Cancer treatment with ROR1 antibody immunoconjugates and BTK inhibitors

Abstract

Methods for treating cancer patients using ROR1 immunoconjugates and BTK inhibitors are provided herein. These methods may be useful for treating a variety of cancers that express ROR1 and are expected to be mediated or regulated by BTK signaling.

Description

[Technical Field]

[0001] The present invention relates to the treatment of cancer (hereinafter referred to as cancer) with ROR1 antibody immunoconjugates and BTK inhibitors.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 428,744, filed November 30, 2022, which is incorporated by reference in its entirety.

[0003] Sequence Listing This application contains a Sequence Listing in XML format, which is incorporated herein by reference in its entirety. The XML copy is referred to as 25615-WO-PCT_SL.xml and has a size of 8,192 bytes. [Background technology]

[0004] Background of the Invention Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a cell surface protein that mediates signals from its ligand, the secreted glycoprotein Wnt5a. ROR1 expression is observed in invasive malignancies that revert to embryonic transcriptional programs, consistent with its role in influencing stem cell fate during embryonic development. ROR1 is commonly expressed on malignant cells in patients with hematologic cancers and is also present on the cell surface of multiple solid tumors, where it appears to be a marker of cancer stem cells. However, ROR1 expression is not commonly observed in normal adult tissues, thus demonstrating a favorable selectivity profile for ROR1 as a therapeutic target.

[0005] Branton tyrosine kinase (BTK) is a non-receptor tyrosine kinase expressed in all hematopoietic cells except T cells and plasma cells. BTK is a key regulator of the BCR signaling pathway. BTK controls all aspects of B-cell development, including proliferation, maturation, differentiation, apoptosis, and cell migration. Because BTK plays a critical role in the initiation, survival, and progression of B-cell lymphoproliferative malignancies, BTK inhibitors (BTKi) are being investigated as potential therapeutic agents for hematologic malignancies.

[0006] Mantle cell lymphoma (MCL) is an aggressive small B-cell lymphoma that arises linearly from naive B cells. MCL accounts for approximately 3% of non-Hodgkin's lymphoma (NHL) and typically exhibits an aggressive course and poor prognosis. The annual incidence rate is 0.5-1 case per 100,000 population, with the rate of new cases increasing in recent years. The chromosomal t(11;14)(q13;q32) translocation, found in more than 95% of all MCL cases, is the primary oncogenic event in MCL pathogenesis, leading to overexpression of cyclin D1.

[0007] Most patients begin treatment at the time of diagnosis of MCL; however, approximately 25% of patients present with an indolent form that does not require immediate treatment. MCL remains incurable, and the National Comprehensive Cancer Network (NCCN) guidelines recommend initial treatment based on patient suitability. For eligible patients younger than 65 years, the NCCN recommends aggressive treatment consisting of high-dose chemoimmunotherapy combined with rituximab, followed by consolidation with high-dose therapy and autologous stem cell transplant (ASCT). The addition of rituximab maintenance therapy improves overall survival after ASCT. Less aggressive treatments for frail elderly patients include bendamustine and rituximab (BR); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP); and lenalidomide and rituximab (R-CHOP). 2and rituximab, bendamustine, and cytarabine (R-BAC500). Despite high initial response rates, most patients eventually relapse.

[0008] The anti-ROR1 antibody-drug conjugate (ADC), girobertamab vedotin, and the BTKi, nemtabrutinib, have shown promising results as monotherapies in the treatment of hematological malignancies. Given the high mortality rate of MCL, there is a high unmet medical need for novel therapies. Summary of the Invention

[0009] Overview of the invention One aspect of the present invention is a compound of formula (I): [ka] and an immunoconjugate of formula (II) [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the immunoconjugate comprises an antibody (Ab) conjugated to a drug moiety shown in Formula (I), wherein the antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively.

[0010] In some embodiments, the number of drug moieties (DAR) per antibody is 1 to 7. In some embodiments, the number of DAR is 3 to 6. In certain embodiments, the number of DAR is 3 to 5.

[0011] In some embodiments, the immunoconjugate of Formula (I) is administered to a subject at a dose of 0.25 to 4.00 mg / kg. In certain embodiments, the immunoconjugate of Formula (I) is administered to a subject at a dose of 2.00, 2.25, or 2.50 mg / kg.

[0012] In some embodiments, the compound of Formula (II) is administered to a subject at a dose of 5-75 mg per day. In certain embodiments, the compound of Formula (II) is administered to a subject at a dose of 65 mg per day.

[0013] In some embodiments, the immunoconjugate of Formula (I) is administered in a three-week cycle, with the doses administered on day 1 of each cycle. In some embodiments, the immunoconjugate of Formula (I) is administered in a three-week cycle, with the doses administered on days 1 and 8 of each cycle. In some embodiments, the immunoconjugate of Formula (I) is administered in a four-week cycle, with the doses administered on days 1, 8, and 15 of each cycle. In some embodiments, the number of cycles is two or more. In some embodiments, the number of cycles is seven or more.

[0014] In some embodiments, the compound of Formula (II) is administered once, twice, three times, or four times daily. In some embodiments, the compound of Formula (II) is administered once daily.

[0015] In some embodiments, the compound of Formula (II) is administered daily for at least one day. In some embodiments, the compound of Formula (II) is administered daily for at least one week. In some embodiments, the compound of Formula (II) is administered daily for at least three weeks. In some embodiments, the compound of Formula (II) is administered daily for at least three months. In some embodiments, the compound of Formula (II) is administered daily for at least 12 months.

[0016] In some embodiments, the immunoconjugate of Formula (I) is administered intravenously. In some embodiments, the compound of Formula (II) is administered orally.

[0017] In some embodiments, the B cell malignancy is an aggressive B cell malignancy. In certain embodiments, the B cell malignancy is mantle cell lymphoma (MCL).

[0018] In some embodiments, the patient has previously been treated for the B cell malignancy, hi some embodiments, the B cell malignancy is relapsed or resistant to treatment (refractory).

[0019] In some embodiments, co-administration of an immunoconjugate of Formula (I) with a compound of Formula (II) results in one or more of the following: disease regression; delay in disease progression; prevention of disease recurrence or residual disease; reduction in the size of lymphatic or extra-lymphatic malignant masses; reduction in the number of malignant cells in bone marrow and / or peripheral blood; reduction in malignant splenomegaly or hepatomegaly; improvement in anemia, neutropenia, or thrombocytopenia; improvement in skin symptoms; improvement in systemic symptoms associated with physical disability; and prolonged survival. In certain embodiments, co-administration of an immunoconjugate of Formula (I) with a compound of Formula (II) results in complete disease eradication.

[0020] In some embodiments, the immunoconjugate of Formula (I) is zilovertamab vedotin. In some embodiments, the compound of Formula (II) is nemtabrutinib.

[0021] Another aspect of the present invention pertains to an immunoconjugate of Formula (I) and a compound of Formula (II) for use in treating a B-cell malignancy in a subject according to any of the methods described herein.

[0022] In some embodiments, the immunoconjugate of Formula (I) is giloveltamab vedotin. In some embodiments, the compound of Formula (II) is nemtabrutinib.

[0023] Another aspect of the present invention relates to the use of an immunoconjugate of Formula (I) and a compound of Formula (II) for the manufacture of a medicament for the treatment of a B-cell malignancy in a subject according to any of the methods described herein.

[0024] In some embodiments, the immunoconjugate of Formula (I) is giloveltamab vedotin. In some embodiments, the compound of Formula (II) is nemtabrutinib.

[0025] Another aspect of the present invention is a compound of formula (I) [ka] and an immunoconjugate of formula (II) [ka] or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the immunoconjugate comprises an antibody (Ab) conjugated to a drug moiety shown in Formula (I), wherein the number of drug moieties (DAR) per antibody is in the range of 3 to 5, and the antibody comprises a heavy chain and a light chain comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively, the immunoconjugate of Formula (I) is administered to the subject at a dose of 2.00, 2.25, or 2.50 mg / kg in 3-week cycles on days 1 and 8 of each cycle, and the compound of Formula (II) is administered to the subject at a dose of 65 mg per day, and the B-cell malignancy is mantle cell lymphoma (MCL).

[0026] In some embodiments, the immunoconjugate of Formula (I) is giloveltamab vedotin. In some embodiments, the compound of Formula (II) is nemtabrutinib.

[0027] Another aspect of the present invention is a compound of formula (I) [ka] and an immunoconjugate of formula (II) [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the immunoconjugate comprises an antibody (Ab) conjugated to a drug moiety shown in Formula (I), the number of drug moieties per antibody (DAR) is in the range of 3 to 5, and the antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively.

[0028] In some embodiments, the immunoconjugate of Formula (I) is giloveltamab vedotin. In some embodiments, the compound of Formula (II) is nemtabrutinib.

[0029] In some embodiments, the effective amount of giloveltamab vedotin is a dose of 2.00, 2.25, or 2.50 mg / kg. In some embodiments, the effective amount of nemtabrutinib is a dose of 65 mg.

[0030] Another aspect of the invention relates to a kit comprising a pharmaceutical composition described herein and instructions for use in treating a B-cell malignancy. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 is a schematic diagram of the treatment regimen described herein.

[0032] Detailed Description of the Invention The present invention provides therapeutic regimens using ROR1 immunoconjugates and BTK inhibitors. These coadministration regimens may be useful for treating various cancers that express ROR1 and are expected to be mediated or regulated by BTK signaling, such as B-cell malignancies. The combination of ROR1 immunoconjugates and BTK inhibitors has the potential to produce stronger and more durable responses in B-cell cancers, such as MCL. In a specific embodiment, the B-cell malignancy is mantle cell lymphoma (MCL).

[0033] 1. Immunoconjugates "Antibody-drug conjugate" or "ADC" or "immunoconjugate" refers to an antibody molecule or antigen-binding fragment thereof covalently or noncovalently attached to one or more biologically active molecules, with or without a linker. The term "antibody" is used in the broadest sense herein and includes polyclonal and monoclonal antibodies, e.g., intact antibodies and functional (antigen-binding) fragments thereof. The term also includes genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific (e.g., bispecific) antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs. Unless otherwise indicated, the term includes intact or full-length antibodies, including antibodies and antibody fragments of any class or subclass (e.g., IgG and its subclasses, e.g., IgG1, IgG2, IgG3, and IgG4; IgM; IgE; IgA; and IgD).

[0034] An antibody may comprise a heavy chain (or a polypeptide sequence derived therefrom) and a light chain (or a polypeptide sequence derived therefrom). The term "variable region" or "variable domain" refers to the domain of an antibody's heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have a similar structure, with each domain containing four conserved framework regions and three complementarity-determining regions. A single VH or VL domain may sometimes be sufficient to confer all or most of the antigen-binding specificity of an antibody. Furthermore, antibodies that bind to a specific antigen can be isolated by screening a library of complementary VL or VH domains, respectively, using a VH or VL domain from an antibody that binds to the antigen. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0035] The terms "complementarity determining region" and "CDR" are synonymous with "hypervariable region" or "HVR" and refer to subregions within an antibody variable domain that confer the specificity and / or affinity of the antibody for its antigen. Generally, there are three CDRs (HCDR1, HCDR2, and HCDR3) in each heavy chain variable domain, and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable domain. "Framework region" ("FR") refers to the non-CDR portions of the variable domain. Generally, there are four FRs in each full-length heavy chain variable domain, and four FRs in each full-length light chain variable domain. The exact amino acid sequence boundaries of a given CDR or FR can be readily determined using any of several well-known schemes, including those described in: Kabat et al., 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) ("Kabat" numbering scheme); Al-Lazikani et al., JMB 273, 927-948 (1997) ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996) ("contact" numbering scheme); Lefranc et al., Dev Comp Immunol. 27(1):55-77 (2003) ("IMGT" numbering scheme); and Honegger and Pluckthun, J. Mol. Biol., 309(3):657-70 (2001) ("Aho" numbering scheme).

[0036] The boundaries of a given CDR or FR may vary depending on the scheme used to identify it. For example, the Kabat scheme is based on sequence alignment, while the Chothia scheme is based on structural information. The numbering in both the Kabat and Chothia schemes is based on the sequence length of the most common antibody region, and insertions are addressed by an insertion letter (e.g., "30a"). The two schemes place certain insertions and deletions ("indels") in different positions, resulting in different numbering. The contact scheme is based on the analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. Unless otherwise specified, the CDRs of antibodies referred to herein may be identified according to any of the Kabat, Chothia, IMGT, and contact methods.

[0037] Antigen-binding fragments of full-length antibodies can be used in the production of immunoconjugates of the present invention. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; recombinant IgG (rIgG) fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); single-domain antibodies (e.g., sdAb, sdFv, nanobodies); and multispecific antibodies formed from antibody fragments. In certain embodiments, the fragment is a single-chain antibody fragment, e.g., scFv, comprising the variable heavy chain region and / or the variable light chain region.

[0038] The immunoconjugate comprises an antibody or fragment thereof specific for human ROR1 and can therefore serve as an excellent targeting moiety for delivering a conjugated payload to cells (e.g., ROR1-positive cells). In certain embodiments, the immunoconjugate used in the therapeutic regimen of the invention is an immunoconjugate described in WO 2018 / 237335.

[0039] Table 1 below provides the SEQ ID NOs for the heavy and light chain complementarity determining regions (HCDRs and LCDRs), heavy and light chain variable domains (VH and VL), and heavy and light chain (HC and LC) amino acid sequences of exemplary anti-ROR1 antibodies (i.e., Ab1) used in the immunoconjugates described herein.

[0040] [Table 1]

[0041] In some embodiments, the antibody or antibody fragment in the immunoconjugate specifically binds to human ROR1, and its heavy and light chains are, respectively: a) the amino acid sequences of HCDRs 1 to 3 in SEQ ID NO: 1 and the amino acid sequences of LCDRs 1 to 3 in SEQ ID NO: 2; b) HCDR1 to 3 containing the amino acid sequences of SEQ ID NOs: 5 to 7, respectively, and LCDR1 to 3 containing the amino acid sequences of SEQ ID NOs: 8 to 10, respectively; c) HCDRs 1-3 comprising residues 26-33, 51-58 and 97-105, respectively, of SEQ ID NO: 3, and LCDRs 1-3 comprising residues 27-32, 50-52 and 89-97, respectively, of SEQ ID NO: 4; d) HCDRs 1-3 comprising residues 26-32, 52-57, and 99-105, respectively, of SEQ ID NO: 3, and LCDRs 1-3 comprising residues 24-34, 50-56, and 89-97, respectively, of SEQ ID NO: 4; or e) HCDRs 1-3 comprising residues 31-35, 50-66, and 99-105, respectively, of SEQ ID NO: 3, and LCDRs 1-3 comprising residues 24-34, 50-56, and 89-97, respectively, of SEQ ID NO: 4. Includes.

[0042] In some embodiments, the amino acid sequences of the antibodies or fragments thereof of the immunoconjugates described herein may further comprise or include post-translational modifications (e.g., C-terminal lysine clipping or alpha amidation in the heavy chain, methionine oxidation and / or asparagine deamidation in the heavy chain, conversion of glutamine or glutamic acid to pyroglutamate at the N-terminus of a variable domain, glycosylation in an antibody Fc region, etc.) that may occur during recombinant expression in a host cell (e.g., a CHO cell) or during purification and / or storage of the antibody, fragment, or immunoconjugate. In some embodiments, the C-terminal lysine of SEQ ID NO: 1 is present. In other embodiments, the C-terminal lysine of SEQ ID NO: 1 is absent. In some embodiments, the N-terminal glutamine of SEQ ID NO: 3 is not converted to pyroglutamate. In other embodiments, the N-terminal glutamine of SEQ ID NO: 3 is converted to pyroglutamate.

[0043] In some embodiments of the immunoconjugates described herein, the antibody can be conjugated to a cytotoxic agent via a linker. In some embodiments, the linker is a cleavable linker. A cleavable linker refers to a linker that includes a cleavable moiety and is typically susceptible to cleavage under in vivo conditions. In certain embodiments, the linker can include a dipeptide, such as a valine-citrulline (Val-Cit or VC) linker. In certain embodiments, the linker is attached to a cysteine ​​residue on the antibody.

[0044] In some embodiments, the conjugation of the linker / payload to the antibody or fragment may be formed by reaction with a maleimide group (which may also be referred to as a maleimide spacer). In certain embodiments, the maleimide group is maleimidocaproyl (mc), and thus the linker / payload is conjugated to the antibody or fragment by reaction of a residue on the antibody or fragment with the mc group in the linker precursor.

[0045] In some embodiments, the linker may comprise a benzoic acid or benzyloxy group or a derivative thereof, hi some embodiments, the linker comprises a paraaminobenzyloxycarbonyl (PAB) group.

[0046] In some embodiments, the bond between the payload or drug component of the immunoconjugate and the antibody can be formed by reaction of the component with a linker comprising a maleimide group, a peptide moiety, and / or a benzoic acid (e.g., PAB) group, in any combination. In certain embodiments, the maleimide group is maleimidocaproyl (mc). In certain embodiments, the peptide group is Val-Cit (VC). In certain embodiments, the linker comprises a Val-Cit-PAB group. In certain embodiments, the conjugation of the linker to the antibody or fragment can be formed from a mc-Val-Cit group. In certain embodiments, the bond between the antibody or fragment and the drug moiety can be formed from a mc-Val-Cit-PAB group.

[0047] Linkers can be conjugated to the anti-ROR1 antibodies and antigen-binding fragments of the present disclosure in a number of ways. Generally, the linker and cytotoxic moiety are synthesized and conjugated prior to binding to the antibody. One method of attaching a linker-drug conjugate to an antibody is to reduce solvent-exposed disulfides with dithiothreitol (DTT) or tris(2-carboxyethyl)phosphine (TCEP), and then modify the resulting thiol with a maleimide-containing linker-drug moiety (e.g., 6-maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-VC-PAB)). Natural antibodies contain four interchain disulfide bonds and 12 intrachain disulfide bonds, as well as an unpaired cysteine. Thus, antibodies modified in this manner can contain multiple linker-drug moieties per antibody.

[0048] In certain embodiments, each of the immunoconjugates comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linker / drug moieties. In certain embodiments, each of the immunoconjugates comprises one or more (e.g., 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2) linker / drug moieties. When the linkers are branched, each capable of binding multiple drug moieties, the ratio of drug moieties to antibody is higher than when unbranched linkers are used.

[0049] In some embodiments, a suitable cytotoxic agent for use in the immunoconjugates described herein can be, for example, an antitubulin agent, such as an auristatin. In certain embodiments, the cytotoxic agent is monomethylauristatin E (MMAE).

[0050] In some embodiments, the immunoconjugates described herein are constructed as follows.

[0051] [Table 2]

[0052] The anti-ROR1 antibody can be an anti-ROR1 antibody described herein, for example, an antibody having a heavy chain amino acid sequence of SEQ ID NO:1 and a light chain amino acid sequence of SEQ ID NO:2.

[0053] In certain embodiments, the immunoconjugate used in the treatment regimen of the invention has the formula (I): [ka] It has the following structure.

[0054] In some embodiments, the antibody (Ab) is Ab1, which has a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO: 2. In some embodiments, the immunoconjugate can have a DAR of 3-6 and is referred to herein as "ADC-A." In some embodiments, the payload MMAE is conjugated to Ab1 via a cysteine ​​residue in the antibody polypeptide chain. In some embodiments, the immunoconjugate is selected from the disclosures of WO 2018 / 237335. In some embodiments, the immunoconjugate is giloveltamab vedotin.

[0055] 2.BTK inhibitors The term "BTK inhibitor" or "BTKi" refers to a compound capable of inhibiting BTK or a pharmaceutically acceptable salt thereof. In certain embodiments, a BTKi is a compound having the formula (II): [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is nemtabrutinib. In some embodiments, the compound of Formula (II) is useful for treating diseases and disorders associated with the modulation of BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is mutant BTK.

[0056] In some embodiments, compounds of Formula (II) inhibit the kinase activity of mutant BTK, such as a drug-resistant mutant BTK having a drug-resistant mutation (e.g., a C481S mutation). In certain embodiments, the BTK mutation is a C481S mutation.

[0057] The compound of formula (II) can form salts, which are also within the scope of this application. The present invention is directed, in part, to compounds of formula (II) and pharmaceutically acceptable salts thereof.

[0058] The compounds of the present application, as well as the pharmaceutically acceptable salts, tautomers, prodrugs and polymorphs of the compounds of formula (II) thereof, can exist in unsolvated or solvated form with other solvent molecules.

[0059] "Solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds or salts have a tendency to trap a certain molar ratio of solvent molecules in the crystalline solid state, forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with one molecule of the substance, where the water retains its molecular state as HO.

[0060] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including all stereoisomers of the salts, solvates, esters, and prodrugs of the compounds, and all stereoisomers of the salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons on various substituents (including enantiomeric forms) (which may exist even in the absence of asymmetric carbons), rotamers, atropisomers, and diastereomeric forms, are included within the scope of the present application, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl). For example, when a compound of Formula (II) contains a double bond or a fused ring, both the cis- and trans-forms and mixtures thereof are included within the scope of the present application. Individual stereoisomers of the compounds of the present application can, for example, be substantially free of other isomers, or can be, for example, racemic or mixed with all other or selected stereoisomers. The asymmetric centers of the present application can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Use of the terms "salt," "solvate," "ester," "prodrug," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the compound.

[0061] The term "isomers" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural differences can be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, compounds of formula (II) can have one or more asymmetric carbon atoms and can exist as racemates, racemic mixtures, or individual enantiomers or diastereomers.

[0062] In this specification, the structural formula of a compound may in some cases conveniently represent a particular isomer, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like.

[0063] "Isomerism" means that compounds have the same molecular formula but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0064] The compounds of formula (II) may contain asymmetric or chiral centers and therefore may exist as different stereoisomers. All stereoisomers of the compounds of the present application, as well as mixtures thereof (including racemic mixtures), are intended to form part of this application. This application also includes all geometric and positional isomers. For example, if a compound of the present application contains a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures thereof, are included within the scope of this application. Each compound disclosed herein includes all enantiomers that conform to the compound's general structure. Compounds may be racemic or enantiomerically pure, or any other form with respect to stereochemistry. Assay results may reflect data collected for a racemic, enantiomerically pure, or any other form with respect to stereochemistry.

[0065] A carbon atom bonded to four non-identical substituents is termed a "chiral center." "Chiral isomer" means a compound having at least one chiral center. Compounds with multiple chiral centers can exist as individual diastereomers or as a mixture of multiple diastereomers (termed a "diastereomeric mixture"). When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0066] "Geometric isomers" refers to diastereomers that exist due to hindered rotation about a double bond. These configurations are distinguished in names by the prefixes cis and trans or Z and E, which indicate that groups are on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0067] In another embodiment of the present application, the compound of formula (II) is an enantiomer. In some embodiments, the compound is an (S)-enantiomer. In other embodiments, the compound is an (R)-enantiomer. In still other embodiments, the compound of formula (II) can be a (+)- or (-)-enantiomer. The compound can contain multiple stereocenters.

[0068] In another embodiment of the present application, the compound of formula (II) is a diastereomer. In some embodiments, the compound is a syn-diastereomer. In other embodiments, the compound is an anti-diastereomer.

[0069] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0070] The compounds of the present application may exist in different tautomeric forms, and all such forms are included within the scope of the application. Also included are, for example, all keto-enol and imine-enamine forms of the compounds.

[0071] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This conversion results in the formal migration of a hydrogen atom accompanied by the inversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism.

[0072] Of the various types of tautomers possible, two are commonly observed: keto-enol tautomerism, in which the simultaneous migration of an electron and a hydrogen atom occurs; ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, forming it into the ring (cyclic) form exhibited by glucose.

[0073] Common tautomeric pairs include ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomers in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), amine-enamine, and enamine-imine. The following tautomeric pair, (pyrrolopyrimidinyl)methanone-(pyrrolopyrimidinyl)methanol, is also included in this application.

[0074] [ka]

[0075] The compounds can be converted to N-oxides by treatment with an oxidizing agent [e.g., 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxide] to yield other compounds. Thus, all shown and claimed nitrogen-containing compounds, where permitted by valence and structure, include the shown compounds and their N-oxide derivatives (which can be N→O or N+-O). - and N-alkoxy (which may be represented as N-hydroxy or N-alkoxy). Additionally, in other cases, the nitrogen in the compound may be converted to an N-hydroxy or N-alkoxy compound. For example, an N-hydroxy compound may be prepared by oxidation of the parent amine with an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are considered to include both the shown compound and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR; where R is a substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3- to 14-membered carbocyclic, or 3- to 14-membered heterocyclic) derivatives, where permitted by valence and structure.

[0076] The term "prodrug", as used in this application, means a compound that is convertible in vivo by metabolic means (eg, hydrolysis) to a compound of formula (II).

[0077] Because prodrugs are known to improve many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compound of formula (II) or a pharmaceutically acceptable salt thereof may be delivered in prodrug form. Accordingly, the present application is intended to include prodrugs of the compound of formula (II) or a pharmaceutically acceptable salt thereof, methods for their delivery, and compositions containing them. "Prodrug" is intended to include any covalently bonded carrier that releases an active parent drug of the present application in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound, where the modification is cleaved, either in routine manipulation or in vivo, to produce the parent compound. Prodrugs include compounds of the present application in which a hydroxyl or amino group is bonded to either group, such that, when the prodrug of the present application is administered to a mammalian subject, the bond is cleaved to produce the free hydroxyl or free amino group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0078] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all having the same elemental composition. Crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rate, storage temperature, and other factors can cause one crystalline form to predominate. Crystalline polymorphs of the compound of formula (II) can be produced by crystallization under different conditions.

[0079] Also included in this application are isotopically labeled immunoconjugates and compounds identical to those set forth in each of the formulas set forth herein, where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into an immunoconjugate of formula (I) or a compound of formula (II) include isotopes of hydrogen, carbon, nitrogen, and fluorine, such as H, C, C, H, and F.

[0080] Immunoconjugates of Formula (I) and compounds of Formula (II) or their pharmaceutically acceptable salts containing the aforementioned isotopes and / or other isotopes of other atoms are also within the scope of the present application. Isotopically labeled immunoconjugates and compounds of the present application, for example, those incorporating radioactive isotopes such as H and C, are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes (i.e., H) and carbon-14 labeled isotopes (i.e., C) are useful for ease of preparation and detectability. C and F isotopes are useful in positron emission tomography (PET). PET is useful in brain imaging. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., H), can offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some situations. Isotopically labeled immunoconjugates of Formula (I) and compounds of Formula (II) or pharmaceutically acceptable salts thereof may generally be prepared by following the procedures described herein and substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0081] The compounds of the present application can be prepared by several methods well known to those skilled in the art of organic synthesis, for example by the methods described in US Pat. No. 9,630,968.

[0082] 3. Treatment Regimen The present invention provides therapeutic regimens comprising co-administering effective amounts of a ROR1 immunoconjugate and a BTK inhibitor to a patient in need thereof. In certain embodiments, the ROR1 immunoconjugate is an immunoconjugate of Formula (I) and the BTK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof. These co-administration regimens may be useful for treating various ROR1-expressing cancers that are expected to be mediated or modulated by BTK signaling. In certain embodiments, the cancer is a B-cell malignancy. In certain embodiments, the B-cell malignancy is mantle cell lymphoma (MCL).

[0083] As used herein, the terms "administer," "administered," "administering," or "administration" refer to providing an effective amount of a ROR1 immunoconjugate and / or a BTK inhibitor directly to a patient or subject in need thereof. As used herein, the terms "co-administer," "co-administered," "co-administering," or "co-administration" refer to providing an effective amount of a ROR1 immunoconjugate and a BTK inhibitor to a patient or subject in need thereof. A co-administered ROR1 immunoconjugate and a BTK inhibitor can be administered on the same day or on different days of the same administration cycle. In some embodiments, a co-administered ROR1 immunoconjugate and a BTK inhibitor are administered on the same day of an administration cycle. In some embodiments, a co-administered ROR1 immunoconjugate and a BTK inhibitor are administered on different days of an administration cycle.

[0084] A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0085] An "effective amount" or "therapeutically effective amount" as used in reference to an immunoconjugate, compound, or pharmaceutical composition is an amount effective to treat or prevent a disease in a subject, as described herein.

[0086] The term "treatment" with respect to a subject means ameliorating at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially alleviating the disorder.

[0087] As used herein, "prevention" or "preventing" refers to the inhibition or elimination of the onset of symptoms or complications of a disease, condition or disorder.

[0088] The term "disorder" is used in this application to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0089] As used herein, the terms "BTK-mediated" or "BTK-regulated" disease or disorder refer to any disease or other deleterious condition in which BTK or a mutant thereof is known to be involved. Accordingly, another embodiment of the present application relates to treating or reducing the severity of one or more diseases in which BTK or a mutant thereof is known to be involved. In particular, the present application relates to a method for treating or reducing the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder, the method comprising co-administering to a patient in need thereof an immunoconjugate of Formula (I) and a compound of Formula (II) or a pharmaceutically acceptable salt thereof, or a composition described herein.

[0090] As used herein, the term "cell proliferative disorder" refers to a condition in which uncontrolled or abnormal proliferation (growth) of cells, or both, can lead to the development of an undesirable condition or disease, which may be cancerous or non-cancerous. Exemplary cell proliferative disorders in this application include various conditions in which cell division is deregulated. Exemplary cell proliferative disorders include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell that divides at a rate that exceeds or is greater than that expected or observed in adjacent or juxtaposed cells within the same tissue. Cell proliferative disorders include precancerous conditions or precancerous conditions. Cell proliferative disorders include cancer. Preferably, the methods provided herein are used to treat cancer or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematological tumors and / or malignancies. A "precancerous cell" or "precancerous cell" is a cell that exhibits a cell proliferative disorder that is a precancer or precancerous state. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferative disorder that is cancer. Any reproducible means of measurement can be used to identify cancerous or precancerous cells. Cancerous or precancerous cells can be identified by histological classification or grading of a tissue sample (e.g., a biopsy sample). Cancerous or precancerous cells can be identified by the use of appropriate molecular markers.

[0091] As used herein, "relapsed" and "refractory" ("resistant") are defined as follows: relapsed disease is disease progression after at least one line of treatment or prior treatment, and refractory disease is failure to achieve a complete response (CR) or partial response (PR) with at least one prior line of treatment. In some embodiments, relapsed disease, e.g., recurrent hematological malignancy, is disease progression after the most recent treatment. In some embodiments, refractory disease, e.g., relapsed hematological malignancy, is failure to achieve a CR or PR with the most recent treatment.

[0092] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; chronic graft-versus-host disease (cGVHD), lymphoproliferative conditions; acromegaly; rheumatoid spinal disease; osteoarthritis; gout, other arthritic conditions; sepsis, septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis. fibrosis; acute and chronic kidney disease; irritable bowel syndrome; fever; restenosis; cerebral malaria; stroke and ischemic injury; neurotrauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndromes; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration; bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcomatosis; bone resorption diseases, such as osteoporosis; graft-versus-host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases, such as shingles, herpes simplex type I or II, influenza virus, and cytomegalovirus; and diabetes.

[0093] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal Neuroectodermal tumors, visual pathway and hypothalamic gliomas, breast cancer, bronchial adenoma / carcinoid, carcinoid tumors, gastrointestinal tract, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid tumors, mycosis fungoides, Sedgary syndrome, endometrial cancer, esophageal cancer, extracranial embryonic cell gallbladder cancer, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (abdominal) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, B-cell non-Hodgkin's lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous cell neck cancer, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, bacteria Symptoms include: myelodysplastic syndromes, myelodysplastic / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell neoplasm / multiple myeloma,Pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma family, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary tract, gestational trophoblastic neoplasia, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus Cancer, vaginal cancer, vulvar cancer, chronic lymphocytic leukemia (CLL), Richter's transformation, small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), primary central nervous system (CNS) lymphoma, secondary central nervous system (CNS) lymphoma, marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), acute myeloid leukemia (AML), multiple myeloma (MM), childhood sarcoma, childhood brain tumor, and Wilms' tumor.

[0094] In some embodiments, the cancer is a B cell malignancy. In certain embodiments, the B cell malignancy is mantle cell lymphoma (MCL).

[0095] In some embodiments, the ROR1 immunoconjugate of Formula (I) is administered at a dose of 0.25 to 10 mg / kg, e.g., 0.25 to 4 mg / kg. For example, the immunoconjugate of Formula (I) can be administered at a dose of 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 8, 9, or 10 mg / kg, or any combination thereof for multiple doses. In specific embodiments, the immunoconjugate of Formula (I) is administered at a dose of 2.00, 2.25, or 2.50 mg / kg.

[0096] In some embodiments, the immunoconjugate of Formula (I) is administered in repeated cycles of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In certain embodiments, the immunoconjugate of Formula (I) is administered in a 3-week cycle. In certain embodiments, the immunoconjugate of Formula (I) is administered in a 4-week cycle. A treatment regimen may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more administration cycles (e.g., 3 or more cycles or 4 or more cycles). In certain embodiments, the immunoconjugate of Formula (I) is administered on day 1, 2, 3, 4, 5, 6, or 7 of a cycle. The administration days may be consecutive, or there may be an interval of 1, 2, 3, 4, 5, or 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks, or any combination thereof, between the administration days. In certain embodiments, the immunoconjugate of Formula (I) is administered only on day 1 of each cycle (e.g., a 3-week cycle). In certain embodiments, the immunoconjugate of Formula (I) is administered on days 1 and 8 of each cycle (e.g., a 3-week cycle). In certain embodiments, the immunoconjugate of Formula (I) is administered on days 1, 8, and 15 of each cycle (e.g., a 4-week cycle).

[0097] The immunoconjugate of Formula (I) may be initially administered according to a dosing regimen described herein and then administered according to a different dosing regimen described herein (e.g., to increase or decrease the frequency of administration). In some embodiments, the immunoconjugate of Formula (I) is administered weekly for the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, and then every three weeks thereafter. In certain embodiments, the immunoconjugate of Formula (I) is administered weekly for the first 2, 3, 4, 5, or 6 weeks, and then every three weeks. In certain embodiments, the immunoconjugate of Formula (I) is administered weekly for the first 1, 2, 3, 4, 5, or 6 weeks, and then every four weeks.

[0098] In some embodiments, the dosing regimens described herein provide a patient with at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 μg / mL of immunoconjugate plasma C max In some embodiments, the dosing regimens described herein achieve an area under the immunoconjugate plasma concentration-time curve (AUC) of at least 500, 750, 1000, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, or 3500 h·μg / mL in a patient.

[0099] In some embodiments, the dosing regimens described herein maintain at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, or 95% ROR1 receptor immunoconjugate occupancy in a patient. In some embodiments, the dosing regimens described herein maintain at least 50% ROR1 receptor immunoconjugate occupancy for at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the time period. In some embodiments, the dosing regimens described herein maintain at least 75% ROR1 receptor immunoconjugate occupancy for at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the time period. In some embodiments, the dosing regimens described herein maintain at least 90% ROR1 receptor immunoconjugate occupancy for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% of the time period.

[0100] The immunoconjugate of Formula (I) can be administered parenterally. As used herein, "parenteral administration" of an immunoconjugate includes any route of administration characterized by creating a physical entry point into the tissue of interest and administering the immunoconjugate through the entry point in the tissue, resulting in direct administration into the bloodstream, intramuscularly, or into an internal organ. Thus, parenteral administration includes, but is not limited to, administration of the immunoconjugate by injection of the immunoconjugate, application of the immunoconjugate through a surgical incision, application of the immunoconjugate through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intraspinal, intraventricular, intraurethral, ​​intracranial, intratumoral, and intrasynovial injection or infusion; as well as kidney dialysis infusion techniques. Regional perfusion is also contemplated. In some embodiments, the infusion may be administered by one route (eg, intravenously) for the first dose, and then by another route for subsequent doses.

[0101] In certain embodiments, the immunoconjugate of Formula (I) is administered by intravenous (IV) infusion. The IV infusion can be administered over a period of about 0.1 to about 4 hours (e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180 hours). In certain embodiments, the infusion time is 30 minutes. The infusion time can be extended as needed to accommodate an individual patient's therapeutic tolerance. When the immunoconjugate is administered in multiple doses, in some embodiments, the infusion time for the first dose is longer than the infusion time for subsequent doses, or alternatively, the infusion time for the first dose is shorter than the infusion time for subsequent doses.

[0102] In some embodiments, the immunoconjugate of Formula (I) is administered for a period of time until the patient no longer exhibits symptoms of the disease or disorder. In some embodiments, the immunoconjugate of Formula (I) is administered for a period of time until the patient is cured of the disease or disorder. In some embodiments, the immunoconjugate of Formula (I) is administered for a period of time until the patient exhibits tolerance to the immunoconjugate. In some embodiments, the immunoconjugate of Formula (I) is administered for a period of time until the patient exhibits side effects that require discontinuation of treatment with the immunoconjugate.

[0103] In some embodiments, the immunoconjugate of Formula (I) is co-administered to a patient or subject with another therapeutic agent. In some embodiments, the immunoconjugate of Formula (I) is co-administered with a BTK inhibitor. In certain embodiments, the BTK inhibitor is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to about 75 mg per day.

[0105] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 5 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 10 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 15 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 20 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 25 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 30 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 35 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 40 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 45 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 50 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 55 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 60 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 65 mg per day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 70 mg per day. In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of at least 75 mg per day.

[0106] For any of the doses disclosed herein, in some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered once, twice, three times, or four times per day. For example, the compound is administered once per day. For example, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered twice per day. For example, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered three times per day. For example, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered four times per day. For example, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered once per day in an amount of about 5 mg to about 75 mg per day. For example, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered twice per day in an amount of about 5 mg to about 75 mg per day. For example, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered three times per day in an amount of about 5 mg to about 75 mg per day. For example, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of about 5 mg to about 75 mg per day, four times a day. In certain embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered in an amount of about 65 mg per day, once a day.

[0107] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered daily (i.e., every other day) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered at least 1 day per week, at least 2 days per week, at least 3 days per week, at least 4 days per week, at least 5 days per week, or at least 6 days per week.

[0108] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days per week. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered every other day. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered every other day.

[0109] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered for a period of at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks.

[0110] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered for a period of at least 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, 3 years, 4 years, or 5 years.

[0111] The total dose for one treatment interval is generally at least 0.05 μg / kg body weight, more generally at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / kg, 0.25 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 5.0 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg or more.

[0112] The compound of Formula (II) or a pharmaceutically acceptable salt thereof can be administered at a dose such as daily, 1 to 7 times per week, weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every other month, quarterly, semi-annually, or annually. The dose can be administered, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or by inhalation. In certain embodiments, the dose is administered intravenously. In certain embodiments, the dose is administered subcutaneously. In certain embodiments, the dose is administered orally.

[0113] In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered for a period of time until the patient no longer exhibits symptoms of the disease or disorder. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered for a period of time until the patient is cured of the disease or disorder. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered for a period of time until the patient exhibits tolerance to the compound. In some embodiments, the compound of Formula (II) or a pharmaceutically acceptable salt thereof is administered for a period of time until the patient exhibits side effects that require discontinuation of treatment with the compound.

[0114] In some embodiments, the subject has fasted for at least 1, 2, 3, 4, 6, 8, 12 hours before the compound is administered, hi some embodiments, the subject is required to fast for at least 1, 2, 3, 4, 6, 8, 12 hours after the compound is administered.

[0115] It is understood that the therapeutic regimens of the present invention can be the methods of treatment described herein, the immunoconjugates of Formula (I) and compounds of Formula (II) or pharmaceutically acceptable salts thereof described herein for use in the therapeutic regimens described herein, or the use of the immunoconjugates of Formula (I) and compounds of Formula (II) or pharmaceutically acceptable salts thereof described herein for the manufacture of a medicament for use in the therapeutic regimens described herein.

[0116] This application also includes pharmaceutical compositions comprising an effective amount of the immunoconjugate of Formula (I) and the compound of Formula (II) or a pharmaceutically acceptable salt thereof disclosed herein, and a pharmaceutically acceptable carrier. As used herein, the term "carrier" includes carriers, excipients, and diluents and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical substance from one organ or body part of a subject to another.

[0117] 4. Patient Selection The therapeutic regimen of the present invention can be used to treat cancer patients. In some embodiments, the therapeutic regimen of the present invention includes selecting a cancer patient as described herein. In certain embodiments, the patient may have previously been treated for the cancer and / or have cancer that is recurrent or resistant to one or more (or all) existing treatments for the cancer.

[0118] In some embodiments, the therapeutic regimen is administered to a human patient, e.g., an adult patient (18 years of age or older), a juvenile patient (12-17 years of age), or a pediatric patient (under 18 years of age). In some embodiments, the therapeutic regimen is administered to an adult patient (18 years of age or older) with adequate performance status and organ function who (i) has a histologically confirmed, advanced hematologic cancer and / or (ii) has a malignancy that is unlikely to respond to established therapies known to provide clinical benefit or has developed intolerance to established therapies known to provide clinical benefit. In certain embodiments, the patient meets both criteria.

[0119] "Treate," "treating," and "treatment" refer to a method of alleviating or eliminating at least one of a biological disorder and / or its attendant symptoms. As used herein, "alleviating" ("alleviating") a disease, disorder, or condition means reducing the severity and / or frequency of occurrence of the symptoms of the disease, disorder, or condition. Furthermore, references to "treatment" herein include references to curative, palliative, and prophylactic treatment. Treating cancer includes inhibiting cancer proliferation (growth) (including partial or complete regression of cancer), inhibiting cancer progression or metastasis, preventing cancer recurrence or residual disease, and / or prolonging patient survival.

[0120] In some embodiments, patients treated with the therapeutic regimen of the present invention have ROR1-expressing cancers. ROR1-expressing cancers can be determined by any suitable method for determining gene or protein expression, such as histology, flow cytometry, radiopharmaceutical methods, RT-PCR, or RNA-Seq. Cancer cells used for the determination can be obtained by tumor biopsy or by sampling circulating tumor cells. In certain embodiments, when using an antibody-based assay, such as flow cytometry or immunohistochemistry, a ROR1-expressing cancer is any cancer with cells that exhibit higher anti-ROR1 antibody reactivity than an isotype control antibody. In certain embodiments, when using an RNA-based assay, a ROR1-expressing cancer is a cancer that exhibits elevated ROR1 RNA levels compared to negative control cells or non-ROR1-expressing cancers.

[0121] In certain embodiments, the patient has a hematological malignancy, e.g., a lymphoid malignancy. In certain embodiments, the patient has a solid tumor. The patient may have a cancer selected from, for example, lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), marginal cell B-cell lymphoma, Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma undergoing Richter's transformation, T-cell leukemia, T-cell lymphoma (e.g., T-cell non-Hodgkin's lymphoma), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia (WM), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hairy cell leukemia (HCL), myeloma, multiple myeloma (MM), sarcoma ( For example, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, soft tissue sarcoma, or uterine sarcoma), brain cancer, glioblastoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, neuroblastoma, head and neck cancer, nasopharyngeal carcinoma, thyroid cancer, breast cancer (for example, ER / PR-positive breast cancer, HER2-positive breast cancer, or triple-negative breast cancer), lung cancer (for example, non-small cell lung cancer or small cell lung cancer), malignant mesothelioma, bile duct / gallbladder cancer ( For example, cholangiocarcinoma), colon cancer, colorectal cancer, esophageal cancer, abdominal cancer, gastric cancer, gastrointestinal stromal tumor (GIST), liver (hepatocellular) cancer, pancreatic cancer, renal cell carcinoma, bladder cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer, testicular cancer, epithelial squamous cell carcinoma, melanoma, adrenocortical carcinoma, gastrointestinal carcinoid tumor, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, cutaneous neuroendocrine carcinoma (Merkel cell carcinoma), and pheochromocytoma. In certain embodiments, the patient has a cancer that is resistant to other treatments (e.g., triple-negative breast cancer).

[0122] In certain embodiments, the patient has MCL. In certain embodiments, the patient has PET-positive disease, defined as a score of 4-5 on the Lugano 5-point scale and verified locally by the investigator at screening. In certain embodiments, the patient has radiologically measurable disease based on the Lugano Response Criteria, assessed locally by the investigator, which includes at least one (non-irradiated) lymph node lesion with a long axis greater than 1.5 cm, regardless of short axis length, or an extranodal lesion with a long and short axis of 1.0 cm or greater.

[0123] In certain embodiments, the patient may have previously been treated for the cancer and / or has a cancer that is relapsed or resistant (refractory) to one or more (e.g., all) existing treatments for the cancer. In some embodiments, the patient is resistant to or has relapsed after treatment with ibrutinib, acalabrutinib, autologous hematopoietic stem cell transplant, bendamustine, bortezomib, brentuximab vedotin, carmustine, chimeric antigen receptor T (CAR-T) cells, cisplatin, copanlisib, cyclophosphamide, cytarabine, daratumumab, dexamethasone, doxorubicin, etoposide, gemcitabine, idelalisib, lenalidomide, melphalan, methotrexate, methylprednisolone, mosunetuzumab, obinutuzumab, ofatumumab, oxaliplatin, pinatuzumab, polatuzumab, rituximab, prednisone, radiation therapy, venetoclax, vincristine, or any combination thereof (e.g., any combination of prior therapeutic agents described in the Examples). In certain embodiments, the patient has not previously received treatment with a non-covalent BTK inhibitor.

[0124] 5.Treatment results In some embodiments, the therapeutic regimens of the invention result in one or more of the following: disease regression; delay in disease progression; prevention of disease recurrence or residual disease; reduction in the size of lymphatic or extra-lymphatic malignant masses; reduction in the number of malignant cells in the bone marrow and / or peripheral blood; reduction in malignant splenomegaly or hepatomegaly; improvement in anemia, neutropenia, or thrombocytopenia; improvement in skin symptoms; improvement in systemic symptoms associated with physical dysfunction (e.g., fever, headache, unexplained fatigue, malaise, lethargy, weight loss or gain, weakness, arthralgia (joint pain), myalgia (muscle pain), shivering, chills, nausea, vomiting, loss of appetite, abdominal pain, altered bowel function, back pain, difficulty sleeping, and difficulty breathing); and prolonged survival.

[0125] In certain embodiments, the therapeutic regimens of the present invention result in complete disease eradication.

[0126] In some embodiments, the treatment regimens of the present invention result in an improvement in the primary efficacy endpoint. In some embodiments, the primary efficacy endpoint is the achievement of an objective response (OR), meaning a best overall response of partial response (PR) or complete response (CR) as defined according to the Lugano response criteria as assessed by the investigator. This assessment includes calculation of lymph node, extranodal, spleen, and liver size by computed tomography (CT) and / or magnetic resonance imaging (MRI), whole-body metabolic imaging by fluorodeoxyglucose positron emission tomography (FDG-PET), and clinical findings such as physical examination and biopsy results, when available and appropriate.

[0127] Patients are considered to have achieved a CR if: the target lymph node / lymph node mass has regressed to 1.5 cm or less in the longest diameter (LDi) with no residual extranodal disease (i.e., a PET-based response score of 1, 2, or 3); there is no evidence of new or non-target disease; previously enlarged organs have regressed to normal size; and the bone marrow appears normal on PET and CT / MRI.

[0128] Patients are considered to have achieved PR if they have: a 50% or greater reduction from baseline in the sum of the products of target lymph nodes and extranodal sites (SPD) (i.e., a reduced overall uptake score compared to the baseline measurement, no new lesions, and a PET-based response score of 4 or 5); no evidence of disease progression; spleen that has regressed in excess length by 50% or greater; no evidence of new lesions; and residual uptake in the bone marrow that is higher than normal but lower than baseline, as determined by PET.

[0129] In some embodiments, the therapeutic regimens of the invention do not cause abnormalities in one or more (e.g., any one, two, three, four, five, or six) of the following: urine, serum, blood, systolic blood pressure, diastolic blood pressure, pulse, body temperature, blood oxygen saturation, and electrocardiogram (ECG) measurements. In certain embodiments, the therapeutic regimens of the invention do not cause abnormalities in any of the foregoing.

[0130] In some embodiments, the treatment regimens of the present invention do not result in detectable levels of circulating immunoconjugate-reactive antibodies in the patient's serum.

[0131] In certain embodiments, the therapeutic regimens of the invention do not result in dose-limiting toxicities (DLTs). In some embodiments, the therapeutic regimens of the invention do not result in adverse events (AEs) or serious adverse events (SAEs).

[0132] AE means any untoward medical occurrence in a clinical trial participant that is temporally related to the administration of the study intervention (regardless of whether it is considered related to the study intervention). Thus, AE means any untoward or unexpected sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally related to the administration of the study intervention.

[0133] An SAE is defined as any untoward medical occurrence, at any dose, that results in death or is life-threatening, or requires hospitalization or prolonged hospitalization in an already hospitalized patient, or results in persistent or significant disability / incapacity, or results in congenital anomalies / birth defects in the offspring of participants taking the product.

[0134] It is understood that the therapeutic regimens described herein can be the methods of treatment described herein, the immunoconjugates and / or compounds described herein for use in the therapeutic regimens described herein, or the use of the immunoconjugates and / or compounds described herein for the manufacture of a medicament for the therapeutic regimens described herein.

[0135] 6. Manufactured Products and Kits The present invention also provides articles of manufacture, e.g., kits, comprising one or more containers (e.g., single-use or multi-use containers) containing a pharmaceutical composition of an immunoconjugate of Formula (I) described herein in the dosages described herein, a pharmaceutical composition of a compound of Formula (II) described herein in the dosages described herein, optionally including additional biologically active molecules (e.g., other therapeutic substances), and instructions for use in accordance with the treatment regimens described herein. The immunoconjugate, compound, and additional biologically active molecule may be packaged together or separately in suitable packing, e.g., non-reactive glass or plastic vials or ampoules.

[0136] In some embodiments, the vial or ampoule contains a liquid containing the immunoconjugate or a lyophilized powder containing the immunoconjugate, which may optionally contain an additional therapeutic agent or biologically active molecule. In certain embodiments, the vial or ampoule contains a concentrated stock (e.g., 2x, 5x, 10x, or more) of the immunoconjugate, and optionally, a biologically active molecule. In certain embodiments, the pharmaceutical composition of the immunoconjugate (i.e., gilovertamab vedotin) described herein is packaged in a disposable glass vial containing 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of the immunoconjugate (e.g., an amount suitable for use at a dose described herein, e.g., 2.00, 2.25, or 2.50 mg / kg).

[0137] In certain embodiments, the compound described herein (i.e., nemtabrutinib) is packaged as a 65 mg dose solid form (e.g., tablet). In certain embodiments, the solid form may optionally include an additional therapeutic agent or biologically active molecule.

[0138] In certain embodiments, the articles of manufacture, such as kits, include medical devices (e.g., syringes and needles) and / or suitable diluents (e.g., sterile water and saline) for administering the immunoconjugates and / or bioactive molecules. The invention also includes methods of making the articles of manufacture.

[0139] Unless the context clearly indicates otherwise, throughout this specification and claims, the word "comprises" and variations thereof (e.g., "comprises" and "including") are intended to be interpreted in an open and inclusive sense, i.e., "including, but not limited to." As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the word "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise. As used herein, the word "about" refers to a numerical range of ±10%, ±5%, or ±1% from the stated numerical value, in the context of the particular use. Furthermore, the headings provided herein are merely for convenience and do not interpret the scope or meaning of the claimed embodiments.

[0140] The details of this application are described in further detail in the Examples and Claims below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, exemplary methods and materials are described herein. Other features, objects, and advantages of this application will be apparent from the specification and claims. In this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0141] Example The following examples illustrate representative embodiments of the present invention and are not intended to be limiting in any way.

[0142] Example 1: Dose finding using a modified toxicity probability interval (mTPI) design Dose setting follows the mTPI design with a target dose-limiting toxicity rate of 27%. The mTPI design is described in Ji Y, Li Y, Bekele BN. Dose-finding in phase 1 clinical trials based on toxicity probability intervals. Clin Trials 2007;4:235-44. See also Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase 1 trials. J Clin Oncol 2013;31:1-12. Dose escalation and deescalation decisions based on the mTPI design depend on the number of subjects enrolled and the number of DLTs observed at the current dose level. The mTPI design applies only to the initial DLT evaluation period.

[0143] At least three participants are required at each dose. In Table 2 below, the columns indicate the number of participants receiving treatment at the current dose level, and the rows indicate the number of participants who experienced DLT. The entries in the table are the dose-finding decisions, with E, S, and DU representing dose escalation, maintaining the same dose, and dose deescalation and removal of that dose from the study due to unacceptable toxicity, respectively. If the posterior probability of a DLT rate greater than 27% exceeds 80%, the dose is deemed to result in unacceptable toxicity. For example, if zero of three participants at a given dose level experience DLT, the dose may be escalated to the next level. If two or three of three participants experience DLT, this indicates unacceptable toxicity at that dose. The dose should be tapered, and the current dose will not be further investigated. If one of three participants at a given dose level experiences DLT, additional participants should be enrolled at that dose level according to the rules described below.

[0144] When adding participants to a dose level in response to a "maintenance" decision, a cap is placed on the number of additional participants enrolled to minimize exposure to doses that may result in unacceptable toxicity (labeled DU in Table 2). Second, to determine how many more participants may be enrolled at that dose level, count diagonally (downward and to the right) from the current cell to the first cell labeled DU. For example, if one of three participants experiences a DLT at a given dose level, one additional participant should be enrolled at that dose level until additional DLT data are available. This is because if an additional participant experiences a DLT (i.e., two of four participants experience a DLT in Table 2), that dose level is considered to result in unacceptable toxicity. The same principle applies if three, four, five, or six participants are initially enrolled at that dose level.

[0145] A determination of DU at the lowest dose level will terminate the study. A determination of E at the highest tolerated dose level will lead to maintenance at that dose. During dose-finding, tapering to an alternative dose of either compound that has not been previously tested or predetermined may be acceptable if evaluation of toxicity at such a dose is desirable. If this approach is taken, 3 to 6 new participants may be enrolled at the new alternative dose, and the above rules should be used to determine further enrollment at this dose level.

[0146] After 15 participants have been enrolled at any of the study doses, titration will cease if the mTPI table indicates "S," meaning maintenance of the current dose. Otherwise, up to 15 new participants may be enrolled at a lower dose if "DU" is indicated, or at a higher dose if "E" is indicated. To further refine the selected dose, once the mTPI indicates "S," additional participants will be enrolled at the next lower dose level until a total of 15 participants have been enrolled at that dose level.

[0147] [Table 3]

[0148] Example 2: Dose-Escalation Study to Evaluate the Safety, Tolerability, and Efficacy of Co-Administering Giloveltamab Vedotin with Nemtabrutinib Below, we describe a protocol to evaluate the safety, tolerability, and efficacy of gilovertamab vedotin and nemtabrutinib when coadministered in patients with previously treated relapsed or refractory MCL. The primary objective of this study is to evaluate the objective response rate (ORR) based on Lugano response criteria. We will also evaluate adverse events (AEs), AEs leading to treatment discontinuation, and dose-limiting toxicities (DLTs).

[0149] 2.1 Patient Screening and Selection 2.1.1 Inclusion criteria To participate in this study, patients must meet the following inclusion criteria: Adult patients, male or female, aged 18 years or older. Histologically confirmed and biopsy-proven MCL according to the 2016 WHO classification of tumors of the hematopoietic and lymphoid tissues. Disease progression during or recurrence after previous systemic therapy; · No previous exposure to non-covalent BTKi; PET-positive disease (defined as 4–5 on the Lugano 5-point scale and verified locally by the investigator at screening); and Radiologically measurable disease according to the Lugano response criteria, assessed locally by the investigator, with at least one (non-irradiated) lymph node lesion measuring >1.5 cm in its long axis regardless of its short axis, or an extranodal lesion measuring ≥1.0 cm in its long and short axes.

[0150] 2.1.2 Exclusion criteria Patients must be excluded from this study if they meet any of the following criteria:

[0151] medical conditions ·Having received a solid organ transplant at any time; · have clinically significant (i.e., active) cardiovascular disease, including cerebrovascular accident / stroke (less than 6 months before enrollment), myocardial infarction (less than 6 months before enrollment), unstable angina (less than 6 months before enrollment), congestive heart failure (New York Heart Association classification class II or higher), or serious arrhythmia requiring medication, or the patient has significant ECG abnormalities, including second-degree atrioventricular (AV) block type II, third-degree AV block, bradycardia (ventricular rate less than 50 beats / min), or prolonged QTc interval greater than 450 ms (according to the Fridericia formula); · Previous allogeneic stem cell transplant (allo-SCT), acute graft-versus-host disease (GVHD), or ongoing evidence of chronic GVHD manifesting as grade 2 or higher serum bilirubin, grade 3 or higher skin lesions, or grade 3 or higher diarrhea, or requiring systemic immunosuppression for treatment / prophylaxis of GVHD; ·Pericardial effusion or clinically significant pleural effusion; ·Continued peripheral neuropathy greater than grade 1; -Having demyelinating Charcot-Marie-Tooth disease; · Have a history of secondary malignancy, unless potentially curative treatment has been completed and there has been no evidence of malignancy for 2 years; this time requirement does not apply to participants who have had a successful curative resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancer; Have follicular lymphoma (FL) that is transforming into a more aggressive form of lymphoma; if transformation is suspected, it must be ruled out before screening; or · Have a clinically significant gastrointestinal abnormality that may alter absorption.

[0152] Previous treatments / concomitant therapies ·having received prior treatment with ROR1-targeted therapy; ·Having received previous treatment with a non-covalent BTKi; ·Having a contraindication to any of the study intervention components; · Received previous systemic anti-cancer treatment, including the investigational agent, within 5 half-lives or 4 weeks (if the previous treatment was a monoclonal antibody) or 2 weeks (if a small molecule such as a kinase inhibitor) before the first dose of the study intervention; Participants must have recovered from all AEs from previous treatment to Grade 1 or less or to baseline; If participants have undergone major surgery, participants must have adequately recovered from the surgery and / or any complications from the surgery before starting the study; Previous radiation therapy within 28 days prior to the start of the study intervention; participants must have recovered from all radiation-related toxicities; a 1-week washout is allowed for palliative radiation therapy for non-central nervous system disease (within 2 weeks of radiation therapy); Receiving continuous corticosteroid therapy >30 mg prednisone equivalent per day; if so, must have been stable at ≤30 mg prednisone equivalent per day for at least 4 weeks prior to Cycle 1 Day 1 (C1D1), unless corticosteroid therapy is required for lymphoma symptom control prior to C1D1, in which case a maximum of 100 mg prednisone equivalent per day can be administered for up to 5 days, and tumor evaluation must be completed prior to initiation of corticosteroid therapy; · Received a live or live-attenuated vaccine within 30 days prior to the first dose of the study intervention; administration of an inactivated vaccine is acceptable; Have received a strong CYP3A4 inhibitor or inducer (including itraconazole, ketoconazole, posaconazole, or voriconazole) within 7 days prior to C1D1 or are expected to require chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention and for 30 days after the final dose of the study intervention; For subjects requiring antifungal prophylaxis / treatment, oral fluconazole or isavuconazonium may be considered; Echinocandins (e.g., caspofungin, anidulafungin, or micafungin) are also acceptable, recognizing the drawback of requiring intravenous administration; or Currently receiving treatment with a CYP2C8 substrate with a narrow therapeutic index (e.g., paclitaxel) or a P-gp substrate with a narrow therapeutic index (e.g., digoxin); a washout period of at least 5 half-lives after the last dose of either CYP2C8 or P-gp substrate is required for participants to be eligible for study enrollment.

[0153] Previous / concurrent clinical research experience Currently participating or have participated in a clinical trial of an investigational substance or have used an investigational device within 4 weeks prior to the first dose of the study intervention; participants entering the follow-up phase of the trial are eligible to participate if 4 weeks have passed since their last dose of any previous investigational substance.

[0154] Diagnostic evaluation Have known active central nervous system (CNS) lymphoma involvement or active CNS involvement by lymphoma; participants with previous CNS involvement are eligible if their CNS disease is in radiological, cytological (in the case of cerebrospinal fluid disease), and clinical remission; · have an active infection requiring systemic treatment; ·Having a history of human immunodeficiency virus (HIV) infection; · Have active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; · have history or current evidence of any condition, therapy or test abnormality or other situation that may confound the results of the study or prevent the participant from participating for the entire duration of the study, such that, in the investigator's judgment, it is not in the participant's best interest to participate; or · Have a known mental or substance abuse disorder that may prevent the participant from cooperating with the requirements of the study.

[0155] 2.2 Dose Levels and Administration Schedules After screening, participants will receive gilovertamab vedotin co-administered with nemtabrutinib at one of three dose levels:

[0156] [Table 4]

[0157] Girobertamab vedotin will be administered intravenously in repeated 3-week cycles over a scheduled infusion period of approximately 30 minutes on days 1 and 8 of each cycle (Q2 / 3W). The infusion period may be extended as needed to accommodate individual subject treatment tolerance. Nemtabrutinib will be co-administered daily (QD) throughout the study period.

[0158] The starting dose level is DL0. If the number of DLTs observed at DL0 indicates "E" based on the mTPI table, the dose will be escalated to DL1. If DL0 is not tolerated ("DU" based on the mTPI table), the dose will be reduced to DL-1. A minimum of three participants is required for each dose, and up to 15 participants can be treated depending on the dose determination. A total of 15 participants will be enrolled at one dose level above the dose determined to continue based on the mTPI table. Enrollment will then be paused, and the recommended phase 2 dose (RP2D) of the combination will be determined using the entire data, including preliminary activity, safety, tolerability, and pharmacokinetics (PK). Once determined, an additional 15 participants will be enrolled to receive the RP2D dose. A schematic diagram of the described protocol is shown in Figure 1.

[0159] 2.3 Effectiveness evaluation The primary efficacy endpoint of this study was the achievement of an objective response, defined as a best overall response of partial or complete response according to the Lugano response criteria as assessed by the investigator. The Lugano response criteria, published by Cheson, BD et al. in 2014, are revised response criteria for NHL and are recommended by the current NCCN guidelines for B-cell lymphomas. See also National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas; Version 4. 2021. Plymouth Meeting (PA): National Comprehensive Cancer Network (NCCN); 2021. p. 306. This evaluation included anatomical imaging by CT or MRI (evaluation of lymph nodes, extranodal disease, spleen, and liver size), metabolic imaging (whole-body evaluation with FDG-PET), and clinical findings (physical examination and biopsy results), when available and appropriate.

[0160] Anatomical imaging can include CT, MRI, or a combination of both, and details can be found in the institution's imaging manual. CT is the most common method used, and for the purposes of this specification, the term "CT" will be used to refer to all anatomical imaging, regardless of which imaging method is used.

[0161] Before treatment ("baseline"), all localized disease (nodal and extranodal) is classified on CT scan as "target" (selected for quantitative assessment) and "non-target" (selected for qualitative assessment). The spleen is assessed quantitatively (by measuring its perpendicular length), and the liver is assessed qualitatively. FDG-PET scans are assessed using a 5-point scale (5PS), a method similar to the older Deauville criteria. See also Barrington SF, Mikhaeel NG, Kostakoglu L, Meignan M, Hutchings M, Mueller SP, et al., Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas imaging working group. J Clin Oncol. 2014 Sep 20;32(27):3048-58. Erratum in: J Clin Oncol. 2016 Jul 20;34(21):2562. If a biopsy was performed or there are any physical examination findings that cannot be assessed by imaging, these should be recorded.

[0162] After treatment initiation, response assessment includes anatomical response (which includes target lesions, non-target lesions, and new focal lesions) based on CT (if available), as well as spleen and liver size assessment. Metabolic response assessment is based on the 5PS, along with qualitative assessment of change in FDG uptake from previous time points, if FDG-PET is available. Anatomical response, metabolic response, and clinical information are combined to obtain an overall response at each time point. Response assessment criteria are summarized in Table 4 below.

[0163] [Table 5] TIFF2025540056000016.tif200168

[0164] 2.3.1 Anatomic Disease Assessment Anatomical assessment specifically relates to the size of local lesions or organs assessed using computed tomography or magnetic resonance imaging. As noted above, for simplicity, the term "CT" is used to refer to all anatomical imaging.

[0165] 2.3.2 Screening (Baseline) Assessment Recording of local lesions All local lesions attributable to lymphoma will be identified at baseline and classified as measurable or non-measurable. Up to six of the measurable lesions will be selected to serve as "target" lesions, which will then be quantitatively tracked throughout the trial. All other local lesions will be recorded as "non-target" lesions and then qualitatively assessed.

[0166] Measurable and nonmeasurable lesions A malignant lymph node (lymph node lesion) is considered measurable if, when assessed by CT / MRI scan, it is consistent with lymphoma, clearly and reproducibly measurable in two dimensions on an axial slice, and has an LDi greater than 1.5 cm, regardless of scanner type and slice thickness / spacing. An extranodal lesion is considered measurable if, when assessed by CT / MRI scan, it is consistent with lymphoma, clearly and reproducibly measurable in two dimensions on an axial slice, and has both an LDi and short-axis diameter (SDi) greater than or equal to 1.0 cm, regardless of slice thickness. In FDG-rich lymphomas, lesions must be PET-positive (showing higher FDG uptake than surrounding tissue) to be measurable.

[0167] Lesions considered non-measurable include: Lymph nodes and lymph node masses that are PET positive and considered consistent with lymphoma, but do not meet the size and reproducibility requirements to be considered measurable, and the lesions are visible on PET but not on CT; PET-negative lymphomas that meet size criteria for measurability and are considered consistent with lymphoma in lymphomas that show FDG uptake in other lesions; · Unidimensionally measurable lesions (clearly measurable in one dimension only); Extranodal lesions that do not meet the requirements for measurability but are clearly considered to be attributable to lymphoma; · Truly non-measurable / non-assessable disease sites, e.g. - effusion and ascites; - bone lesions; -brain lesions, central nervous system (CNS) lesions, leptomeningeal disease; - mucosal lesions in the gastrointestinal tract; and - Thickening of the pleura, peritoneum or intestinal wall.

[0168] Target and non-target lesions Up to six target lesions are selected from the measurable lesions and recorded as target lymph node lesions and target extra-lymph node lesions. Target lesions should be selected based on their size (the largest lesion is preferred) and suitability for reproducible measurements. Measurements of the longest and shortest axis diameters should be performed in the axial plane on the slice of the tumor with the longest in-plane diameter. The product of perpendicular diameters (PPD) for each target lesion and the sum of the diameter products for all target lesions are calculated.

[0169] Non-target lesions refer to all local (lymph node and extranodal) lesions consistent with lymphoma that were not selected as target lesions, regardless of whether they were measurable. Once lesions are designated as target or non-target, their designation cannot be changed on subsequent evaluation.

[0170] Baseline spleen assessment Splenic involvement is assessed quantitatively, as a separate category from the evaluation of measurable or nonmeasurable focal disease. Splenic length is measured craniocaudal. All splenic measurements mentioned below refer to this craniocaudal measurement. A spleen is considered normal if it is less than 13 cm or if it has been surgically removed. It is considered enlarged if it has a length greater than 13 cm. Any portion measuring greater than 13 cm is considered abnormal.

[0171] Baseline liver assessment Liver involvement is assessed qualitatively, separate from assessment of measurable or nonmeasurable disease. At baseline, the liver is assessed qualitatively as either normal or enlarged, and should be recorded as enlarged only if there is clear evidence (based on biopsy or imaging) that the enlargement is due to lymphomatous infiltration rather than benign etiology.

[0172] 2.3.3 Post-baseline assessments Target lesion At each time point after screening, each target lesion will be measured. PPD for each target lesion and SPD for all target lesions will be calculated. Response categories will be defined as follows:

[0173] Complete response (CR): All target lymph nodes must have regressed to normal size, defined as ≤1.5 cm in LDi; no extra-target lymph node sites must be present (0 × 0 cm); Partial response (PR): A 50% or greater reduction in the SPD of target lesions from baseline, with no individual lesions meeting the criteria for progression; Progressive Disease (PD): Target lesion progression is based on progression of any single lesion (not changes in SPD) that meets all of the following requirements: -The lesion must have increased by 50% or more from its nadir in PPD; -For lymph nodes, it must be greater than 1.5 cm in LDi, and for extranodal disease, it must be greater than 1.0 cm in LDi; -and one of the following: For lesions ≤2 cm at their nadir, the LDi or SDi of the lesion must currently have increased by ≥0.5 cm from its nadir; For lesions greater than 2 cm at their nadir, the LDi or SDi of the lesion must currently have increased by 1 cm or more from its nadir; Stable Disease (SD): Target lesion assessment for SD requires all of the following: - target lesions do not meet criteria for CR or PR; -None of the individual lesions meets the criteria for progression; Not Evaluable (NE): If a target lesion identified at baseline cannot be assessed at a post-baseline time point because of missing images, poor image quality, changes in the lesion or background that prevent assessment, or local therapy or other procedures that change lesion size, the target lesion assessment will be NE unless another target lesion is assessed for progression.

[0174] If two lesions fuse, the entire resulting lesion is measured as a single target lesion. This almost always leads to progression because lesions fuse as they grow. If a target lesion splits into multiple fragments, each fragment is tracked as a separate target lesion.

[0175] Non-target lesions Non-target lesions will be assessed individually and as groups at each post-baseline time point. Response categories will be defined as follows: Absent / Normalized (CR): All individual non-target lymph node lesions must return to normal size; all extranodal lesions must disappear; Overt Progression (PD): To be assessed as PD, any individual non-target lesion must be clearly progressing in terms of overall disease burden. Regarding increases in hollow viscera wall thickness, assessors will use discretion to determine whether the increase is likely caused by disease progression.

[0176] PD should not be judged on the basis of increasing pleural or ascites effusion or expansion of osteolytic lesions; rather, the overall assessment should be based on the residual disease burden. Stable disease (SD): At least one non-target lesion is still present or lymph nodes are enlarged, but no individual lesion shows obvious progression. Not Evaluable (NE): If an individual non-target lesion, lymph node, extranodal disease, or non-measurable disease identified at baseline cannot be evaluated at a post-baseline time point because of missing images, poor image quality, changes in the lesion or background that prevent evaluation, or local therapy for the lesion, the individual non-target lesion is evaluated as NE; if any non-target lesion is NE and none is PD, the overall non-target lesion evaluation is NE.

[0177] New lesions A lesion is considered new if it was not present at baseline but is now visible. A lymph node consistent with lymphoma is recorded as a new lesion if it was previously normal-sized but is now larger than 1.5 cm in LDi. Any size overt new extranodal lesion consistent with lymphoma is considered a new lesion. If multiple new extranodal lesions are present, at least one should be recorded as a new lesion.

[0178] New lesions must be consistent with lymphoma rather than another etiology (e.g., infection, inflammation) and must be PET-positive if PET is available. If PET is not available to confirm uptake, new lesions are treated as PET-positive.

[0179] Some types of truly nonmeasurable lesions require further verification that they are due to lymphoma, generally by biopsy or cytology. These include ascites, pleural or pericardial effusions, and lytic bone lesions. They can only be recorded as new lesions if other evidence of progression is present.

[0180] Other truly non-measurable lesions do not require verification to be considered new lesions, as long as their appearance is obvious in the assessor's judgment: Non-measurable lesions such as lesions of the brain and central nervous system, including leptomeningeal disease caused by lymphoma; and · Non-measurable lymph node masses such as infiltrative mesenteric masses or retroperitoneal masses.

[0181] Extranodal lesions that reappear at a later time point after they have disappeared have the same effect as new lesions but are not designated as "new."

[0182] Splenic response The spleen is measured at baseline as craniocaudal length and the enlarged area is calculated by subtracting 13 cm. Response categories for the spleen are defined as follows:

[0183] Normal (CR): The spleen was enlarged at baseline and has now regressed to 13 cm or less, or the spleen was assessed as normal at baseline and remains normal, or there is radiological evidence of splenectomy at baseline, or the spleen was normal at baseline and has since undergone splenectomy; · Partial resolution (PR): the spleen was assessed as enlarged at baseline and its excess length was reduced by 50% or more; · Stable splenomegaly (SD): no decrease consistent with PR and no increase consistent with progression; Definite Growth (PD): A spleen is assessed as PD if any of the following is true: -Recurrent splenomegaly: The spleen was abnormal at baseline (greater than 13 cm) and initially returned to normal, but now the spleen has increased by more than 2 cm from its nadir and is greater than 13 cm in length; New splenomegaly: spleen has increased by more than 2 cm from baseline and is greater than 13 cm in length in the absence of previous splenomegaly; or - Progression of pre-existing splenomegaly: A spleen that was abnormal at baseline now shows a greater than 50% increase in fractional enlargement from its nadir and an increase of 1 cm or more in absolute measurement.

[0184] Hepatic response The liver is assessed qualitatively. Response categories are defined as follows: · Normal (CR): liver assessed as enlarged at baseline and has regressed to normal size, or is still enlarged but there is no evidence of lymphoma involvement, or liver assessed as normal at baseline and remains normal; · Stable disease (SD): The liver is considered stable if there is persistent liver involvement with imaging (CT or MRI) or biopsy-based evidence of lymphomatous infiltration of the entire liver; Overt enlargement (PD): New liver enlargement, recurrent liver enlargement, or a clear increase in liver size from previous years, with evidence that this is due to lymphoma infiltration.

[0185] Anatomical Response Anatomical response should be assessed at each post-baseline time point based on the criteria shown in Table 5 below. Liver size should never be the sole basis for response assessment; it is merely used as supplementary information to support the assessment.

[0186] [Table 6]

[0187] 2.3.4 Metabolic response In addition to anatomic imaging, metabolic imaging using FDG-PET can also contribute to the assessment if available, or may be the only evidence of response if anatomic imaging is not performed at some time points. FDG-PET is required at screening. Subsequent time points at which PET is required are indicated in the Schedule of Activities (SoA). If lesions are not FDG-avid at baseline, PET is not required at follow-up unless clinically indicated.

[0188] PET evaluation For each FDG-PET scan, a 5PS score is obtained by comparing the maximum standardized uptake value (SUVmax) of the lesion showing the greatest tracer uptake (the "hottest" lesion) with surrounding normal tissue, with regions of interest (ROIs) placed over the major mediastinal vessels (the "mediastinal blood pool") or the blood in the heart, and with ROIs placed over the normal liver. Depending on the uptake, a score of 1 to 5 is assigned as follows:

[0189] [Table 7]

[0190] After screening, evaluation of the FDG-PET included, in addition to the 5PS score, an assessment of the overall uptake (combination of extent and intensity) by tissue consistent with lymphoma and a comparison of this uptake with baseline and with the scan that had the lowest overall uptake (nadir).

[0191] Determining metabolic response The metabolic response categories are defined as follows:

[0192] [Table 8]

[0193] In Waldeyer's ring or extranodal sites with high physiologic uptake or activation in the spleen or bone marrow (e.g., due to chemotherapy or bone marrow colony-stimulating factors), uptake may be higher than in normal mediastinum and / or liver. In this situation, CMR can be presumed if uptake in the site of initial involvement is not as high as in surrounding normal tissue, even though the tissue shows high physiologic uptake.

[0194] 2.3.5 Clinical Data Bone marrow evaluation To allow for a CR overall response, the bone marrow must be lymphoma-free (negative for lymphoma). Lugano allows for FDG-PET-based bone marrow evaluation if the lymphoma type is FDG-accumulating. The bone marrow on FDG-PET may be normal, may show diffuse uptake (which is consistent with responsive changes to chemotherapy or colony-stimulating factors, requiring clinical judgment), or may show focal increased uptake, which is highly suggestive of lymphoma.

[0195] A negative PET result allows the bone marrow to be determined to be negative without biopsy and supports an overall CR (diffuse uptake consistent with reactive changes due to chemotherapy or growth factor use may fall into this category). PR may occur when there is residual uptake higher than normal bone marrow but reduced compared to baseline. If persistent focal changes in the bone marrow are observed in the setting of a nodal response, further evaluation with MRI or biopsy or interval scans should be considered.

[0196] Bone marrow aspiration or biopsy is necessary only if clinically indicated or if FDG-PET evaluation of the bone marrow is inconclusive. In lymphomas that are shown to be FDG-negative at baseline, aspiration or biopsy is required to determine a negative bone marrow. If a bone marrow biopsy is performed and shows lymphoma, the bone marrow is considered positive regardless of the PET results.

[0197] Physical examination findings Rarely, lesions may be present on physical examination but not on imaging at all. An example is lymphadenopathy in the popliteal fossa, in which case "whole-body" imaging includes only the anatomy up to the mid-femur. Such lesions should be recorded as non-target lesions in the study report. They may contribute to progression if new lesions appear in this way, and if any were present at baseline, they must disappear for an overall response of CR.

[0198] Other clinical data Information regarding the use of hematopoietic growth factors and other agents may influence the response assessment. At specific time points defined in the protocol, additional tissue biopsies may be taken and incorporated into the response assessment.

[0199] 2.3.6 Overall Response The overall response at each time point is determined by a combination of anatomical, metabolic, and clinical data. When both CT and FDG-PET are available, the overall response is primarily driven by the metabolic response. When only one imaging modality is available at a given time point, that modality is the primary determinant of the overall response.

[0200] [Table 9]

[0201] In determining overall response (general response), if FDG-PET has not been performed at that time, the previous PET result may be "carried forward" as long as CT scans do not show disease progression. For example, if a post-baseline evaluation shows CMR on PET and PR on CT, the overall response is CR. If the next time point shows ongoing PR on CT but PET is not available, the overall response at that visit is still CR.

[0202] If a partial response based on anatomical or metabolic imaging is observed, but a biopsy shows that the tissue is not malignant, the response may be upgraded to a complete response (complete response).

[0203] 2.4 Safety Assessment The primary safety endpoints are DLTs, AEs, and discontinuation of study treatment due to AEs. Safety and tolerability will be assessed by clinical evaluation of all relevant parameters, including AEs, laboratory tests, and vital signs. Safety parameters analyzed include, but are not limited to, AEs, SAEs, fatal AEs, and laboratory changes. The test samples to be obtained and the parameters to be analyzed are listed in Table 9.

[0204] [Table 10] TIFF2025540056000022.tif54167

[0205] 2.4.1 Definition of AE Adverse events are monitored throughout the study period and classified by severity according to the guidelines outlined in the NCI CTCAE version 5.0. An AE is any undesired medical occurrence in a clinical study participant that is temporally related to the use of the study intervention, regardless of whether it is considered related to the study intervention. Thus, an AE can be any unfavorable and unexpected sign (including abnormal laboratory findings), symptom, or disease (new or worsening) that is temporally related to the use of the study intervention.

[0206] For purposes of the AE definition, a study intervention includes any drug, biological product, vaccine, diagnostic, medical device, combination product, or protocol-specified procedure, whether investigational or commercially available (including placebo, active comparator product, or lead-in intervention), manufactured, licensed, provided, or distributed by the sponsor for human use in the study.

[0207] Events that meet the definition of AE Any abnormal clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiology scan, vital sign measurements), including those that worsen from baseline, that are deemed clinically significant in the investigator's medical and scientific judgment; · Chronic or intermittent worsening of existing symptoms, including an increase in the frequency and / or intensity of the condition; ·New medical conditions that may have been present before the start of the study but are detected or diagnosed after administration of the study intervention; ·Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction; ·Signs, symptoms, or clinical sequelae suggestive of overdose of the study intervention or concomitant medication; For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term should reflect clinical symptoms or abnormal laboratory results; overdoses without associated clinical symptoms or abnormal laboratory results should be reported using the phrase "accidental or intentional overdose without adverse effects."

[0208] Events that do not meet the definition of AE Medical or surgical procedures (e.g., endoscopy, appendectomy): the condition leading to the procedure is an AE; · Situations in which no adverse medical events occurred (social and / or convenience admission); No worsening, expected day-to-day fluctuations in pre-existing diseases or conditions present or detected at the start of the study; and · Surgical procedures that were scheduled before informed consent to treat a pre-existing condition that has not worsened.

[0209] 2.4.2 Definition of SAE If an event is not an AE according to the above definition, it cannot be a serious adverse event, even if the seriousness criteria are met. An SAE is defined as any untoward medical occurrence at any dose that: ·Causing death; · Life-threatening; - The term "life-threatening" in the definition of "serious" refers to events in which the participant was at risk of death at the time of the event; it does not refer to events that, if more severe, might have caused death; · Requires hospitalization or an extension of hospitalization if already hospitalized; -Hospitalization is defined as hospitalization regardless of the length of stay, even if the hospitalization was a precaution for continued observation; - Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not an SAE; a pre-existing condition is a clinical condition that has been diagnosed prior to use of an MSD product and is documented in the participant's medical history; ·Resulting in persistent or significant impairment / incapacity; - The term disability means a significant impairment in a person's ability to perform normal life functions; this definition is not intended to include experiences of lesser medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle), which may impair or interfere with daily living functions but do not constitute a significant impairment; ·Causing birth defects / congenital anomalies; - In offspring of participants who took the product, regardless of time to diagnosis; · other significant medical events; - Medical or scientific judgment should be used in determining whether reporting an SAE is appropriate in other circumstances (e.g., a significant medical event that is not immediately life-threatening or does not result in death or hospitalization, but which may endanger the participant or require medical or surgical intervention to prevent one of the other outcomes described in the definition); these events should generally be considered serious. Examples of such events include invasive or malignant cancer, intensive care in the emergency room or at home for allergic bronchospasm, hematologic disorders or seizures not resulting in hospitalization, or the development of drug dependence or abuse.

[0210] 2.4.3 Potency / Toxicity Assessment An event is defined as "serious" if it meets at least one of the predetermined outcomes described in the SAE definition, but not if it is rated as serious. Investigators will perform intensity ratings for each AE and SAE (and other reportable safety events) according to the NCI CTCAE version 5. For any AE that changes CTCAE grade over the course of a given episode, each change in grade will be recorded on the AE CRF / Worksheet. Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; intervention not indicated; Grade 2: Moderate; minimal local or non-invasive intervention is indicated; age-appropriate instrumental ADLs are limited; Grade 3: Severe or medically significant, but not immediately life-threatening; hospitalization or prolonged hospitalization is indicated; disabling; limiting self-care ADLs; Grade 4: Life-threatening consequences; urgent intervention is indicated; or Grade 5: Death related to an AE.

[0211] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now be apparent to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

Claims

1. Formula (I) 【Chemistry 1】 and an immunoconjugate of formula (II) 【Chemistry 2】 or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the immunoconjugate comprises an antibody (Ab) conjugated to a drug moiety shown in Formula (I), the antibody comprising heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively.

2. 2. The method of claim 1, wherein the number of drug moieties (DAR) per antibody is 1-7.

3. 2. The method of claim 1, wherein the number of DARs is 3 to 6.

4. 2. The method of claim 1, wherein the number of DARs is 3 to 5.

5. The method of any one of claims 1 to 4, wherein the immunoconjugate of formula (I) is administered to the subject at a dose of 0.25 to 4.00 mg / kg.

6. The method of any one of claims 1 to 5, wherein the immunoconjugate of formula (I) is administered to the subject at a dose of 2.00, 2.25, or 2.50 mg / kg.

7. The method of any one of claims 1 to 6, wherein the compound of formula (II) is administered to the subject at a dose of 5 to 75 mg per day.

8. The method of any one of claims 1 to 7, wherein the compound of formula (II) is administered to the subject at a dose of 65 mg per day.

9. 9. The method of any one of claims 1 to 8, wherein the immunoconjugate of formula (I) is administered in three-week cycles, with said dosage administered on day 1 of each cycle.

10. 9. The method of any one of claims 1 to 8, wherein the immunoconjugate of formula (I) is administered in three-week cycles, with said dosages being administered on days 1 and 8 of each cycle.

11. 9. The method of any one of claims 1 to 8, wherein the immunoconjugate of Formula (I) is administered in four-week cycles, with said dosages being administered on days 1, 8, and 15 of each cycle.

12. The method according to any one of claims 9 to 11, wherein the number of cycles is 2 or more.

13. The method according to any one of claims 9 to 11, wherein the number of cycles is 7 or more.

14. 10. The method of any one of the preceding claims, wherein the compound of formula (II) is administered once, twice, three times or four times daily.

15. 15. The method of claim 14, wherein the compound of formula (II) is administered once daily.

16. The method of any one of claims 1 to 15, wherein the compound of formula (II) is administered daily for at least one day.

17. The method of any one of claims 1 to 15, wherein the compound of formula (II) is administered daily for at least one week.

18. The method of any one of claims 1 to 15, wherein the compound of formula (II) is administered daily for at least 3 weeks.

19. 16. The method of any one of claims 1 to 15, wherein the compound of formula (II) is administered daily for at least three months.

20. 16. The method of any one of claims 1 to 15, wherein the compound of formula (II) is administered daily for at least 12 months.

21. 10. The method of any one of the preceding claims, wherein the immunoconjugate of formula (I) is administered intravenously.

22. 10. The method of any one of the preceding claims, wherein the immunoconjugate of formula (I) is administered orally.

23. 2. The method of any one of the preceding claims, wherein the B cell malignancy is an aggressive B cell malignancy.

24. 10. The method of any of the preceding claims, wherein the B-cell malignancy is mantle cell lymphoma (MCL).

25. 10. The method of any of the preceding claims, wherein the patient has previously been treated for a B-cell malignancy.

26. 2. The method of any one of the preceding claims, wherein the B-cell malignancy is relapsed or resistant to treatment (refractory).

27. Co-administration of an immunoconjugate of formula (I) with a compound of formula (II) a) disease regression, b) delay in disease progression; c) prevention of disease recurrence or residual disease; d) a decrease in the size of lymphatic or extranodal malignant masses; e) a reduction in the number of malignant cells in the bone marrow and / or peripheral blood; f) reduction of malignant splenomegaly or hepatomegaly; g) improvement of anemia, neutropenia, or thrombocytopenia; h) improvement of skin symptoms, i) improvement of general symptoms accompanied by physical dysfunction, and j) Prolonged survival The method of any preceding claim, wherein the method results in one or more of:

28. 10. The method of any one of the preceding claims, wherein co-administration of the immunoconjugate of formula (I) with the compound of formula (II) results in complete disease eradication.

29. 10. The method of any one of the preceding claims, wherein the immunoconjugate of formula (I) is gilovertamab vedotin.

30. 10. The method of any one of the preceding claims, wherein the compound of formula (II) is nemtabrutinib.

31. 10. An immunoconjugate of formula (I) and a compound of formula (II) for use in treating a B-cell malignancy in a subject according to the method of any one of the preceding claims.

32. 32. The immunoconjugate of formula (I) and the compound of formula (II) according to claim 31 , wherein the immunoconjugate of formula (I) is dirovertamab vedotin.

33. 33. The immunoconjugate of formula (I) and a compound of formula (II) according to claim 31 or 32, wherein the compound of formula (II) is nemtabrutinib.

34. 10. Use of an immunoconjugate of formula (I) and a compound of formula (II) for the manufacture of a medicament for the treatment of a B-cell malignancy in a subject according to the method of any one of the preceding claims.

35. 35. The use of claim 34, wherein the immunoconjugate of formula (I) is giloveltamab vedotin.

36. 36. The use according to claim 34 or claim 35, wherein the compound of formula (II) is nemtabrutinib.

37. Formula (I) 【Transformation 3】 and an immunoconjugate of formula (II) 【Chemistry 4】 or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the immunoconjugate comprises an antibody (Ab) conjugated to a drug moiety shown in Formula (I), wherein the number of drug moieties (DAR) per antibody is in the range of 3 to 5, and the antibody comprises a heavy chain and a light chain comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively; the immunoconjugate of Formula (I) is administered to the subject at a dose of 2.00, 2.25, or 2.50 mg / kg in 3-week cycles on days 1 and 8 of each cycle; and the compound of Formula (II) is administered to the subject at a dose of 65 mg per day; and the B-cell malignancy is mantle cell lymphoma (MCL).

38. 38. The method of claim 37, wherein the immunoconjugate of formula (I) is giloveltamab vedotin.

39. 39. The method of claim 37 or claim 38, wherein the compound of formula (II) is nemtabrutinib.

40. Formula (I) 【Transformation 5】 and an immunoconjugate of formula (II) 【Transformation 6】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the immunoconjugate comprises an antibody (Ab) conjugated to a drug moiety shown in Formula (I), the number of drug moieties (DAR) per antibody is in the range of 3 to 5, and the antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively.

41. 41. The pharmaceutical composition of claim 40, wherein the immunoconjugate of formula (I) is giloveltamab vedotin.

42. 42. The pharmaceutical composition of claim 40 or claim 41, wherein the compound of formula (II) is nemtabrutinib.

43. 43. The pharmaceutical composition of claim 41 or claim 42, wherein the effective amount of giloveltamab vedotin is at a dose of 2.00, 2.25, or 2.50 mg / kg.

44. 44. The pharmaceutical composition of claim 42 or claim 43, wherein the effective amount of nemtabrutinib is a dose of 65 mg.

45. A kit comprising the pharmaceutical composition of any one of claims 40 to 44 and instructions for use in the treatment of a B-cell malignancy.

Images