a buffer solution selected from sodium citrate, potassium phosphate, histidine, histidine hydrochloride, or a combination thereof; (iii) about 3% to about 10% of sucrose or trehalose or a combination thereof; (iv) about 0.05 to 2 mg / ml of a surfactant, optionally selected from polysorbate 20 or polysorbate 80 or a combination thereof; and (v) water, wherein the pH of the composition is about 5.3 to about 7, preferably about 6.6.

[0145] The chemotherapeutic agent formulations contemplated for use herein are provided as those typically used in cancer treatment, including doxorubicin, vinblastine and dacarbazine.For example, doxorubicin, vinblastine and dacarbazine are commercially available and are approved by the US FDA and other regulatory agencies for use in treating patients with multiple types of cancer.

[0146] The present invention also provides a kit for treating hematological cancer. The kit can include (a) a container containing an antibody-drug conjugate, and optionally, a container containing one or more of doxorubicin, vinblastine, or dacarbazine. Such a kit can optionally further include one or more conventional pharmaceutical kit components, such as, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Printed instructions, such as an insert or label, indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components can also be included in the kit. [Example]

[0147] Example 1 In this open-label, multicenter, phase 3 trial, patients with previously untreated stage III / IV classical Hodgkin lymphoma were randomized to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD; n=664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; n=670). The primary endpoint was modified progression-free survival (PFS) based on central review committee assessment, with overall survival as a key secondary endpoint.

[0148] material and method In the trial design, patients were randomized 1:1 to receive A+AVD, which consisted of brentuximab vedotin 1.2 mg / kg and doxorubicin 25 mg / m 2 , vinblastine 6 mg / m 2 , dacarbazine 375 mg / m 2 ) or ABVD (doxorubicin 25 mg / m 2 , bleomycin 10 units / m 2 , vinblastine 6 mg / m 2 , dacarbazine 375 mg / m 2) was administered intravenously on days 1 and 15 of a 28-day cycle for up to six cycles. Brentuximab vedotin was administered over 30 minutes, starting approximately 1 hour after completion of AVD. Dose reductions / modifications are described in Figure 7. Patients were stratified by region (America vs. Europe vs. Asia) and International Prognostic Score (IPS) 15 (0-1 vs. 2-3 vs. 4-7). End-of-Cycle-2 PET (PET2) results determined the Deauville score. 16 Patients with a ≥5% risk of relapse were guided to switch to alternative frontline therapy options at the treating physician's discretion.

[0149] Patients: Eligible patients were patients (≥18 years of age) with histologically advanced (Ann Arbor stage III / IV) classical Hodgkin lymphoma according to the World Health Organization classification,18 who had not previously been treated with systemic chemotherapy / radiotherapy. Patients had an Eastern Cooperative Oncology Group performance status of 2 or less. 19 Patients were required to have favorable absolute neutrophil and platelet counts, hemoglobin concentrations, and liver and kidney function marker levels (excluding patients with bone marrow or liver or Gilbert's syndrome disease). Patients with nodular lymphocyte-predominant Hodgkin lymphoma were ineligible, as were those with peripheral sensory / motor neuropathy, a positive pregnancy test, known brain / meningeal disease, evidence of residual disease from or a diagnosis of another malignancy within 3 years before the first dose, or clinically relevant cardiovascular disease.

[0150] Endpoints: The primary endpoint was modified progression-free survival (PFS), defined as the time to evidence of progression, death, or non-CR after completion of frontline therapy based on an Independent Review Board (IRF) assessment, followed by anticancer therapy. Modified event timing was the date after completion of the first PET scan of frontline therapy demonstrating lack of CR, defined as a Deauville score of 3 or greater. Switching to an alternative frontline therapy for any reason before completion of treatment with the randomized treatment plan in the absence of disease progression was not considered an event.

[0151] The key secondary endpoint was overall survival (OS), defined as the time from randomization to death from any cause.

[0152] Evaluation: Revised Response Criteria for Malignant Lymphoma 20 Response and progression were assessed according to the MRI scan. Computed tomography scans were performed at screening, after two cycles, after the last dose of frontline therapy, and during follow-up, every 3 months for the first year and every 6 months thereafter. PET scans were performed at the end of cycle 2 and at the end of treatment.

[0153] Safety was assessed by the incidence of adverse events using the Medical Dictionary for Regulatory Activities (MedDRA; v19.0) and the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.03, as well as changes in vital signs and laboratory test results.

[0154] Statistical Analysis: Statistical calculations estimated that 260 modified PFS events were required to detect a hazard ratio (HR) of 0.67 with 90% power at a one-sided significance level of 0.025. The study was based on 2-year modified PFS of 81% of patients in the A+AVD arm and 73% of patients in the ABVD arm. Approximately 1,240 patients were randomized and planned to achieve 260 modified PFS events (95% probability). The primary endpoint was summarized using the Kaplan-Meier method and assessed using a stratified log-rank test. A stratified Cox regression model was used to estimate the HR and 95% confidence interval (CI) of the treatment effect. Stratification factors included region and IPS score at baseline. If the primary endpoint test is statistically significant, an interim OS (overall survival) analysis will be performed (one-sided 0.025 level). The final OS analysis will be performed when 112 patients have died. The overall type I error for the OS analysis will be controlled using the O'Brien-Fleming method with a Landemetz alpha expenditure function.

[0155] Unless otherwise specified, all efficacy assessments were performed using the intention-to-treat analysis population. Safety was analyzed in patients who received at least one dose of study drug (safety population).

[0156] result A total of 1,334 patients from 218 sites in 21 countries were randomized to receive either A+AVD (n=664) or ABVD (n=670) (intention-to-treat population). Overall, 58% of patients were male, 64% had stage IV disease, 62% had extranodal disease at diagnosis, 58% had B symptoms, and the median age was 36 years (34% of patients were 45 years or older). Baseline characteristics were generally balanced between the two groups [Figure 2 (Table 1)].

[0157] After a median follow-up of 24.9 months (range, 0.0–49.3), a statistically significant difference was observed between A+AVD and ABVD in the primary endpoint of adjusted PFS per IRF (2-year adjusted PFS rates were 82.1% [95% CI, 85.0–78.7] for A+AVD and 77.2% [95% CI, 80.4–73.7] for ABVD, respectively) (HR, 0.770; CI, 0.982–0.603; P = 0.035), corresponding to a 23% risk reduction, with 117 events in the A+AVD arm and 146 events in the ABVD arm (Figure 1A). Modified PFS events consisted of disease progression (90 vs. 102), death from any cause (18 vs. 22), or receipt of anticancer therapy after failure to achieve CR at the completion of frontline therapy (9 vs. 22) for the A+AVD and ABVD treatment groups, respectively [Figure 3 (Table 2)]. The majority of subsequent anticancer therapy (71%) consisted of salvage chemotherapy (7 / 9 A+AVD; 15 / 22 ABVD), with radiation therapy administered for the remainder in both treatment groups (Figure 8). Most events were associated with a Deauville score of 4 or 5 on the end-of-treatment PET scan, fulfilling the criteria for a progression event per investigator.

[0158] For investigator-determined modified PFS, the HR was 0.725 (95% CI, 0.574–0.916; P = 0.007; Figure 1B). There was 91% agreement between the IRF and investigator determination of modified PFS events. According to investigator assessment, the 2-year modified PFS event rate was 81.0% (95% CI, 77.6–83.9) for A+AVD and 74.4% (95% CI, 70.7–77.7) for ABVD.

[0159] Prespecified subgroup analysis of adjusted PFS showed HRs of <1 for A+AVD versus ABVD in most subgroups (Figure 1C). Certain subgroups of patients appeared to benefit more from A+AVD compared with ABVD (patients from North America, patients with one or more extranodal sites, patients with IPS 4-7, men, stage IV disease, and patients under 60 years of age). The PET2-negative rate (Deauville score 1-3) was 89% for A+AVD and 86% for ABVD.

[0160] Twenty-eight patients died in the A+AVD arm (nine in the study [within 30 days after the last dose of frontline therapy]) and 19 died during follow-up (after 30 days after the last dose of frontline therapy), while 39 patients died in the ABVD arm (26 in 13 studies during follow-up). The interim OS HR was 0.721 (95% CI, 0.443-1.173; P = 0.186), favoring A+AVD compared with ABVD (Figure 6). Other secondary endpoints are shown in Figure 4 (Table 3). Only 15 / 662 patients randomized to A+AVD and 9 / 659 patients randomized to ABVD switched to alternative chemotherapy during frontline therapy for reasons other than progressive disease (Deauville score of 5 in 1 / 15 and 4 / 9 patients, adverse events in 12 / 15 and 1 / 9 patients, and other reasons in 2 / 15 and 4 / 9 patients) (Figure 9).

[0161] Overall, fewer patients in the A+AVD treatment group received subsequent anticancer therapy: radiation therapy (n=52), chemotherapy (n=66 vs. n=99, respectively), high-dose chemotherapy and transplant (n=36 vs. n=54), immunotherapy (n=10 vs. n=16), and chemotherapy plus radiation therapy (n=2 vs. n=3).

[0162] The median duration of treatment and number of completed cycles were similar between treatment groups (Figure 10). The percentage of patients receiving each treatment regimen agent as intended, without dose modifications such as delays / holds / reductions, is shown in Figure 10.

[0163] The safety profiles of both treatment groups are summarized in Figure 5 (Table 4). Overall, neutropenia was reported in 58% of patients receiving A+AVD and 45% of patients receiving ABVD, and febrile neutropenia was reported in 19% and 8%, respectively. In both groups, the incidence of febrile neutropenia was higher in patients 60 years of age or older compared with those younger than 60 years (A+AVD: 37% vs. 17%, and ABVD: 17% vs. 6%) and earlier in the treatment cycle compared with later (A+AVD: 9% in cycle 1 vs. 1-6% cumulatively in cycles 2-6; ABVD: 4% in cycle 1 vs. ≤1% in cycles 2-6). The incidence of study drug discontinuation due to neutropenia or febrile neutropenia was ≤1% in both treatment groups.

[0164] The infection rate (determined by the MedDRA Primary System Organ Class term "infections and infestations") was 55% (361 / 662) in the A+AVD treatment group and 50% (331 / 659) in the ABVD treatment group. The rates of grade 3 or higher infections were 18% (116 / 662) and 10% (66 / 659), respectively. Following discussion with the independent data monitoring committee (after 76% of patients were enrolled), primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was recommended for newly randomized patients receiving A+AVD based on the high incidence of febrile neutropenia. In the A+AVD treatment group, all patients who received primary G-CSF prophylaxis (defined as use of G-CSF by day 5 of study treatment; n=83) experienced a reduction in the incidence of febrile neutropenia (from 21% [119 / 579] to 11% [9 / 83]) and a reduction in the incidence of grade 3 or higher infections and infestations (from 18% [107 / 579] to 11% [9 / 83]).

[0165] Peripheral neuropathy (determined by protocol-specified standardized MedDRA query [SMQ]; Figure 11) occurred in 67% (442 / 662) of patients receiving A+AVD and 43% (286 / 659) of patients receiving ABVD. The incidence of grade 3 or higher was 11% (70 / 662) of patients in the A+AVD treatment group (one patient with grade 4) vs. 2% (11 / 659) of patients in the ABVD treatment group, leading to discontinuation of study drug in 10% (44 / 442) vs. 4% (11 / 286), respectively. Two-thirds (295 / 442) of patients who experienced peripheral neuropathy in the A+AVD treatment group showed resolution or improvement (grade 1 or higher) of peripheral neuropathy events at last follow-up. 92% of ongoing peripheral neuropathy events at last follow-up were grade 1 (64%) or 2 (29%) in the A+AVD treatment group. Pulmonary toxicity, as defined by Interstitial Lung Disease (SMQ) events, was reported in 12 / 662 (2%) patients in the A+AVD arm vs. 44 / 659 (7%) patients in the ABVD arm. Grade 3 or higher events were reported in 5 / 662 [<1%] vs. 21 / 659 [3%] patients, respectively.

[0166] There were 9 on-study deaths in the A+AVD arm and 13 in the ABVD arm. In the A+AVD arm, 7 / 9 deaths were related to neutropenia (all occurred in patients who had not received primary G-CSF prophylaxis before the onset of neutropenia), and 2 were due to myocardial infarction. Of the 13 on-study deaths in the ABVD arm, 11 were due to or related to lung-related toxicity, 1 was due to pneumonia / cardiac arrest, and 1 was unknown.

[0167] The large, international, randomized, Phase 3 ECHELON-1 trial in patients with newly diagnosed stage III / IV classical Hodgkin lymphoma demonstrated a statistically and clinically meaningful improvement in modified PFS with brentuximab vedotin plus AVD compared to the standard of care, ABVD, corresponding to a 23% reduction in first-line chemotherapy failure as measured by IRF and a 28% reduction in investigator-measured chemotherapy failure A+AVD is the first treatment regimen to demonstrate superior outcomes in frontline Hodgkin lymphoma while eliminating bleomycin exposure compared with ABVD.

[0168] The goal of frontline chemotherapy for Hodgkin lymphoma is to cure patients without the need for additional therapy. Because metabolically detectable residual disease reliably predicts imminent progression, it is accepted practice to initiate subsequent chemotherapy / radiotherapy based on a positive PET scan at the end of frontline treatment. 21~23 In this setting, the traditional endpoint of PFS does not accurately assess the therapeutic intent of frontline chemotherapy. Thus, in ECHELON-1, the primary endpoint was a "modified" PFS, which included disease progression or death, as well as evidence of non-CR after subsequent anticancer therapy as an event after completion of frontline chemotherapy (based on PET results by IRF), thereby accurately assessing the curative potential of frontline chemotherapy.

[0169] Results from the interim analysis of overall survival, the key secondary endpoint, and all other secondary efficacy endpoints tended to favor A+AVD, further supporting the conclusion that A+AVD is a more effective frontline treatment for advanced Hodgkin lymphoma than ABVD. Furthermore, the benefit of A+AVD was consistently observed in the majority of prespecified subgroups, including patients with one or more extranodal sites and IPS 4-7 involvement. The PET2-positive rate in ECHELON-1 was low, and the proportion of PET2-negative patients was higher in the A+AVD treatment group compared with the ABVD treatment group.

[0170] Adverse events were consistent with the components of the individual treatment plans. The pulmonary toxicity of bleomycin, which caused the majority of on-study deaths in the ABVD arm, is unpredictable, and the only approach known to mitigate the risk of pulmonary adverse events is to discontinue bleomycin. In the response-adapted approach adopted in the RATHL study, omission of bleomycin from ABVD after two cycles and negative interim PET findings resulted in a lower incidence of pulmonary toxicities than continuation of ABVD without a significant reduction in efficacy. 8 ECHELON-1 demonstrates that the addition of brentuximab vedotin to the A+AVD treatment regimen and the elimination of bleomycin from frontline therapy reduces the incidence of pulmonary toxicity while improving efficacy compared with ABVD. No new safety risks were identified with A+AVD, but the incidence of febrile neutropenia was higher than expected and the incidence of infections increased in the A+AVD treatment group. The majority of deaths during the study were related to febrile neutropenia. However, G Primary prophylaxis with CSFs appeared to reduce the increased risk of febrile neutropenia and its associated sequelae in the subgroup of 83 patients who received primary prophylaxis, resulting in similar rates of neutropenia, febrile neutropenia, and serious infections as in the ABVD-treated group. One-third of patients treated with A+AVD received subsequent salvage chemotherapy and high-dose chemotherapy and transplant compared with patients treated with ABVD, and were therefore less likely to experience toxicities associated with aggressive salvage therapy.

[0171] The results of ECHELON-1 are particularly important given that A+AVD offers the opportunity to safely administer a potentially therapeutic treatment to elderly patients, a special group given the disease incidence in the elderly (approximately 20% of all cases), the known low treatment response rate, and the generally more severe toxicities, particularly pulmonary toxicity, associated with bleomycin. 6、24、25 When selecting frontline patient management, it is also important to consider the lifelong burden of late and long-term adverse effects from salvage chemotherapy, radiation therapy, and ASCT (including infertility, pulmonary toxicity, cardiac toxicity, and secondary malignancies). 26、27 ECHELON-1 demonstrated that brentuximab vedotin in combination with AVD is more effective than ABVD for the frontline treatment of advanced-stage classical Hodgkin lymphoma with a manageable toxicity profile, establishing A+AVD as the new frontline standard of care.

[0172] Example 2 A follow-up study of the ECHELON-1 trial is underway to investigate the impact of G-CSF primary prophylaxis in patients with advanced-stage HL, as described in the Examples above. Patients to be treated are aged 18 years or older and have previously untreated HL with Ann Arbor stage 3 or 4 disease. Subjects must have histologically confirmed classical HL according to the current World Health Organization (WHO) classification, demonstrating two-dimensional measurable disease documented by radiographic techniques. Subjects will be excluded if any of the following criteria are met: nodular lymphocyte-predominant HL, history of another malignancy within 2 years of first dose; evidence of drug or residual disease from a previously diagnosed malignancy; patients with non-melanoma skin cancer, localized prostate cancer, or carcinoma in situ of any kind are not excluded if they have undergone complete resection; prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy within 12 weeks of first study drug administration; active brain / meningeal disease related to the underlying malignancy; active grade 3 or greater viral, bacterial, or fungal infection within 2 weeks of first study drug administration (National Cancer Institute Common Terminology Criteria for Adverse Events for NCI CTCAE Version Grade 3 as defined in 4.03); current therapy with other systemic antineoplastic or investigational drugs; Grade 3 or higher pulmonary disease unrelated to malignancy; history of cerebrovascular event within 6 months of first dose of investigational drug; Child-Pugh B or C liver disorder; peripheral sensory or motor neuropathy; pregnant or lactating patient; other serious condition that impairs the patient's ability to receive or tolerate the planned treatment and follow-up.

[0173] Patients will receive A+AVD therapy in combination with G-CSF. G-CSF will be administered 24–36 hours after each A+AVD cycle (brentuximab vedotin 1.2 mg / kg, doxorubicin 25 mg / m 2 , vinblastine 6 mg / m 2 , dacarbazine 375 mg / m 2) for six cycles (12 doses, days 1 and 15 of a 28-day cycle). Primary endpoints evaluated included whether the drug combination reduced the number of patients experiencing the side effect of febrile neutropenia, efficacy, and dose intensity. Secondary endpoints included primary refractory response rate, complete response rate, progression-free survival, utilization of subsequent anticancer therapy, mean dose intensity, and analysis of dose reduction and delay rates.

[0174] Administration of G-CSF following the treatment regimen herein, for example, prophylactic administration of G-CSF 24-36 hours after each dose / administration of anti-CD30 antibody-drug conjugate combination therapy, is predicted to reduce the incidence of febrile neutropenia and the incidence of grade 3 or higher infections and infestations in A+AVD therapy patients.

[0175] Numerous modifications and variations of the invention described in the illustrative examples above are expected to occur to those skilled in the art, and therefore only such limitations as appear in the appended claims should be placed on the invention. References 1.Engert A.ABVD or BEACOPP for Advanced Hodgkin Lymphoma.J Clin Oncol 2016;34:1167-9. 2.Canellos GP,Anderson JR,Propert KJ,et al.Chemotherapy of advanced Hodgkin's disease with MOPP,ABVD,or MOPP alternating with ABVD.N Engl J Med 1992;327:1478-84. 3.Carde P,Karrasch M,Fortpied C,et al.Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV,International Prognostic Score > / = 3,High-Risk Hodgkin Lymphoma:First Results of the Phase III EORTC 20012 Intergroup Trial.J Clin Oncol 2016;34:2028-36. 4.Gordon LI,Hong F,Fisher RI,et al.Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma:an intergroup study coordinated by the Eastern Cooperative Oncology Group(E2496).J Clin Oncol 2013;31:684-91. 5.Canellos GP,Duggan D,Johnson J,Niedzwiecki D.How important is bleomycin in the adriamycin+bleomycin+vinblastine+dacarbazine regimen? J Clin Oncol 2004;22:1532-3. 6.Martin WG,Ristow KM,Habermann TM,Colgan JP,Witzig TE,Ansell SM.Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin’s lymphoma.J Clin Oncol 2005;23:7614-20. 7.Borchmann P,Goergen H,Kobe C,et al.Treatment Reduction in Patients with Advanced-Stage Hodgkin Lymphoma and Negative Interim PET:Final Results of the International,Randomized Phase 3 Trial HD18 by the German Hodgkin Study Group.Presented at the 22nd Annual Meeting of the European Hematology Association,Madrid,Spain,June 22-25,2017.Haematologica 2017;102:Abstract S150. 8.Johnson P,Federico M,Kirkwood A,et al.Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma.N Engl J Med 2016;374:2419-29. 9.Borchmann P,Eichenauer DA,Pluetschow A,et al.Targeted Beacopp Variants in Patients with Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma:Final Analysis of a Randomized Phase II Study.Presented at the 57th Annual Meeting of the American Society of Hematology,Orlando,FL,December 5-8,2015.Blood 2015;126. 10. Schwab U, Stein H, Gerdes J, et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 1982;299:65-7. 11. ADCETRIS (registered trademark) (brentuximab vedotin) US Prescribing Information. Available at: http: / / www.seattlegenetics.com / application / files / 9414 / 7621 / 9892 / adcetris_USPI.pdf[Last accessed 10 August 2017]. 12. ADCETRIS (registered trademark) (brentuximab vedotin) EU Summary of Product Characteristics. Available at: http: / / www.ema.europa.eu / docs / en_GB / document_library / EPAR_-_Product_Information / human / 002455 / WC500135055.pdf[Last accessed 10 August 2017]. 13. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 2013;14:1348-56. 14.Connors JM,Ansell SM,Fanale M,Park SI,Younes A.Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced stage classical Hodgkin lymphoma.Blood 2017. 15.Hasenclever D,Diehl V.A prognostic score for advanced Hodgkin’s disease.International Prognostic Factors Project on Advanced Hodgkin’s Disease.N Engl J Med 1998;339:1506-14. 16.Meignan M,Gallamini A,Haioun C,Polliack A.Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton,France,8-9 April 2010.Leuk Lymphoma 2010;51:2171-80. 17.Fauci AS,Braunwauld E,Kasper DL,et al.Ann Arbor Staging System for Hodgkin’s Disease.Harrison’s Manual of Medicine.17th ed.New York,NY:McGraw-Hill;2009. 18.Campo E,Swerdlow SH,Harris NL,Pileri S,Stein H,Jaffe ES.The 2008 WHO classification of lymphoid neoplasms and beyond:evolving concepts and practical applications.Blood 2011;117:5019-32. 19.Oken MM,Creech RH,Tormey DC,et al.Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol 1982;5:649-55. 20.Cheson BD,Pfistner B,Juweid ME,et al.Revised response criteria for malignant lymphoma.J Clin Oncol 2007;25:579-86. 21.Barnes JA,LaCasce AS,Zukotynski K,et al.End-of-treatment but not interim PET scan predicts outcome in nonbulky limited-stage Hodgkin’s lymphoma.Ann Oncol 2011;22:910-5. 22.Engert A,Haverkamp H,Kobe C,et al.Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma(HD15 trial):a randomised,open-label,phase 3 non-inferiority trial.Lancet 2012;379:1791-9. 23.Spaepen K,Stroobants S,Dupont P,et al.Can positron emission tomography with[(18)F]-fluorodeoxyglucose after first-line treatment distinguish Hodgkin’s disease patients who need additional therapy from others in whom additional therapy would mean avoidable toxicity? 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Claims

1. A method of treating a subject who has exhibited Grade 2 or greater peripheral neuropathy after initiating treatment with anti-CD30 antibody drug conjugate therapy at a dose of 1.2 mg / kg or greater, comprising administering anti-CD30 antibody drug conjugate therapy at a dose of 0.9 mg / kg.

2. 2. The method of claim 1, wherein if the subject exhibits Grade 3 neuropathy, administration of the anti-CD30 antibody-drug conjugate therapy is withheld until peripheral neuropathy is reduced to Grade 2 or less, after which 0.9 mg / kg of anti-CD30 antibody-drug conjugate therapy is administered.

3. 3. The method of claim 1 or 2, wherein the subject exhibited grade 2 or 3 peripheral neuropathy after initiating anti-CD30 antibody drug conjugate therapy at a dose of 1.8 mg / kg.

4. 3. The method of claim 1 or 2, wherein the subject exhibited grade 2 or 3 peripheral neuropathy after initiation of anti-CD30 antibody drug conjugate therapy at a dose of 1.2 mg / kg, optionally in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD).

5. 3. The method of claim 1 or 2, wherein after the Grade 2 or Grade 3 peripheral neuropathy improves to Grade 1 or less, the dose of the anti-CD30 antibody-drug conjugate is increased to 1.8 mg / kg or 1.2 mg / kg, and when the dose is increased to 1.2 mg / kg, the administration is optionally in combination with chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD).

6. 3. The method of claim 1 or 2, wherein the anti-CD30 antibody-drug conjugate is administered at 1.2 mg / kg, and further comprising administering to the subject chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as combination therapy.

7. 7. The method of claim 6, wherein the combination therapy is administered every two weeks.

8. 8. The method of claim 7, wherein the combination therapy is administered on days 1 and 15 of a 28-day cycle.

9. 9. The method of claim 7 or 8, wherein the combination therapy is administered for no more than 6 cycles.

10. 9. The method of claim 7 or 8, wherein the combination therapy is administered for 4 to 6 cycles.

11. The method of any one of claims 1 to 10, wherein the therapy is administered until a PET scan determines that there is no tumor or no tumor progression.

12. 12. The method of any one of claims 1 to 11, wherein the treatment reduces paresthesia, hypoesthesia, polyneuropathy, muscle weakness, and demyelinating polyneuropathy.

13. The method of any one of claims 1 to 12, wherein the neuropathy is peripheral motor neuropathy or peripheral sensory neuropathy.

14. 14. The method of any one of claims 1-13, wherein if peripheral neuropathy appears, the dose of the anti-CD30 antibody drug conjugate is delayed for one week, and therapy is continued if the neuropathy resolves or is determined to be Grade 1 or less.

15. 1. A method of treating a hematological cancer in a subject, comprising administering a therapy comprising an anti-CD30 antibody-drug conjugate and prophylactically administering a granulopoiesis stimulating factor, wherein the granulopoiesis stimulating factor is administered starting from cycle 1 of administration of the anti-CD30 antibody-drug conjugate.

16. 16. The method of claim 15, wherein the granulopoiesis stimulating factor is administered 1 to 7 days after the start of cycle 1 of administration of the anti-CD30 antibody-drug conjugate.

17. 17. The method of claim 16, wherein the granulopoiesis stimulating factor is administered 2 to 5 days after the start of cycle 1 of administration of the anti-CD30 antibody drug conjugate.

18. 18. The method of any one of claims 15 to 17, wherein the granulopoiesis stimulating factor is administered 1 to 7 days after the second or subsequent administration of the anti-CD30 antibody drug conjugate.

19. 18. The method of any one of claims 15 to 17, wherein the granulopoiesis stimulating factor is administered 2 to 5 days after the second or subsequent administration of the anti-CD30 antibody drug conjugate.

20. 20. The method of any one of claims 15 to 19, wherein the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate.

21. The method of any one of claims 15 to 20, wherein the granulopoiesis stimulating factor is administered 24 to 36 hours after each administration of the anti-CD30 antibody drug conjugate.

22. 22. The method of any one of claims 15 to 21, wherein the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy.

23. The method of any one of claims 15 to 22, wherein the subject does not experience treatment-emergent Grade 3-4 neutropenia following administration of the anti-CD30 antibody-drug conjugate.

24. A method for reducing the incidence of neutropenia in a subject undergoing treatment with a therapy comprising an anti-CD30 antibody-drug conjugate, comprising administering a granulogenesis stimulating factor to the subject, wherein the granulogenesis stimulating factor is administered starting with one cycle of administration of the anti-CD30 antibody-drug conjugate.

25. 25. The method of claim 24, wherein the neutropenia is febrile neutropenia and the subject is 60 years of age or older.

26. The method according to any one of claims 15 to 25, wherein the granulopoiesis stimulating factor is granulocyte colony-stimulating factor (GCSF).

27. 27. The method of claim 26, wherein the GCSF is a long-acting GCSF or a non-long-acting GCSF.

28. 28. The method of claim 26 or 27, wherein the GCSF is a long-acting GCSF and is administered one or two days after starting cycle 1 of administration of the anti-CD30 antibody-drug conjugate.

29. 29. The method of claim 28, wherein the G-CSF is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody-drug conjugate.

30. 30. The method of claim 28 or 29, wherein the G-CSF is administered 24 to 36 hours after each administration of the anti-CD30 antibody-drug conjugate.

31. 28. The method of claim 26 or 27, wherein the GCSF is non-long-acting and is administered 1, 2, 3, 4, 5, 6, or 7 days after starting cycle 1 of administration of the anti-CD30 antibody-drug conjugate.

32. 32. The method of any one of claims 15 to 31, wherein the anti-CD30 antibody-drug conjugate is administered every three weeks.

33. The method of any one of claims 15 to 31, wherein the anti-CD30 antibody-drug conjugate is administered every two weeks.

34. 34. The method of claim 33, wherein the anti-CD30 antibody-drug conjugate is administered on days 1 and 15 of a 28-day cycle.

35. The method of any one of claims 15 to 34, wherein the anti-CD30 antibody-drug conjugate is administered for no more than six cycles.

36. The method of any one of claims 15 to 35, wherein the anti-CD30 antibody-drug conjugate is administered in 4 to 6 cycles.

37. 37. The method of any one of claims 15 to 36, further comprising administering chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as a combination therapy.

38. the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is i) a heavy chain CDR1 set forth in SEQ ID NO: 4, a heavy chain CDR2 set forth in SEQ ID NO: 6, a heavy chain CDR3 set forth in SEQ ID NO: 8, and ii) a light chain CDR1 set forth in SEQ ID NO: 12, a light chain CDR2 set forth in SEQ ID NO: 14, and a light chain CDR13 set forth in SEQ ID NO:

16.

39. the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is i) an amino acid sequence that is at least 85% identical to the heavy chain variable region set forth in SEQ ID NO:2, and ii) an amino acid sequence that is at least 85% identical to the light chain variable region set forth in SEQ ID NO:

10.

40. The method of any one of claims 1 to 39, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a monoclonal anti-CD30 antibody.

41. The method of any one of claims 1 to 39, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a chimeric AC10 antibody.

42. 42. The method of any one of claims 1 to 41, wherein the antibody-drug conjugate comprises monomethyl auristatin E and a protease-cleavable linker.

43. 43. The method of claim 42, wherein the protease-cleavable linker comprises a thiol-reactive spacer and a dipeptide.

44. 44. The method of claim 42 or 43, wherein the protease-cleavable linker consists of a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer.

45. The method of any one of claims 1 to 44, wherein the anti-CD30 antibody-drug conjugate is brentuximab vedotin.

46. The anti-CD30 antibody-drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg, and doxorubicin is administered at 25 mg / m ２ and vinblastine at 6 mg / m ２ and dacarbazine at 375 mg / m ２ 46. ​​The method of claim 45, wherein the

47. 47. The method of any one of claims 15 to 46, wherein the granulopoiesis stimulating factor is administered in a dose range of 5 to 10 mcg / kg / day, or 300 to 600 mcg / day, or 6 mg / dose.

48. 48. The method of any one of claims 15 to 47, wherein the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy.

49. The method of any one of claims 15 to 48, wherein the subject does not experience treatment-emergent Grade 3-4 neutropenia following administration of the anti-CD30 antibody drug conjugate.

50. 50. The method of any one of claims 15 to 49, wherein the granulopoiesis stimulating factor is given intravenously or subcutaneously.

51. 51. The method of any one of claims 15 to 50, wherein the granulopoiesis stimulating factor is given in a single dose or in multiple doses.

52. 52. The method of any one of claims 1 to 51, wherein the subject is suffering from a hematological cancer.

53. 53. The method of claim 52, wherein the hematological cancer is selected from the group consisting of classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL).

54. 54. The method of claim 53, wherein the hematological cancer is classical Hodgkin's lymphoma.

55. 54. The method of claim 53, wherein the hematological cancer is stage III or IV classical Hodgkin's lymphoma.

56. 56. The method of any one of claims 53-55, wherein the hematological cancer in the subject is not being treated.

57. 1. A method for reducing the incidence of infection in a subject receiving therapy comprising an anti-CD30 antibody-drug conjugate, comprising administering to the subject an amount of a granulopoiesis stimulating factor effective to reduce infection, wherein the granulopoiesis stimulating factor is administered starting with cycle 1 of administration of the anti-CD30 antibody-drug conjugate.

58. 58. The method of claim 57, wherein the granulopoiesis stimulating factor is administered 1 to 7 days after beginning cycle 1 of the administration of the anti-CD30 antibody drug conjugate.

59. 58. The method of claim 57, wherein the granulopoiesis stimulating factor is administered 2 to 5 days after the start of cycle 1 of administration of the anti-CD30 antibody drug conjugate.

60. 60. The method of any one of claims 57-59, wherein the granulopoiesis stimulating factor is administered 1 to 7 days after the second or subsequent administration of the anti-CD30 antibody drug conjugate.

61. 60. The method of any one of claims 57-59, wherein the granulopoiesis stimulating factor is administered 2 to 5 days after the second or subsequent administration of the anti-CD30 antibody drug conjugate.

62. 62. The method of any one of claims 57-61, wherein the granulopoiesis stimulating factor is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate.

63. 63. The method of any one of claims 57 to 62, wherein the granulopoiesis stimulating factor is administered 24 to 36 hours after each administration of the anti-CD30 antibody drug conjugate.

64. 64. The method of any one of claims 57 to 63, wherein the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody drug conjugate therapy.

65. 64. The method of any one of claims 57-63, wherein the subject does not experience treatment-emergent Grade 3-4 neutropenia following administration of the anti-CD30 antibody drug conjugate.

66. The method of any one of claims 57 to 65, wherein the granulopoiesis stimulating factor is granulocyte colony stimulating factor (GCSF).

67. 67. The method of claim 66, wherein the GCSF is a long-acting GCSF or a non-long-acting GCSF.

68. 68. The method of claim 66 or 67, wherein the GCSF is long-acting and is administered one or two days after starting cycle 1 of administration of the anti-CD30 antibody drug conjugate.

69. 69. The method of claim 68, wherein the G-CSF is administered about 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate.

70. 70. The method of claim 68 or 69, wherein the G-CSF is administered 24 to 36 hours after each administration of the anti-CD30 antibody drug conjugate.

71. 68. The method of claim 66 or 67, wherein the GCSF is not long-acting and is administered 1, 2, 3, 4, or up to 7 days after starting cycle 1 of administration of the anti-CD30 antibody drug conjugate.

72. 72. The method of any one of claims 57 to 71, wherein the anti-CD30 antibody-drug conjugate is administered every three weeks.

73. 72. The method of any one of claims 57 to 71, wherein the anti-CD30 antibody-drug conjugate is administered every two weeks.

74. 74. The method of claim 73, wherein the anti-CD30 antibody-drug conjugate is administered on days 1 and 15 of a 28-day cycle.

75. 75. The method of claim 73 or 74, wherein the anti-CD30 antibody drug conjugate is administered for six cycles or less.

76. 76. The method of any one of claims 73 to 75, wherein the anti-CD30 antibody-drug conjugate is administered in 4 to 6 cycles.

77. 77. The method of any one of claims 73-76, further comprising administering chemotherapy consisting essentially of doxorubicin, vinblastine, and dacarbazine (AVD) as a combination therapy.

78. the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is i) a heavy chain CDR1 set forth in SEQ ID NO: 4, a heavy chain CDR2 set forth in SEQ ID NO: 6, a heavy chain CDR3 set forth in SEQ ID NO: 8, and ii) a light chain CDR1 set forth in SEQ ID NO: 12, a light chain CDR2 set forth in SEQ ID NO: 14, and a light chain CDR13 set forth in SEQ ID NO:

16.

79. the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is i) an amino acid sequence that is at least 85% identical to the heavy chain variable region set forth in SEQ ID NO:2, and ii) an amino acid sequence that is at least 85% identical to the light chain variable region set forth in SEQ ID NO:

10.

80. The method of any one of claims 57 to 79, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a monoclonal anti-CD30 antibody.

81. The method of any one of claims 57 to 79, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a chimeric AC10 antibody.

82. 82. The method of any one of claims 57 to 81, wherein the antibody-drug conjugate comprises monomethyl auristatin E and a protease-cleavable linker.

83. 83. The method of claim 82, wherein the protease-cleavable linker comprises a thiol-reactive spacer and a dipeptide.

84. 84. The method of claim 82 or 83, wherein the protease-cleavable linker consists of a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer.

85. 85. The method of any one of claims 57 to 84, wherein the anti-CD30 antibody-drug conjugate is brentuximab vedotin.

86. The anti-CD30 antibody-drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg, and doxorubicin is administered at 25 mg / m ２ and vinblastine at 6 mg / m ２ and dacarbazine at 375 mg / m ２ 86. The method of claim 85, wherein the

87. 87. The method of any one of claims 57-86, wherein the granulopoiesis stimulating factor is administered in a dose range of 5-10 mcg / kg / day, or 300-600 mcg / day, or 6 mg / dose.

88. 88. The method of any one of claims 57 to 87, wherein the granulopoiesis stimulating factor is given intravenously or subcutaneously.

89. 89. The method of any one of claims 57 to 88, wherein the granulopoiesis stimulating factor is given in a single dose or in multiple doses.

90. 90. The method of any one of claims 1 to 89, wherein the subject is suffering from a hematological cancer.

91. 91. The method of claim 90, wherein the hematological cancer is selected from the group consisting of classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL).

92. 92. The method of claim 91, wherein the hematological cancer is classical Hodgkin's lymphoma.

93. 93. The method of claim 92, wherein the hematological cancer is stage III or IV classical Hodgkin's lymphoma.

94. 94. The method of any one of claims 90-93, wherein the hematological cancer in the subject is not being treated.

95. 92. The method of claim 91, wherein the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL).

96. 92. The method of claim 91, wherein the cutaneous T-cell lymphoma (CTCL) is mycosis fungoides (MF).

97. 97. The method of claim 96, wherein the mycosis fungoides (MF) is CD30-positive mycosis fungoides (MF).

98. 92. The method of claim 91, wherein the cutaneous T-cell lymphoma (CTCL) is primary cutaneous anaplastic large cell lymphoma (pcALCL).

99. 99. The method of claim 98, wherein the subject has previously received systemic therapy.

100. 100. The method of any one of claims 1 to 99, wherein the subject is an adult patient.

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