Combination of anti-CD30 ADC, anti-PD-1, and chemotherapy agents for the treatment of hematopoietic cancers

Abstract

The present disclosure relates generally to methods for treating hematological cancers that involve administering an anti-CD30 antibody drug conjugate in combination with an additional cancer therapeutic, such as a checkpoint inhibitor, and a chemotherapy regimen.

Description

Related Applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 905,701, filed September 25, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Incorporation by Reference of Electronically Submitted Materials The sequence listing, which is part of this disclosure, is submitted as a text file at the same time as the specification. The name of the text file containing the sequence listing is "54784_Seqlisting.txt", which was created on September 24, 2020, and is 7,899 bytes in size. The contents of the sequence listing are incorporated herein by reference. [Technical field]

[0003] The present disclosure relates generally to methods of treating Hodgkin's lymphoma and other hematopoietic cancers with anti-CD30 antibody drug conjugate therapy in combination with an anti-PD-1 antibody, and optionally in combination with a chemotherapy regimen including doxorubicin and dacarbazine. [Background technology]

[0004] 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 first-line regimen, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), has not changed since its first description in 1975.

[0005] Up to 30% of patients with stage III / IV Hodgkin lymphoma have refractory disease or relapse after first-line ABVD (Canellos et al., N Engl J Med 1992;327:1478-84; Carde et al., J Clin Oncol 2016;34:2028-36; Gordon et al., J Clin Oncol 2013;31:684-91). Bleomycin is considered the least active of the four components of ABVD and is associated with unpredictable and sometimes fatal pulmonary toxicity, often leading to withdrawal from later cycles of chemotherapy due to pulmonary symptoms (Canellos et al., J Clin Oncol 2004;22:1532-3; Martin et al., J Clin Oncol 2005;23:7614-20). Recent studies indicate that response-adaptive therapy with interim positron emission tomography (PET) using 18F-fluorodeoxyglucose can provide a more personalized treatment approach with a gradual reduction / intensification of treatment intensity depending on early response to treatment (Borchmann et al., Haematologica 2017;102:Abstract S150; Johnson et al., N Engl J Med 2016;374:2419-29). Efforts are also being made to incorporate new drugs into established scaffolds to improve efficacy and reduce toxicity (Borchmann et al., Blood 2015;126).

[0006] CD30 is a characteristic surface antigen expressed on Reed-Sternberg cells of classical Hodgkin lymphoma (Schwab et al., Nature 1982;299:65-7). Brentuximab vedotin is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated to a microtubule-disrupting agent, monomethyl auristatin E, by a protease-cleavable linker. 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 multi-agent chemotherapy regimens in patients who are not ASCT candidates, and as post-ASCT consolidation for Hodgkin lymphoma patients at increased risk of relapse / progression (ADCETRIS® (brentuximab vedotin) US prescribing information). It is also approved for systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. A previous phase 1, dose-escalation study in advanced Hodgkin lymphoma evaluated first-line brentuximab vedotin in combination with either ABVD or AVD (doxorubicin, vinblastine, dacarbazine) (Younes et al., Lancet Oncol 2013;14:1348-56).

[0007] Nivolumab is a fully humanized monoclonal antibody (HuMAb, immunoglobulin G4 [IgG4]) that targets programmed cell death protein 1 (PD-1). In vitro, nivolumab binds with high affinity to PD-1 and inhibits binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab specifically binds to PD-1 and does not bind related members of the CD28 family such as CD28, ICOS, CTLA-4, and BTLA. Nivolumab blocks the PD-1 pathway, resulting in reproducible enhancement of both proliferation and interferon-gamma (IFN-γ) release in mixed lymphocyte reactions (MLRs). Previous studies have shown that treatment of patients with refractory Hodgkin lymphoma with the combination of brentuximab vedotin and nivolumab was safe and allowed patients to undergo subsequent stem cell transplantation (Herrera et al., Blood 131(11):1183-94). The combination of nivolumab has also been shown to be well tolerated when combined with doxorubicin, vinblastine, and dacarbazine (N+AVD) (Ramchandren et al., J Clin Oncol 37(23):1997-2007). Summary of the Invention

[0008] The present disclosure relates to methods of treating hematological cancers comprising administering an anti-CD30 antibody drug conjugate (ADC) in combination with a cancer therapeutic agent as a first line treatment for previously undiagnosed cancer or as a treatment for relapsed or refractory disease. Additional cancer therapeutic agents used in combination with the anti-CD30 ADC include anti-PD-1 antibodies, and chemotherapy regimens including doxorubicin and dacarbazine.

[0009] Provided herein are methods for treating hematological cancer in a subject, comprising administering an anti-CD30 antibody drug conjugate and a therapy comprising an anti-PD-1 antibody, doxorubicin and dacarbazine.

[0010] In various embodiments, the anti-PD-1 antibody is administered at least 30 minutes after each administration of the anti-CD30 antibody drug conjugate. In various embodiments, the anti-CD30-antibody drug conjugate is administered by intravenous infusion over a period of about 30 minutes. In various embodiments, the anti-PD-1 antibody is administered by intravenous infusion over a period of about 60 minutes.

[0011] In various embodiments, the anti-PD-1 antibody is administered to a subject who has not previously received an anti-CD30 antibody drug conjugate therapy. In various embodiments, the anti-CD30 antibody drug conjugate is administered to a subject who has not previously received an anti-CD30 antibody drug conjugate therapy. In various embodiments, the subject has not previously received a checkpoint inhibitor therapy or an anti-PD-1 antibody.

[0012] In various embodiments, the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered every two weeks. In various embodiments, the anti-PD-1 antibody is administered beginning with cycle 1 of administration of the anti-CD30 antibody drug conjugate. In various embodiments, the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered on days 1 and 15 of a 28 day cycle. In various embodiments, the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered for six cycles or less. In various embodiments, the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered for four to six cycles.

[0013] In various embodiments, the methods further comprise administering chemotherapy consisting essentially of doxorubicin and dacarbazine (AD) as a combination therapy.

[0014] 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.

[0015] In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises 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.

[0016] In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a monoclonal anti-CD30 antibody. In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate is a chimeric AC10 antibody. 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. In various embodiments, the anti-CD30 antibody drug conjugate is brentuximab vedotin.

[0017] In various embodiments, the anti-PD-1 antibody is a monoclonal antibody. In various embodiments, (i) the anti-PD-1 antibody cross-competes with nivolumab or pembrolizumab for binding to human PD-1, (ii) the anti-PD-1 antibody binds to the same epitope as nivolumab or pembrolizumab, (iii) the anti-PD-1 antibody is nivolumab, or (iv) the anti-PD-1 antibody is pembrolizumab. In various embodiments, the anti-PD-1 antibody is nivolumab or pembrolizumab. In various embodiments, the anti-PD-1 antibody is nivolumab.

[0018] In various embodiments, the hematological cancer comprises one or more cells that express PD-L1, PD-L2, or both PD-L1 and PD-L2.

[0019] In various embodiments, the hematological cancer is a CD30-expressing cancer, and CD30 expression is greater than or equal to 10%. In various embodiments, CD30 expression is measured by an FDA approved test.

[0020] In various embodiments, the anti-CD30 antibody drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg and the anti-PD-1 antibody is nivolumab and is administered at 240 mg / dose.

[0021] In various embodiments, the anti-CD30 antibody drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg and the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 1-2 mg / kg, or 100-300 mg.

[0022] In various embodiments, doxorubicin is administered at 25 mg / m 2 and dacarbazine was administered at a dose of 375 mg / m 2 is administered at a dose of

[0023] In various embodiments, the method further comprises administering a granulopoiesis stimulating factor. In various embodiments, the granulopoiesis stimulating factor is administered 1 to 7 days after administration of the anti-CD30 antibody drug conjugate. In various embodiments, the granulopoiesis stimulating factor is administered 2 to 5 days after 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 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 non-long-acting GCSF. In various embodiments, the GCSF is long-acting GCSF and is administered 1 or 2 days after administration of the anti-CD30 antibody drug conjugate. In various embodiments, the G-CSF is administered about 24 hours to about 36 hours after administration of the anti-CD30 antibody drug conjugate. In various embodiments, the GCSF is not long-acting and is administered 1, 2, 3, 4, 5, 6, or 7 days after administration of the anti-CD30 antibody drug conjugate.

[0025] In various embodiments, the granulopoiesis stimulating factor is administered in a dosage range of 5-10 mcg / kg / day, or 300-600 mcg / day, or 6 mg / dose.

[0026] In various embodiments, the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody drug conjugate therapy.

[0027] In various embodiments, the subject does not experience treatment-emergent grade 3-4 neutropenia following administration of the anti-CD30 antibody drug conjugate. 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.

[0028] In various embodiments, if the subject exhibits grade 3 or grade 4 neuropathy, administration of anti-CD30 antibody drug conjugate therapy is withheld until peripheral neuropathy is reduced to grade 2 or less, and then 0.9 mg / kg of anti-CD30 antibody drug conjugate therapy is administered. In various embodiments, the neuropathy is motor neuropathy or sensory neuropathy. In various embodiments, if peripheral neuropathy appears, the dose of anti-CD30 antibody drug conjugate is delayed for one week, and therapy is continued if neuropathy resolves or is determined to be grade 1 or less.

[0029] In various embodiments, the hematological cancer is a CD30-expressing 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).

[0030] In various embodiments, the hematological cancer is classical Hodgkin's lymphoma. In various embodiments, the hematological cancer is stage IIA, stage IIB, stage III, or stage IV classical Hodgkin's lymphoma with bulky tumors.

[0031] In various embodiments, the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL).

[0032] 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).

[0033] In various embodiments, the subject's hematological cancer has not been treated with a checkpoint inhibitor, hi various embodiments, the subject has previously received systemic therapy.

[0034] In various embodiments, the subject is an adult patient.

[0035] It is specifically provided herein that all aspects of the disclosure described above involving methods of treatment are applicable to anti-CD30 antibody drug conjugate combination therapy for use in any of the indications described above.

[0036] It is understood that each feature or embodiment, or combination described herein is a non-limiting, illustrative example of any of the aspects of the disclosure, and as such is meant to be combinable with any other feature or embodiment, or combination described herein. For example, when a feature is described using words such as "one embodiment," "some embodiments," "certain embodiments," "further embodiments," "specific exemplary embodiments," and / or "another embodiment," each of these types of embodiments 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 the need to recite every possible combination. Such features or combinations of features apply to any of the aspects of the disclosure. When examples of values ​​falling within a range are disclosed, each of these examples is contemplated as a possible endpoint for a range, and any and all numerical values ​​of such endpoints and endpoints are contemplated, with any and all combinations of upper and lower endpoints being envisioned. [Brief description of the drawings]

[0037] [Figure 1] Details of brentuximab vedotin dose adjustment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The present disclosure provides methods for treating hematological cancers with anti-CD30 antibody-drug conjugates in combination with anti-PD-1 checkpoint inhibitors and chemotherapy regimens including doxorubicin and dacarbazine. Without being bound by theory, it is hypothesized that administration of the combination therapy provides improved patient outcomes with less toxicity due to the elimination of vincristine from typical treatment regimens.

[0039] definition

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The following references provide those skilled in the art with general definitions for many of the terms used in this disclosure: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2d ed.1994), THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker ed.,1988), THE GLOSSARY OF GENETICS,5TH ED.,R.Rieger et al.(eds.),Springer Verlag(1991), and Hale&Marham,THE HARPER COLLINS DICTIONARY OF BIOLOGY(1991).

[0040]

[0041] Each publication, patent application, patent, and other reference cited herein is incorporated by reference in its entirety, to the extent it is not inconsistent with this disclosure.

[0041]

[0042] As used in this specification and the appended claims, the singular forms "a," "and," 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 subject" includes reference to one or more subjects, and so forth.

[0042]

[0043] It should be further understood that where the description of various embodiments uses the term "comprising," those skilled in the art will understand that in some specific instances, the embodiments can be alternatively described using the words "consisting essentially of" or "consisting of."

[0043]

[0044] 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. 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.

[0044]

[0045] "Treatment" refers to prophylactic or therapeutic or diagnostic treatment. In certain embodiments, "treatment" refers to the administration of a compound or composition to a subject for therapeutic, prophylactic or diagnostic purposes.

[0045]

[0046] A "prophylactic" treatment is a treatment administered to a subject who does not show signs of disease or who shows only early signs of disease, for the purpose of reducing the risk of developing a condition. A compound or composition of the present disclosure may be given as a prophylactic treatment to reduce the likelihood of developing a condition, or to minimize its severity if a condition does develop.

[0046]

[0047] A "therapeutic" treatment is a treatment administered to a subject who exhibits signs or symptoms of a medical condition with the intent of reducing or eliminating those signs or symptoms. The signs or symptoms may be biochemical, cellular, histological, functional or physical, subjective or objective.

[0047]

[0048] As used herein, a "therapeutically effective amount" refers to an amount of an agent effective to produce an intended beneficial effect on health.

[0048]

[0049] As used herein, "AN+AD therapy" refers to treatment of a subject with an anti-CD30 antibody-drug conjugate (brentuximab vedotin) described herein in combination with an antibody against PD-1 (nivolumab) and chemotherapy consisting essentially of doxorubicin, and dacarbazine (AD therapy).

[0049]

[0050] "Lymphoma" as used herein is a hematological malignancy that usually arises from hyperproliferative cells of lymphatic origin. Lymphoma is sometimes classified into two major types, namely, Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). Lymphoma can also be classified according to the normal cell type that is most similar to the cancer cell, according to phenotypic, molecular, or cytogenetic markers. Lymphoma subtypes under the classification include, but are not limited to, mature B-cell tumors, mature T-cell and natural killer (NK) cell tumors, Hodgkin's lymphoma, and immunodeficiency-associated lymphoproliferative disorders. Lymphoma subtypes 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 the mixed cellularity subtype of Hodgkin lymphoma.

[0050]

[0051] "Leukemia," as the term is used herein, is a hematological malignancy that usually arises from hyperproliferative cells of myeloid origin, 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.

[0051]

[0052] As used herein, "prophylactic" or "primary prevention" refers to administration of an agent such as a colony-stimulating factor or granulopoiesis-stimulating factor prior to the onset of neutropenia or neutropenic symptoms in a subject. Prevention is intended 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 a therapy consisting essentially of an anti-PD-1 antibody, doxorubicin, and / or dacarbazine (N+AD 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.

[0052]

[0053] 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).

[0053]

[0054] As used herein, "neutropenia" refers to an abnormally low concentration of neutrophils in the blood. "Reducing the incidence of neutropenia in a subject" refers to a reduction in the incidence of neutropenia in a treated subject and / or a reduction in the severity of the occurrence of neutropenia in a subject. "Prevention of neutropenia" refers to the prevention or inhibition of the onset of neutropenia, for example, as a result of prophylactic treatment with a granulopoiesis stimulating factor. The normal reference range for absolute neutropenia count (ANC) in adults is 1500-8000 cells per microliter (μl) of blood. Neutropenia can be classified as follows: mild neutropenia (1000<=ANC<1500), moderate neutropenia (500<=ANC<1000), severe neutropenia (ANC<500). Hsieh et al., Ann. Intern. Med. 146:486-92, 2007.

[0054]

[0055] The term "checkpoint inhibitors" as used herein refers to molecules or therapeutic agents that block certain proteins made by some types of immune system cells, such as T cells, and some cancer cells. These proteins help to suppress immune responses and can prevent T cells from killing cancer cells. Examples of checkpoint proteins found on T cells or cancer cells include PD-1, PD-L1, PD-L2, CD28, CTLA-4, B7-1, B7-2 (see National Cancer Institute Dictionary of Cancer Terms), as well as ICOS and BTLA.

[0055]

[0056] "Programmed Death-1" (PD-1) refers to an immune inhibitory receptor belonging to the CD28 family. PD-1 is expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. The complete human PD-1 sequence can be found under GenBank accession number U64863.

[0056]

[0057] "Programmed Death Ligand-1" (PD-L1) and PD-L2 are cell surface ligands of PD-1 that downregulate T cell activation and cytokine secretion after binding to PD-1. The complete human PD-L1 sequence can be found under GenBank accession number Q9NZQ7.

[0057]

[0058] The terms "specific binding" and "specifically binds" mean that an anti-CD30 antibody reacts in a highly selective manner with its respective target, CD30, and not with many other antigens.

[0058]

[0059] The term "monoclonal antibody" refers to an antibody derived from a single cell clone, including any eukaryotic or prokaryotic cell clone, and not the method by which it is produced. Thus, the term "monoclonal antibody" as used herein is not limited to antibodies produced via hybridoma technology.

[0059]

[0060] The term "identical" or "% identity" in the context of two or more nucleic acid or polypeptide sequences refers to two or more sequences or subsequences that are the same or have a stated percentage of nucleotides or amino acid residues that are the same when compared and aligned for maximum correspondence. To determine % identity, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of the first amino acid or nucleic acid sequence for optimal alignment with the second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at the corresponding amino acid or nucleotide positions are then compared. If a position of the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position of the second sequence, the molecules are identical at that position. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions (e.g., overlapping positions) x 100). In certain embodiments, the two sequences are the same length.

[0060]

[0061] The term "substantially identical," in the context of two nucleic acids or polypeptides, refers to two or more sequences or subsequences having 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 set forth below).

[0061]

[0062] The determination of percent identity between two sequences can be achieved using a mathematical algorithm.A preferred non-limiting example of the mathematical algorithm used to compare two sequences is the algorithm of Karlin and Altschul, 1990, Proc.Natl.Acad.Sci.USA 87:2264-2268, which has been 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 with the NBLAST program, score=100, word length=12, to obtain nucleotide sequences that are homologous to the nucleic acid that codes for the protein of interest. BLAST protein searches can be performed with 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 iterative 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 include ADVANCE and ADAM, described in Torellis and Robotti, 1994, Comput. Appl. Biosci. 10:3-5, and FASTA, described in Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. 85:2444-8.Alternatively, protein sequence alignments can be performed using the CLUSTAL W algorithm described in Higgins et al., 1996, Methods Enzymol. 266:383-402.

[0062]

[0063] The abbreviation "MMAE" refers to monomethylauristatin E.

[0063]

[0064] The abbreviations "vc" and "val-cit" refer to the dipeptide valine-citrulline.

[0064]

[0065] The abbreviation "PAB" refers to self-immolating spacer. [ka]

[0065]

[0066] The abbreviation "MC" refers to the elongation factor maleimidocaproyl. [ka]

[0066]

[0067] cAC10-MC-vc-PAB-MMAE refers to the chimeric AC10 antibody conjugated to the drug MMAE via the MC-vc-PAB linker.

[0067]

[0068] Anti-CD30 MC-vc-PAB-MMAE antibody-drug conjugate refers to an anti-CD30 antibody conjugated 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.

[0068]

[0069] The term "pharmacologically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are pharma- ceutically acceptable, within the scope of sound medical judgment, suitable for 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 pharma- ceutically acceptable diluent, adjuvant, excipient, or vehicle with which an antibody-drug conjugate is administered.

[0069] antibody

[0070] 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 a Fab expression library, and binding fragments of any of the above. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to an antigen of interest. The immunoglobulin molecules of the present disclosure may be 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.

[0070]

[0071] In certain embodiments of the present disclosure, the antibody is a human antigen-binding antibody fragment of the present disclosure, including Fab, Fab', and F(ab') 2 , Fd, single chain Fv (scFv), single chain antibodies, disulfide-linked Fv (sdFv), and V L Domain or V HThe antibody fragments include, but are not limited to, fragments containing any of the above domains. Antigen-binding antibody fragments, including single-chain antibodies, can contain the variable region alone or in combination with all or part of the following: hinge region, CH1 domain, CH2 domain, CH3 domain, and CL domain. Antigen-binding fragments that also contain any combination of the variable region with the hinge region, CH1 domain, CH2 domain, CH3 domain, and CL domain are also included in the present disclosure. Preferably, the antibody is human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken. As used herein, a "human" antibody includes antibodies having the amino acid sequence of a human immunoglobulin, including antibodies isolated from a human immunoglobulin library, from human B cells, or from animals transgenic for one or more human immunoglobulins, as described below, for example, in U.S. Patent No. 5,939,598 to Kucherlapati et al.

[0071]

[0072] 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 Publications WO93 / 17715, WO92 / 08802, WO91 / 00360, WO 92 / 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, 5,601,819, Kostelny et al., 1992, J.Immunol.148:1547 1553.

[0072]

[0073] The antibodies of the present disclosure may be described or specified in terms of the particular CDRs they contain. In addition, 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 at least 98% identity (as known in the art and calculated using methods described herein) with the variable regions described herein are also included in the present disclosure. Antibodies useful in the present method disclosure may also be described or specified in terms of their binding affinity. A preferred binding affinity is 5×10 2 M, 10 -2 M, 5×10 -3 M, 10 -3 M, 5×10 -4 M, 10 -4 M, 5×10 -5 M, 10 -5 M, 5×10 -6 M, 10 -6 M, 5×10 -7 M, 10 -7 M, 5×10 -8 M, 10 -8 M, 5×10 -9 M, 10 -9 M, 5×10 -10 M, 10 -10 M, 5×10 -11 M, 10 -11 M, 5×10 -12 M, 10 -12 M, 5×10 -13 M, 10 -13 M, 5×10 -14 M, 10 -14 M, 5×10 -15 M, or 10 -15 These include those having a dissociation constant or Kd less than M.

[0073]

[0074] Antibodies also include derivatives that are 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 exerting a cytostatic or cytotoxic effect on Hodgkin's disease cells. For example, but not limited to, antibody derivatives include antibodies that are modified by, for example, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, binding to cellular ligands or other proteins. Any of a number of chemical modifications may be performed by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, and the like. In addition, derivatives may contain one or more non-classical amino acids.

[0074]

[0075] The antibodies described herein may be generated by any suitable method known in the art.

[0075] Anti-CD30 antibody

[0077] Murine anti-CD30 mAbs known in the art have been generated by immunization of mice with Hodgkin's Disease (HD) cell lines or purified CD30 antigen. AC10, originally called C10 (Bowen et al., 1993, J. Immunol. 151:5896 5906), differs in that this anti-CD30 mAb was prepared against a 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 downregulation of cell surface expression of CD28 and CD45 molecules, upregulation of cell surface CD25 expression, and induction of homotypic adhesion after binding of C10 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, incorporated herein by reference, which discloses chimeric AC10 antibodies.

[0076]

[0078] In general, the antibodies of the present disclosure immunospecifically bind to CD30 and exert cytostatic and cytotoxic effects on malignant cells of Hodgkin's disease.

[0077]

[0079] In various embodiments, antibodies useful in the methods comprise one or more CDRs of AC10. The present disclosure encompasses antibodies or derivatives thereof comprising a heavy chain variable domain or a light chain variable domain comprising (a) a set of three CDRs, which set of CDRs is derived from monoclonal antibody AC10, and (b) a set of four framework regions, which differ from the set of framework regions of monoclonal antibody AC10, such that the antibody or derivative thereof immunospecifically binds CD30.

[0078]

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

[0079]

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

[0080]

[0082] Also included in the present invention are 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 at least 98% identity (as calculated using methods known in the art and described herein) to the variable regions of AC10, preferably including the CDRs of AC10.

[0081]

[0083] The present disclosure further provides nucleic acids comprising nucleotide sequences encoding proteins, including but not limited to the proteins and fragments thereof of the present disclosure. The nucleic acids 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 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 present disclosure include SEQ ID NO:1 or SEQ ID NO:9. (See Table A). [Table 1]

[0082]

[0084] In various embodiments, the antibody is an IgG antibody, such as an IgG1, IgG2, IgG3, or IgG4 antibody, preferably an IgG1 antibody.

[0083]

[0085] 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 CDR3 set forth in SEQ ID NO: 16.

[0084]

[0086] In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises i) an amino acid sequence at least 85%, 90%, or 95% identical to the heavy chain variable region set forth in SEQ ID NO:2, and ii) an amino acid sequence at least 85%, 90%, or 95% identical to the light chain variable region set forth in SEQ ID NO:10. In various embodiments, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises i) an amino acid heavy chain variable region set forth in SEQ ID NO:2, and ii) an amino acid light chain variable region set forth in SEQ ID NO:10.

[0085]

[0087] In various embodiments, the anti-CD30 antibody cross-competes for binding to CD30 with an antibody comprising (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 CDR3 set forth in SEQ ID NO: 16, or binds to the same epitope as an antibody comprising (ii) 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 CDR3 set forth in SEQ ID NO: 16.

[0086] Anti-PD-1 antibody

[0089] Human monoclonal antibodies that bind to PD-1 are disclosed in U.S. Patent Nos. 8,008,449, 6,808,710, 7,488,802, 8,168,757, 8,354,509, and PCT Publication No. 2012 / 145493.

[0087]

[0090] In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab (also known as "OPDIVO®" and previously designated as 5C4, BMS-936558, MDX-1106, or ONO-4538) is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2) and blocks downregulation of anti-tumor T cell function (U.S. Patent No. 8,008,449, Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). In another embodiment, the anti-PD-1 antibody or a fragment thereof cross-competes with nivolumab. In some embodiments, the anti-PD-1 antibody binds to the same epitope as nivolumab. In certain embodiments, the anti-PD-1 antibody has the same CDRs as nivolumab.

[0088]

[0091] In one embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab ("KEYTRUDA®", lambrolizumab, MK-3475) is a humanized monoclonal IgG4 antibody against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). Pembrolizumab is described, for example, in U.S. Patent No. 8,900,587. Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma and advanced NSCLC. In various embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with pembrolizumab. In various embodiments, the anti-PD-1 antibody binds to the same epitope as pembrolizumab. In various embodiments, the anti-PD-1 antibody has the same CDRs as pembrolizumab.

[0089]

[0092] Additional anti-PD-1 antibodies contemplated for use herein include MEDI0680 (U.S. Patent No. 8,609,089), BGB-A317 (U.S. Patent Publication No. 2015 / 0079109), INCSHR1210 (SHR-1210) (WO2015 / 085847), REGN-2810 (WO2015 / 112800) PDR001 (WO2015 / 112900), TSR-042 (ANB011) (WO2014 / 179664), and STI-1110 (WO2014 / 194302).

[0090]

[0093] In various embodiments, the anti-PD-1 antibody or antigen-binding portion thereof is a chimeric, humanized, or human monoclonal antibody, or portion thereof. In various embodiments, the antibody is a human or humanized antibody. Antibodies having an IgG1, IgG2, IgG3, or IgG4 isotype are contemplated.

[0091]

[0094] In various embodiments, the anti-PD-1 antibody (i) cross-competes with nivolumab or pembrolizumab for binding to human PD-1, (ii) binds to the same epitope as nivolumab or pembrolizumab, (iii) is nivolumab, or (iv) is pembrolizumab.

[0092] Antibody-drug conjugates

[0095] Contemplated herein is the use of an antibody-drug conjugate comprising an anti-CD30 antibody covalently attached to MMAE via an MC-vc-PAB linker. [ka] The antibody-drug conjugate is delivered to the 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.

[0093]

[0096] In various embodiments, the anti-CD30 antibody-drug conjugates of the disclosure have the following formula: or a pharma- ceutically 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.

[0094]

[0100] Drug loading is represented by p, the average number of drug molecules per antibody in the pharmaceutical composition. For example, if p is about 4, then 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 may be about 3, about 4, or about 5. The average number of drugs per antibody in the preparation of the conjugate reaction 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 homogenous antibody-drug-conjugates where p is a certain value from antibody-drug-conjugates with other drug loadings can be achieved by means such as reverse-phase HPLC or electrophoresis.

[0095]

[0101] The stretcher unit (A) can link the antibody unit to the valine-citrulline amino acid unit through the 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 attached to the antibody through the sulfur atom generated from the reduction of the interchain disulfide bond of the antibody. In some embodiments, the stretcher unit is attached to the antibody only through 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 reaction of 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.

[0096]

[0102] 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.

[0097]

[0103] Representative Stretcher units are set forth within the brackets of Formulae IIIa and IIIb of US Pat. No. 9,211,319, incorporated herein by reference.

[0098]

[0104] In various embodiments, the anti-CD30 antibody drug conjugate comprises monomethyl auristatin E and a protease cleavable linker. It is contemplated that 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.

[0099]

[0105] In a preferred embodiment, the anti-CD30 antibody drug conjugate is brentuximab vedotin, which has the following structure: [ka]

[0100]

[0106] 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 that covalently attaches MMAE to cAC10. The drug-to-antibody ratio or drug loading is represented by "p" in the structure of Brentuximab vedotin and ranges from integer values ​​of 1 to 8. The average drug loading of Brentuximab vedotin in pharmaceutical compositions is approximately 4.

[0101] How to use

[0097] Provided herein is a method for administering an anti-CD30 antibody-drug conjugate in combination with an additional cancer therapeutic agent to treat hematological cancer. The method includes treating a subject with hematological cancer, for example, a CD30-expressing hematological cancer, by administering an anti-CD30 antibody-drug conjugate in combination with an anti-PD-1 antibody and a chemotherapy regimen. In various embodiments, the chemotherapy regimen consists essentially of doxorubicin and dacarbazine.

[0102]

[0098] Additional chemotherapeutic agents are disclosed in the table below and may be used alone or in combination with one or more additional chemotherapeutic agents, which in turn may also be administered in combination with the anti-CD30 antibody-drug conjugates described herein.

[0103] Chemotherapeutic agents [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0104] Blood or hematological cancer refers to cancer that occurs in blood-forming tissue or in cells of the immune system. CD30-expressing blood cancer refers to blood cancer that expresses the CD30 antigen. The CD30 antigen is expressed in large numbers on selected lymphoma and leukemia tumor cells. Blood cancers such as classical Hodgkin's lymphoma, non-Hodgkin's lymphoma, anaplastic large cell lymphoma, and cutaneous T-cell lymphoma (CTCL) are examples of blood cancers that can be treated with the present method.

[0105] In various embodiments, the subject has a tumor comprising one or more cells expressing CD30. In various embodiments, at least about 0.01%, at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the tumor cells express CD30.

[0106] It is also contemplated that the subject has a tumor that expresses PD-1 or a ligand of PD-1, such as PD-L1 or PD-L2.Methods for measuring the level of PD-1, PD-L1, or PD-L2 known in the art are contemplated herein for determining the level of the molecule in tumor cells.See, for example, WO2017 / 210473.

[0107]

[0103] In various embodiments, the tumor PD-L1 expression level is at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.

[0108] In various embodiments, the anti-PD-1 antibody dose may be administered at least about 0.1 mg / kg to at least about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 5 mg / kg, about 1 mg / kg to about 3 mg / kg, or about 7.5 mg / kg to about 12.5 mg / kg. In various embodiments, the anti-PD-1 antibody is given on a dose basis. In various embodiments, the dose of the anti-PD-1 antibody is about 100 to 600 mg, about 400 to 500 mg, about 100 to 200 mg, about 200 to 400 mg, or about 100 to 300 mg. In various embodiments, the anti-PD-1 antibody is administered at a dose of about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 130 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, at least about 300 mg, about 320 mg, about 360 mg, about 400 mg, about 440 mg, about 480 mg, about 500 mg, about 550 mg, or about 600 mg.

[0109] In any of the aspects or embodiments herein, the method herein is provided for treating subjects who are newly diagnosed and have not been previously treated for hematological cancer, or subjects who have relapsed.In various embodiments, it is contemplated that the subject has classical Hodgkin lymphoma (stage IIA with bulky tumor, stage IIB, stage III, or stage IV), including advanced classical Hodgkin lymphoma (e.g., stage III or stage IV).

[0110] In various embodiments, the present disclosure provides a method of treating a subject with newly diagnosed classical Hodgkin lymphoma (HL), comprising administering a composition comprising an effective amount of brentuximab vedotin (A) and an anti-PD-1 antibody in combination with chemotherapy consisting essentially of doxorubicin and dacarbazine (AD therapy), wherein brentuximab vedotin is administered at 1.2 mg / kg, the anti-PD-1 antibody is administered at 100-300 mg / dose, and doxorubicin is administered at 25 mg / m 2 and dacarbazine was administered at 375 mg / m 2 and optionally, brentuximab vedotin is administered within 1 hour after administration of the AD therapy.

[0111] In various embodiments, the method herein provides the progression-free survival (PFS) of the subject after therapy is maintained for more than one year. In various embodiments, the progression-free survival (PFS) of the subject after therapy is maintained for approximately two years. In certain embodiments, after 4-6 cycles of AN+AD therapy, the subject has a Deauville score of 3 or less, or 2 or less. In certain embodiments, after 2 cycles of therapy (i.e., 4 doses), the subject has a Deauville score of 1 or 2.

[0112] In various embodiments, when the anti-CD30 antibody drug conjugate is administered at 1.2 mg / kg with a combination therapy, such as an N+AD combination therapy, the combination therapy is administered every two weeks, e.g., on days 1 and 15 of a 28-day cycle.

[0113]

[0109] In various embodiments, the anti-CD30 antibody drug conjugate+N+AD combination therapy is administered for six cycles or less, for example, four to six cycles, or four, five, or six cycles.

[0114] It is contemplated that therapy is administered until PET scan determines that there is no tumor or tumor progression.If tumor is still seen on PET scan after completion of therapy, for example after 4-6 cycles, the treating physician may repeat the course of therapy as necessary until PET scan becomes negative, tumor progression slows, or tumor progression ceases.Repeated cycles may be started without interruption or may be started 1, 2, 3, 4, 5, 6 weeks or more after initial treatment with AN+AD therapy.

[0115] In various embodiments, the anti-CD30 antibody drug conjugate, e.g., brentuximab vedotin therapy, is administered by intravenous infusion over the course of about 30 minutes. In various embodiments, the anti-PD-1 antibody is administered by intravenous infusion over the course of about 60 minutes.

[0116]

[0112] 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).

[0117] 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 is untreated.

[0118]

[0114] In various embodiments, the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL).

[0119] 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).

[0120] In various embodiments, the subject has previously undergone systemic therapy or previously undergone radiation.

[0121] The efficacy of the treatments described herein can be measured using various biomarkers, progression of tumor size or other symptoms in the subject, including reducing serum thymus and activation-regulated chemokine (TARC) levels in the subject, increasing levels of proinflammatory cytokines, such as interleukin-18 (IL-18) and / or interferon-γ, increasing levels of T cell chemokines, such as IP10, activating T cell activity (e.g., increasing T cells, CD4+ T cells, regulatory T cells (Tregs)), and slowing or reducing tumor cell growth. In various embodiments, tumor cell growth is slowed or reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, or at least about 80%, at least about 90%, at least about 95%, or at least about 100%, as compared to untreated subjects or subjects receiving a different therapeutic regimen.

[0122] Peripheral neuropathy Neuropathy, or peripheral neuropathy, refers to damage to nerves (peripheral nerves) outside the brain and spinal cord. Peripheral neuropathy develops as a result of peripheral nervous system damage during treatment with anti-CD30 antibody drug conjugates. Symptoms include numbness or tingling, tingling sensations (paresthesia), and muscle weakness. Motor nerve damage is most commonly associated with muscle weakness.

[0123] The method contemplates a dose adjustment of the anti-CD30 drug conjugate if neuropathy appears in the subject. It is contemplated that the neuropathy is peripheral neuropathy. Provided herein is a method for treating a subject who exhibits grade 2 or higher peripheral neuropathy after initiating administration of an anti-CD30 antibody drug conjugate combination therapy described herein, for example, where brentuximab vedotin is administered at a dose of 1.2 mg / kg or higher, comprising 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, for example brentuximab vedotin, is withheld until the peripheral neuropathy is reduced to grade 2 or lower, and then 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. In various embodiments, if a subject exhibits grade 4 neuropathy, administration of the anti-CD30 antibody drug conjugate, e.g., brentuximab vedotin, is withheld 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.

[0124] In various embodiments, if the subject exhibits grade 3 neuropathy, administration of the anti-CD30 antibody drug conjugate is reduced, e.g., to 0.9 mg / kg, after which 0.9 mg / kg of the anti-CD30 antibody drug conjugate is administered or maintained until peripheral neuropathy is reduced to grade 2 or less. In various embodiments, if peripheral neuropathy is grade 2, the reduced dose of 0.9 mg / kg is given every two weeks up to a maximum dose of 90 mg.

[0125] Methods for measuring neuropathy are known in the art and are utilized by treating physicians to monitor and diagnose neuropathy in subjects undergoing 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, and grade 3 PN is characterized by sensory loss and / or paresthesia that interferes with function.Grade 4 PN is characterized by paralysis.

[0126]

[0123] 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.

[0127] Neutropenia Neutropenia is a common side effect of chemotherapy regimens and results from the depletion of neutrophils in the blood of patients receiving chemotherapy. Neutropenia is also observed with treatment with brentuximab vedotin. Neutropenia is generally diagnosed based on the level of neutrophils in the blood. For example, grade 3 neutropenia is defined as an absolute blood neutrophil count [ANC] < 1.0 × 10 9 / L, and grade 4 neutropenia was defined as an absolute blood neutrophil count [ANC] <0.5 × 10 9 / L, and febrile neutropenia refers to neutropenia accompanied by fever, with subjects having a single oral temperature ≥ 38.3°C or ≥ 38.0°C for > 1 hour, and grade 3 / 4 neutropenia.

[0128]

[0126] It is contemplated herein that subjects receiving an anti-CD30 antibody drug conjugate, for example, brentuximab vedotin, or an anti-CD30 antibody drug conjugate in combination with chemotherapy, such as an anti-PD-1 antibody and AD combination therapy, receive a granulopoiesis stimulating factor prophylactically beginning with cycle 1 of administration of the anti-CD30 antibody drug conjugate, for example, as primary prevention. Exemplary granulopoiesis stimulating factors include granulocyte colony stimulating factor (GCSF), derivatives of GCSF, or granulocyte monocyte colony stimulating factor (GMCSF). Commercially available GCSFs contemplated for use herein are filgrastim (NEUPOGEN®) and pegfilgrastim (NEULASTA®). Commercially available GMCSF is available as sargramostim (LEUKINE®).

[0129]

[0127] Provided herein is a method for treating hematological cancer in a subject, comprising administering an anti-CD30 antibody drug conjugate combination therapy (AN+AD) as described herein 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 beginning cycle 1 of administration of the anti-CD30 antibody drug conjugate. In further embodiments, the granulopoiesis stimulating factor is administered within 1 or 2 to 5 days after beginning 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 regimen as described herein. In various embodiments, the granulopoiesis stimulating factor is administered 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate, i.e., 24 hours to 36 hours after each dose.

[0130]

[0128] Methods of reducing the incidence of neutropenia and / or febrile neutropenia in a subject undergoing treatment with an anti-CD30 antibody drug conjugate are also contemplated, comprising administering to the subject a granulopoiesis stimulating factor, the stimulating factor being administered 1-7 days starting with cycle 1 of administration of the anti-CD30 antibody drug conjugate, and optionally 1 day or 2-5 days after starting with 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 regimen described herein. In various embodiments, the granulopoiesis stimulating factor is administered 24 hours to about 36 hours after each administration of the anti-CD30 antibody drug conjugate.

[0131]

[0129] Also 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. In certain embodiments, the granulopoiesis stimulating factor is administered 1 or 2 to 5 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 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.

[0132] In various embodiments, the subject has not previously received an anti-CD30 antibody drug conjugate therapy. In various embodiments, the subject has not experienced treatment-emergent grade 3-4 neutropenia following administration of the anti-CD30 antibody drug conjugate.

[0133]

[0131] It is contemplated that the granulopoiesis stimulating factor is granulocyte colony stimulating factor (GCSF). It is contemplated that the GCSF is a long-acting GCSF or is not a long-acting GCSF.

[0134] In various embodiments, if the stimulatory agent is not a long-acting GCSF, e.g., filgrastim, it can be administered, for example, starting 1-7 days, 1-5 days, or 1-3 days after the initiation of cycle 1 administration of a daily dose of the anti-CD30 antibody drug conjugate or AN+AD therapy. In certain embodiments, the GCSF is administered on days 2, 3, 4, 5, 6, and / or 7 after the anti-CD30 antibody drug conjugate or AN+AD therapy. In various embodiments, the filgrastim is administered at a dose of 5ug / kg / day to 10ug / kg / day for a period of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

[0135] 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 1-5 after anti-CD30 antibody drug conjugate treatment or, optionally, after AN+AD therapy. In certain embodiments, GCSF is administered in a single dose or multiple doses on the same day, the second day, the third day, the fourth day, or the fifth day after anti-CD30 antibody drug conjugate or AN+AD 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 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.

[0136]

[0134] In various embodiments, the granulopoiesis stimulating factor is administered intravenously or subcutaneously. It is contemplated that the granulopoiesis stimulating factor is given in a single dose or multiple doses, for example, multiple daily doses.

[0137]

[0135] It is contemplated that antibiotics may also be administered to subjects receiving the granulocyte stimulating factor and anti-CD30 antibody drug conjugate 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®.

[0138]

[0136] In various embodiments, if a subject is receiving 1.2 mg / kg of an anti-CD30 antibody-drug conjugate every two weeks, the dose may be reduced to 0.9 mg / kg to improve neutropenia, e.g., grade 4 neutropenia.

[0139] formulation

[0137] Various delivery systems can be used to administer the antibodies or antibody-drug conjugates contemplated herein. In certain embodiments, the administration of the antibody-drug conjugate compound is by intravenous infusion. In some embodiments, the administration is by intravenous infusion for 30 minutes, 1 hour, or 2 hours. In various embodiments, the administration of the antibody compound is by intravenous infusion. In various embodiments, the administration is by intravenous infusion for 30 minutes, 1 hour, or 2 hours.

[0140] Antibody and / or antibody-drug conjugate compound can be administered as pharmaceutical composition containing one or more pharma-ceutical compatible components.For example, pharmaceutical composition typically contains one or more pharma-ceutical acceptable carriers, such as aqueous carriers (e.g., sterile liquids).When pharmaceutical composition is administered intravenously, water is the more typical carrier.

[0141]

[0139] The composition can also contain, if desired, for example, saline solution salts, buffers, salts, non-ionic surfactants, and / or sugars. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Formulation is appropriate for the mode of administration.

[0142]

[0140] The present disclosure provides a pharmaceutical composition, for example, comprising a therapeutically effective amount of an antibody-drug conjugate, a buffer, optionally a cryoprotectant, optionally a bulking agent, optionally a salt, and optionally a surfactant. Additional agents can be added to the composition. A single agent can serve multiple functions. For example, a sugar such as trehalose can act as both a cryoprotectant and a bulking agent. Any suitable pharma- ceutically acceptable buffer, surfactant, cryoprotectant, and bulking agent can be used according to the present disclosure.

[0143]

[0141] In various embodiments, antibody drug conjugate formulations include drug conjugate formulations that have been subjected to lyophilization, or other methods of protein preservation, as well as antibody drug formulations that have not been subjected to lyophilization.

[0144]

[0142] 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 (e.g., an antibody-drug conjugate of Formula I or a pharma- ceutically acceptable salt thereof); (ii) about 5 to 50 mM, preferably about 10 mM to about 25 mM, of 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% sucrose or trehalose, or a combination thereof; (iv) optionally 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.

[0145]

[0143] In some embodiments, the antibody-drug conjugate formulation comprises about 1 to 25 mg / ml, about 3 to about 10 mg / ml, 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% 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, preferably about 6.6.

[0146]

[0144] In some embodiments, the antibody-drug conjugate formulation comprises about 5 mg / ml of 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 1 mg / ml of a surfactant selected from polysorbate 20 or polysorbate 80, and (v) water, and the pH of the composition is about 5.3 to about 7, preferably about 6.6.

[0147] In various embodiments, the anti-PD-1 antibody, e.g., nivolumab, is in a solution of about 40 mg / 4 mL, 100 mg / 10 mL, or 240 mg / 24 mL. Optionally, the anti-PD-1 antibody is diluted with 0.9% sodium chloride, USP, or 5% dextrose.

[0148] In various embodiments, the anti-PD-1 antibody, e.g., pembrolizumab, is a 50 mg lyophilized powder or 100 mg / 4 mL (25 mg / mL) in solution. In various embodiments, the preparation is in a solution containing 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The final concentration of the diluted solution can be 1 mg / mL to 10 mg / mL.

[0149] Any of the formulations described above can be stored in liquid or frozen form, and can be optionally subjected to a preservation process. In some embodiments, the formulations described above are lyophilized, i.e., they are subjected to freeze-drying. In some embodiments, the formulations described above are subjected to a preservation process, e.g., freeze-drying, and then reconstituted with a suitable liquid, e.g., water. Freeze-drying means that the composition is freeze-dried under vacuum. Freeze-drying 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).

[0150] The formulations of the present disclosure can be used in conjunction with the methods described herein or with other methods for treating disease. The antibody-drug conjugate formulation can be further diluted prior to administration to a subject. In some embodiments, the formulation is diluted with physiological saline solution and held in an IV bag or syringe prior to administration to the subject. Thus, in some embodiments, a method for treating hematological cancer in a subject includes administering to a subject in need thereof a weekly dose of a pharmaceutical composition comprising an antibody-drug conjugate having the formula: (iii) about 3% to about 10% sucrose or trehalose, or a combination thereof, (iv) optionally, about 0.05 to 2 mg / ml of a surfactant selected from polysorbate 20 or polysorbate 80, or a combination thereof, and (v) water, and the pH of the composition is about 5.3 to about 7, preferably about 6.6.

[0151] The formulation of chemotherapy intended for use herein, including doxorubicin and dacarbazine, is provided as typically used in the treatment of cancer.For example, doxorubicin and dacarbazine are commercially available and approved by the US FDA and other regulatory agencies for use in the treatment of patients with multiple types of cancer.

[0152]

[0150] The present disclosure also provides a kit for the treatment of hematological cancer. The kit can include (a) a container containing an antibody-drug conjugate, and optionally a container containing one or more of an anti-PD-1 antibody, doxorubicin, or dacarbazine. Such a kit can further include one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharma- ceutically acceptable carriers, additional containers, as will be readily apparent to those skilled in the art, if desired. Printed instructions, such as inserts or labels, indicating the amount of components to be administered, administration guidelines, and / or mixing guidelines of components, can also be included in the kit. EXAMPLES

[0153] Example 1

[0151] Described herein is an open-label, multicenter, Phase 2 study to evaluate the efficacy of brentuximab vedotin, anti-PD-1 antibody (nivolumab), doxorubicin, and dacarbazine (AN+AD) as first-line therapy in patients with untreated stage III / IV classical Hodgkin lymphoma (cHL).

[0154] The combination of brentuximab vedotin and nivolumab appears to be active and well tolerated in cHL. In one study of 62 subjects in the initial salvage setting, the combination resulted in a CR rate of 61% (Herrera et al., 2018 Blood 131(11):1183-94), and subjects were able to undergo subsequent stem cell transplantation. In another study of 19 subjects with relapsed / refractory cHL who had received a median of three previous therapies, the combination resulted in a CR rate of 50% (Diefenbach et al., 2017, Hematol Oncol 35(Suppl 2):84-5). In another study in 11 previously untreated subjects with cHL who were over 60 years of age and not eligible to refuse conventional combination chemotherapy, the combination of brentuximab vedotin and nivolumab resulted in a CR rate of 55% (Friedberg et al.,2018 HemaSphere 2(S3):T027(0153)). No new safety signals were identified and the combination was deemed well tolerated.

[0155]

[0153] The combination of nivolumab has also been shown to be well tolerated when combined with doxorubicin, vinblastine, and dacarbazine (N+AVD). Ramchandren et al. observed a CR rate of 67% with the combination in 51 subjects with newly diagnosed advanced cHL (Ramchandren et al., 2019 J Clin Oncol 37(23):1997-2007). Neutropenia was reported in 55% of subjects, and treatment-related febrile neutropenia was reported in 10% of subjects.

[0156] material and method Study Design: Patients were randomized to receive AN+AD (brentuximab vedotin 1.2 mg / kg, nivolumab 240 mg, doxorubicin 25 mg / m 2 , dacarbazine 375 mg / m 2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Brentuximab vedotin is administered intravenously over a period of approximately 30 minutes. Nivolumab is administered intravenously as an approximately 60-minute infusion, at least 30 minutes after completion of brentuximab vedotin administration. Doxorubicin and dacarbazine are administered according to institutional standards. Dose reductions / modifications for brentuximab vedotin are described in Figure 1.

[0157] Patients: Patients (ages 12 and older) with histologically confirmed (Ann Arbor stage IIA / IIB / III / IV with bulky mass) classical Hodgkin lymphoma according to the World Health Organization classification who have not been previously treated with systemic chemotherapy / radiotherapy are eligible. Patients are required to have an Eastern Cooperative Oncology Group performance status of 2 or less, good absolute neutrophil and platelet counts, hemoglobin levels, and liver and kidney function marker levels (excluding patients with bone marrow or liver or Gilbert's syndrome involvement). Patients with nodular lymphocyte-predominant Hodgkin lymphoma are ineligible, as are patients previously treated with a checkpoint inhibitor or T-cell costimulatory therapy, patients previously treated with brentuximab vedotin, peripheral sensory / motor neuropathy, a positive pregnancy test, known brain / meningeal disease, any evidence of residual disease from another malignancy or diagnosis of another malignancy within 3 years prior to the first dose, interstitial lung disease, grade 3 or greater pulmonary disease, idiopathic interstitial pneumonia or diffusing capacity of the lung for carbon monoxide, Child-Pugh B or C hepatic dysfunction, or subjects with clinically relevant cardiovascular conditions.

[0158] Exemplary checkpoint inhibitors interfere with the activity of one or more of the following: PD-1, PD-L1, PD-L2, CD28, ICOS, CTLA-4, and BTLA. In addition to the anti-PD-1 antibodies nivolumab, pembrolizumab, and other antibodies described herein, checkpoint inhibitors include ipilimumab (YERVOY®), which binds to and inhibits CTLA-4.

[0159]

[0157] Endpoints: The primary endpoint is complete response rate (CR). Secondary endpoints include evaluation of the safety and tolerability of treatment, as well as overall response rate, duration of response, duration of complete response, event-free survival, progression-free survival, and overall survival.

[0160]

[0158] Complete response rate (CR) at end of therapy (EOT) is defined as the proportion of subjects with CR at EOT according to Lymphoma Response Criteria for Immunomodulatory Therapy (LYRIC) (Cheson et al., 2016 Blood 128(21):2489-96) in subjects with previously untreated advanced cHL.Subjects without post-baseline evaluation are scored as non-responders to calculate CR rate at EOT.

[0161]

[0159] Objective response rate (ORR) is defined as the proportion of subjects with previously untreated advanced cHL who have a CR or partial response (PR) at EOT according to the Lymphoma Response Criteria for Immunomodulatory Therapy (LYRIC) (Cheson 2016, supra).

[0162] Duration of response (DOR) is defined as the time from the first documented objective tumor response (CR or PR) (by Lymphoma Response Criteria to Immunomodulatory Therapy (LYRIC) (Cheson 2016, supra)) to the first documented tumor progression or death, whichever occurs first. Subjects without progression or death are censored, and details are provided in the statistical analysis plan (SAP). Duration of response is calculated only for the subgroup of subjects who achieve CR or PR.

[0163] Duration of complete response (DOCR) is defined as the time from the start of the first documented complete tumor response (CR) (by Lymphoma Response Criteria to Immunomodulatory Therapy (LYRIC) (Cheson 2016, supra)) to the first documented tumor progression or death, whichever occurs first. DOCR is calculated only for the subgroup of subjects who achieve CR. Censoring will be in the same manner as DOR.

[0164]

[0162] Event-free survival (EFS) is defined as the time from the date of randomization to the first documentation of objective tumor progression, death from any cause, or administration of subsequent anticancer therapy to treat residual or progressive disease, whichever occurs first.

[0165]

[0163] Progression-free survival (PFS) is defined as the time from the start of study treatment to the first documentation of objective tumor progression or death.

[0166]

[0164] Overall survival is defined as the time from the start of study treatment to the date of death from any cause. In the absence of confirmed death, survival time is censored at the last day the subject is known to be alive.

[0167] Evaluation: Determination of antitumor activity is based on objective response assessment according to the revised Lugano staging system for malignant lymphoma (Cheson et al., 2014 J. Clin Oncol 32(27):3059-68) incorporating Lymphoma Response Criteria to Immunomodulatory Therapy (LYRIC) (Cheson 2016, supra). ECOG performance status is tested in cycles 2-6.

[0168] Staging is performed by diagnostic-quality CT and PET scans, with disease involvement determined by focal fluorodeoxyglucose (FDG) uptake at nodal and extranodal (including spleen, liver, bone marrow, and thyroid) sites consistent with lymphoma according to uptake patterns and / or CT features. Diagnostic-quality CT may be combined with PET scans if both are required according to protocol. Up to six of the largest nodules, nodal masses, or other associated lesions measurable in two diameters should be identified as target lesions at baseline.

[0169]

[0167] Progressive metabolic disease (PmD), no metabolic response (NmR), partial metabolic response (PmR), or complete metabolic response (CmR) is determined using PET-based response at each evaluation. If only CT-based evaluation is performed, response is classified as progressive disease (PD), stable disease (SD), partial response (PR), or complete response (CR). If clinical progression is determined by the investigator, radiographic staging should also be performed to determine response evaluation according to the Lugano classification criteria. PET scan metabolic uptake is assessed using the Deauville 5-point scale (Barrington et al., 2010 Eur J Nucl Med Mol Imaging 37(10):1824-33; Biggi et al., 2013 J Nucl Med 54(5):683-90), and a score of 3 or less is considered to represent a complete metabolic response. Both PET and CT scans are used until the disease is PET negative, then response is followed by a diagnostic-quality only CT scan.

[0170] Treatment with checkpoint inhibitors such as nivolumab can result in false-positive PET imaging. The LYRIC criteria recommend repeat PET imaging and / or biopsy to further evaluate PET-positive (D4 or D5) lesions identified at EOT response evaluation.

[0171]

[0169] Safety will be assessed by the incidence of adverse events using the Medical Dictionary for Clinical Practice (MedDRA, version 19.0) and the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03), as well as by changes in vital signs and clinical laboratory results.

[0172] Biomarker evaluation in tumor tissue may include, but is not limited to, CD30, PD-L1 measurement, tumor microenvironment characterization (e.g., T cells, NK cells, monocytes, and macrophages, other tumor-associated cell levels), tumor subtyping, profiling of somatic mutations or alterations of genes or RNA commonly altered in cancer, and drug effects. Assays may include, but are not limited to, immunohistochemistry and next-generation sequencing of RNA and DNA.

[0173]

[0171] Laboratory Evaluations: The following laboratory evaluations will be performed by a local laboratory at the scheduled times. Chemistry panel will include the following tests: albumin, alkaline phosphatase, ALT, AST, blood urea nitrogen, calcium, creatinine, chloride, glucose, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, total bilirubin, and uric acid. For Part B, the chemistry panel should also include amylase and lipase, and TSH, free T3, and free T4 will also be tested at cycle 1, cycle 3, and EOT.

[0174]

[0172] A complete blood count (CBC) with differential includes the following tests: white blood cell count with five-part differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils), platelet count, hemoglobin, and hematocrit.

[0175]

[0173] Estimated glomerular filtration rate (GFR) was calculated using the MDRD equation when applicable, and serum creatinine (Scr) is reported in mg / dL.

[0176] Statistical analysis: ORR at EOT and exact 2-sided 95% CI using Clopper-Pearson method (Clopper 1934 Biometrika 26(4):404-13) are calculated. Secondary endpoints of DOR, EFS, PFS, and OS are time-to-event endpoints and are analyzed using Kaplan-Meier methodology.

[0177]

[0175] Numerous adjustments and modifications of the present disclosure described in the above illustrative examples are expected to occur to those skilled in the art. Accordingly, only such limitations as appear in the claims should be imposed on the present invention. The claims as of the international filing are as follows: [Item 1] A method for treating blood cancer in a subject, comprising administering an anti-CD30 antibody-drug conjugate and a therapy comprising an anti-PD-1 antibody, doxorubicin, and dacarbazine. 2. The method of claim 1, wherein the anti-PD-1 antibody is administered at least 30 minutes after each administration of the anti-CD30 antibody-drug conjugate. 3. The method of claim 1 or 2, wherein the anti-PD-1 antibody is administered by intravenous infusion over a period of about 60 minutes. 4. The method of any one of the preceding claims, wherein the anti-PD-1 antibody is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy. 5. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy. 6. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate and anti-PD-1 antibody are administered every two weeks. 7. The method of claim 1, wherein the anti-PD-1 antibody is administered starting with cycle 1 of administration of the anti-CD30 antibody-drug conjugate. 8. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate and anti-PD-1 antibody are administered on days 1 and 15 of a 28-day cycle. 9. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate and anti-PD-1 antibody are administered for six cycles or less. 10. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate and anti-PD-1 antibody are administered for 4 to 6 cycles. 11. The method of any one of the preceding claims, further comprising administering chemotherapy consisting essentially of doxorubicin and dacarbazine (AD) as a combination therapy. [Item 12] The anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is i) a heavy chain CDR1 as set forth in SEQ ID NO: 4, a heavy chain CDR2 as set forth in SEQ ID NO: 6, a heavy chain CDR3 as set forth in SEQ ID NO: 8, and ii) A method according to any one of the preceding claims, comprising a light chain CDR1 as set forth in SEQ ID NO: 12, a light chain CDR2 as set forth in SEQ ID NO: 14, and a light chain CDR13 as set forth in SEQ ID NO: 16. [Item 13] 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) The method according to any one of the preceding claims, comprising an amino acid sequence that is at least 85% identical to the light chain variable region shown in SEQ ID NO:10. 14. The method of any one of the preceding claims, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a monoclonal anti-CD30 antibody. 15. The method of any one of the preceding claims, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a chimeric AC10 antibody. 16. The method of any one of the preceding claims, wherein the antibody-drug conjugate comprises monomethylauristatin E and a protease-cleavable linker. 17. The method of claim 16, wherein the protease-cleavable linker comprises a thiol-reactive spacer and a dipeptide. 18. The method of claim 16 or 17, wherein the protease-cleavable linker consists of a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer. 19. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate is brentuximab vedotin. 20. The method of any one of the preceding claims, wherein (i) the anti-PD-1 antibody cross-competes with nivolumab or pembrolizumab for binding to human PD-1, (ii) the anti-PD-1 antibody binds to the same epitope as nivolumab or pembrolizumab, (iii) the anti-PD-1 antibody is nivolumab, or (iv) the anti-PD-1 antibody is pembrolizumab. 21. The method of any one of the preceding claims, wherein the anti-PD-1 antibody is nivolumab or pembrolizumab. 22. The method of any one of the preceding claims, wherein the anti-PD-1 antibody is nivolumab. 23. The method of any one of the preceding claims, wherein the hematological cancer comprises one or more cells that express PD-L1, PD-L2, or both PD-L1 and PD-L2. 24. The method of any one of the preceding claims, wherein the hematological cancer is a CD30-expressing cancer and the CD30 expression is 10% or greater. 25. The method of claim 24, wherein the CD30 expression is measured by an FDA approved test. 26. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg and the anti-PD-1 antibody is nivolumab and is administered at 240 mg / dose. 27. The method of any one of the preceding claims, wherein the anti-CD30 antibody-drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg, and the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 1 to 2 mg / kg, or 100 to 300 mg. [Item 28] Doxorubicin is 25 mg / m 2 and dacarbazine was administered at a dose of 375 mg / m 2 28. The method of claim 26 or 27, wherein the dose is 29. The method of any one of the preceding claims, further comprising administering a granulopoiesis stimulating factor. [Item 30] The method according to claim 29, wherein the granulocyte-poietin stimulating factor is administered prophylactically 1 to 7 days after administration of the anti-CD30 antibody-drug conjugate. [Item 31] The method according to any one of claims 29 and 30, wherein the granulocyte-poietin stimulating factor is administered 2 to 5 days after administration of the anti-CD30 antibody-drug conjugate. [Item 32] The method according to any one of items 29 to 31, wherein the granulocyte-poietin stimulating factor is administered about 24 hours to about 36 hours after administration of the anti-CD30 antibody-drug conjugate. [Item 33] The method according to any one of items 29 to 32, wherein the granulocyte-poietin stimulating factor is granulocyte-colony stimulating factor (GCSF). [Item 34] The method according to claim 33, wherein the GCSF is long-acting GCSF or non-long-acting GCSF. [Item 35] The method of claim 33 or 34, wherein the GCSF is a long-acting GCSF and is administered one or two days after administration of the anti-CD30 antibody-drug conjugate. [Item 36] The method according to item 35, wherein the G-CSF is administered about 24 hours to about 36 hours after administration of the anti-CD30 antibody-drug conjugate. 37. The method of claim 33 or 34, wherein the GCSF is not long-acting and is administered 1, 2, 3, 4, 5, 6, or 7 days after administration of the anti-CD30 antibody-drug conjugate. [Item 38] The method according to any one of claims 29 to 37, wherein the granulopoiesis stimulating factor is administered in a dosage range of 5 to 10 mcg / kg / day, or 300 to 600 mcg / day, or 6 mg / dose. [Item 39] The method of any one of claims 29 to 38, wherein the granulopoiesis stimulating factor is administered to a subject who has not previously received anti-CD30 antibody-drug conjugate therapy. [Item 40] The method according to any one of claims 29 to 39, wherein the subject does not experience treatment-emergent grade 3 to 4 neutropenia after administration of the anti-CD30 antibody-drug conjugate. [Item 41] The method according to any one of items 29 to 40, wherein the granulopoiesis stimulating factor is administered intravenously or subcutaneously. 42. The method of any one of claims 29 to 41, wherein the granulopoiesis stimulating factor is given in a single dose or multiple doses. 43. The method of any one of the preceding claims, wherein if the subject exhibits grade 3 or grade 4 neuropathy, administration of the anti-CD30 antibody drug conjugate therapy is withheld until peripheral neuropathy is reduced to grade 2 or less, and then 0.9 mg / kg of the anti-CD30 antibody drug conjugate therapy is administered. [Item 44] The method according to claim 43, wherein the neuropathy is a motor neuropathy or a sensory neuropathy. 45. The method of any one of the preceding claims, wherein if peripheral neuropathy appears, the dose of the anti-CD30 antibody-drug conjugate is delayed for one week, and if the neuropathy resolves or is determined to be Grade 1 or less, therapy is continued. 46. ​​The method of any one of the preceding claims, wherein the hematological cancer is selected from the group consisting of classical Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL). 47. The method of claim 46, wherein the hematological cancer is classical Hodgkin's lymphoma. 48. The method of claim 47, wherein the hematological cancer is bulky stage IIA, stage IIB, stage III, or stage IV classical Hodgkin lymphoma. [Item 49] The method according to claim 46, wherein the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL). [Item 50] The method according to claim 46, wherein the cutaneous T-cell lymphoma (CTCL) is mycosis fungoides (MF). [Item 51] The method according to claim 50, wherein the mycosis fungoides (MF) is CD30-positive mycosis fungoides (MF). 52. The method of claim 46, wherein the cutaneous T-cell lymphoma (CTCL) is primary cutaneous anaplastic large cell lymphoma (pcALCL). 53. The method of claim 52, wherein the subject has previously received systemic therapy. [Item 54] The method of any one of claims 45 to 53, wherein the blood cancer of the subject has not been treated with a checkpoint inhibitor. 55. The method of any one of the preceding claims, wherein the subject is an adult patient.

Claims

1. A composition for treating a hematological cancer in a subject, comprising an anti-CD30 antibody-drug conjugate for use in combination therapy with an anti-PD-1 antibody, doxorubicin, and dacarbazine.

2. The composition of claim 1, wherein the anti-PD-1 antibody is administered at least 30 minutes after each administration of the anti-CD30 antibody drug conjugate.

3. The anti-PD-1 antibody is administered to a subject who has not previously received an anti-CD30 antibody-drug conjugate therapy; and / or The anti-CD30 antibody drug conjugate is administered to a subject who has not previously received anti-CD30 antibody drug conjugate therapy. The composition according to claim 1 or 2.

4. i) the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered every two weeks; ii) the anti-PD-1 antibody is administered beginning with cycle 1 of administration of the anti-CD30 antibody drug conjugate; iii) the anti-CD30 antibody-drug conjugate and the anti-PD-1 antibody are administered on days 1 and 15 of a 28-day cycle; and / or iv) the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered for up to 6 cycles, or for 4 to 6 cycles; A composition according to any one of claims 1 to 3.

5. 5. The composition of any one of claims 1 to 4, further comprising administering chemotherapy consisting of doxorubicin and dacarbazine (AD) as a combination therapy.

6. the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate A. i) a heavy chain CDR1 as set forth in SEQ ID NO:4, a heavy chain CDR2 as set forth in SEQ ID NO:6, a heavy chain CDR3 as set forth in SEQ ID NO:8, and ii) comprises a light chain CDR1 as set forth in SEQ ID NO: 12, a light chain CDR2 as set forth in SEQ ID NO: 14, and a light chain CDR13 as set forth in SEQ ID NO: 16; and / or B. 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) comprises an amino acid sequence that is at least 85% identical to the light chain variable region set forth in SEQ ID NO: 10; 6. The composition according to any one of claims 1 to 5.

7. 7. The composition of claim 1, wherein the anti-CD30 antibody of the anti-CD30 antibody-drug conjugate is a monoclonal anti-CD30 antibody, Optionally, the anti-CD30 antibody of the anti-CD30 antibody drug conjugate may be a chimeric AC10 antibody.

8. The composition of any one of claims 1 to 7, wherein the antibody-drug conjugate comprises monomethylauristatin E and a protease-cleavable linker.

9. The protease cleavable linker i) comprises a thiol-reactive spacer and a dipeptide; or ii) consisting of a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-amino-benzyloxycarbonyl spacer; The composition of claim 8.

10. 10. The composition of any one of claims 1 to 9, wherein the anti-CD30 antibody-drug conjugate is brentuximab vedotin.

11. 11. The composition of any one of claims 1 to 10, wherein (i) the anti-PD-1 antibody cross-competes with nivolumab or pembrolizumab for binding to human PD-1, (ii) the anti-PD-1 antibody binds to the same epitope as nivolumab or pembrolizumab, (iii) the anti-PD-1 antibody is nivolumab, or (iv) the anti-PD-1 antibody is pembrolizumab.

12. i) the anti-CD30 antibody drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg and the anti-PD-1 antibody is nivolumab and is administered at 240 mg / dose; ii) the anti-CD30 antibody drug conjugate is brentuximab vedotin and is administered at 1.2 mg / kg and the anti-PD-1 antibody is pembrolizumab and is administered at a dose of 1-2 mg / kg, or 100-300 mg; and / or iii) doxorubicin at 25 mg / m ２ and dacarbazine was administered at a dose of 375 mg / m ２ The composition of any one of claims 1 to 11, wherein the composition is administered in a dose of

13. The composition of claim 1 , further comprising administering a granulopoiesis stimulating factor.

14. 14. The composition of claim 13, 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.

15. 15. The composition of any one of claims 1 to 14, wherein if the subject exhibits grade 3 or grade 4 neuropathy, administration of the anti-CD30 antibody drug conjugate therapy is withheld until peripheral neuropathy is reduced to grade 2 or less, and then 0.9 mg / kg of the anti-CD30 antibody drug conjugate therapy is administered.

16. i) 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); ii) the hematological cancer is classical Hodgkin lymphoma; or iii) the hematological cancer is stage IIA, stage IIB, stage III, or stage IV classical Hodgkin lymphoma with bulky mass; iv) the anaplastic large cell lymphoma (ALCL) is systemic anaplastic large cell lymphoma (sALCL); v) the cutaneous T-cell lymphoma (CTCL) is mycosis fungoides (MF), optionally wherein the mycosis fungoides (MF) is CD30-positive mycosis fungoides (MF); or vi) The cutaneous T-cell lymphoma (CTCL) is primary cutaneous anaplastic large cell lymphoma (pcALCL); 16. The composition of any one of claims 1 to 15.

17. 17. The composition of claim 16, wherein the hematological cancer of the subject has not been treated with a checkpoint inhibitor.

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