Combination therapy comprising an immunoconjugate for the treatment of gastroesophageal cancer

Abstract

The present disclosure relates to methods of treating gastroesophageal cancer in a patient, said methods comprising administering to the patient: (a) an anti-human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimidine; and (c) an Immunoconjugate of Formula (I): wherein: Ab is an antibody that binds to Trop-2; and n is from 1 to 10.

Description

COMBINATION THERAPY COMPRISING AN IMMUNOCONJUGATE FOR THETREATMENT OF GASTROESOPHAGEAL CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 665,001 filed June 27, 2024, the entire contents of which are incorporated by reference herein.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing 25962 -WO-PCT_SL.xml; Size: 44,987 bytes; and Date of Creation: August 6, 2024, are herein incorporated by reference in their entirety.FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to use of an Immunoconjugate for the treatment of gastroesophageal cancer. Specifically, the disclosure relates combination therapies which comprises an immunoconjugate, a fluoropyrimidine, and an anti-human PD-1 antibody or antigen binding fragment thereof, and is useful for the treatment of gastroesophageal cancer.BACKGROUND OF THE DISCLOSURE

[0004] Gastroesophageal adenocarcinomas remain a public health problem and one of the leading causes of cancer mortality worldwide as described above. Despite chemotherapy, immunotherapy, and surgical options, these patients have a poor prognosis. The prognosis for early-stage adenocarcinomas is favorable, with 5-year survival rates exceeding 90% following surgery and chemotherapy. Unfortunately, the majority of cases are diagnosed at an advanced stage, locally advanced unresectable or metastatic (53% at stage 4), where the median overall survival is approximately less than 12 months without appropriate treatments. Therefore, there remains an unmet medical need for novel therapies.

[0005] Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers. Immune therapies targeting the PD-1 axis include monoclonal antibodies directed to the PD-1 receptor (KEYTRUDA™ (pembrolizumab), Merck and Co., Inc., Kenilworth. NJ. USA and OPDIVO™ (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ, USA) and also those that bind to the PD-L1 ligand (MPDL3280A; TECENTRIQ™ (atezolizumab), Genentech, San Francisco, CA, USA). Both therapeutic approaches have demonstrated anti-tumor effects in numerous cancer ty pes.

[0006] It has been proposed that the efficacy of such antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune enhancing agents.

[0007] A treatment option in gastric cancer is FOLFIRI (infusional fluoropyrimidine and irinotecan). A randomized Phase 3 study in metastatic or advanced gastric and GEJ adenocarcinoma showed a significantly longer time to treatment failure with this combination than ECX with better tolerability (Grade 3 / 4 toxicity 69% versus X4%. / ?< 0.001) in IL metastatic setting. Various other clinical studies in 2L have also shown encouraging results for the use of FOLFIRI and fluoropyrimidines in advanced settings in gastric cancers with modest activity and tolerability.

[0008] Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein involved in calcium signal transduction, and is expressed in multiple tumor types. Trop-2 is expressed in normal trophoblasts and allows for trophoblast cell growth, migration, and proliferation. Trop-2 has been implicated in several cell signaling pathways, including intracellular calcium transduction, MAPK signaling pathway, RAF, NF-KB, and Cyclin D / E among others.

[0009] It has been shown that Trop-2 is upregulated in cancer cells when compared to normal cell counterparts. This increased expression has been seen in many different tumor types including HR+ / HER2- metastatic or locally advanced breast cancer, colon cancer, HR+ / HER2- metastatic or locally advanced breast cancer, esophageal squamous cell cancer, thyroid cancer, and hepatobiliary cancers, raising the possibility of Trop-2 as a tumor agnostic biomarker. The reason for Trop-2 upregulation in cancer cells is unclear; however it is postulated that Trop-2 has critical regulatory effects on cellular proliferation and invasion, meaning that overexpression would lead to selective tumor progression. In fact, preclinical data suggests that Trop-2 overexpression stimulates tumor growth while Trop-2 knock-dow n inhibits tumor growth.

[0010] The success of targeting Trop-2 via antibody-drug conjugates (ADCs) in HR+ / HER2- metastatic or locally advanced breast cancer (MBC), and urothelial cancer and ongoing trials in HR+ / HER2- metastatic or locally advanced breast cancer have established Trop-2 targeting as a valid and fruitful strategy, and several Trop-2-targeted therapeutics have recently been developed for clinical use, such as anti-Trop-2 antibodies and Trop-2-targeted ADCs. Subsequently, multiple early-phase clinical trials have demonstrated good safety profiles, and clinical benefit associated with Trop-2-based ADCs across multiple tumor types. This includes clinical benefit, and tolerability' in tumor ty pes with limited treatment options, such as triple-negative HR+ / HER2- metastatic or locally advanced breast cancer, gastric cancer, platinum-resistanturothelial cancer, and small-cell lung cancer. An example of an immunoconjugate that is currently in clinical trials is Immunoconjugate A:Immunoconjugate A wherein Ab is the anti-Trop-2 antibody sacituzumab, and n is an integer from 1 to 8, and which is described in US Patent Publication No. 20200347075.

[0011] Given the promising results anti -human PD-1 antibodies or antigen binding fragments thereof, and immunoconjugates as monotherapy for the treatment of cancer, the combination of these therapeutic agents has the potential to provide more significant and prolonged responses in numerous cancer types, including gastroesophageal cancer.SUMMARY OF THE PRESENT DISCLOSURE

[0012] In a first aspect, the present disclosure provides a method of treating gastroesophageal cancer in a patient, comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof;(b) an amount of a fluoropyrmidine; and(c) an amount of an Immunoconjugate of Formula (I):(I),wherein:Ab is an antibody that binds to Trop-2; and n is from 1 to 10, and the average “n” of the amount of the Immunoconjugate of Formula (I) is from x to y? and wherein the amounts of (a), (b) and (c) administered are together effective to treat gastroesophageal cancer.

[0013] In embodiment no. 1 of this method, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0014] In embodiment no. 2 of this method, the patient is administered 4 mg of Immunoconjugate A.

[0015] In embodiment no. 3 of this method, the patient is administered 3 mg of Immunoconjugate A.

[0016] In an embodiment no. 4 of this method, the fluorpyrimidine is 5-FU.

[0017] In an embodiment no. 5 of this method, the fluorpyrimidine is capecitabine.

[0018] In embodiment no. 6 of this method, the patient is administered 400 mg / m2bolus of 5- FU, plus 2400 mg / m2(continuous) 5-FU, every 2 weeks.

[0019] In embodiment no. 7 of this method, the patient is administered 1000 mg / m2capecitabine twice per day for 14 concecutive days, every 3 weeks.

[0020] In embodiment no. 8 of this method, the anti -human PD-1 antibody or antigen binding fragment is pembrolizumab.

[0021] In embodiment no. 9 of this method, the patient is administered 400 mg of pembrolizumab every 6 weeks.

[0022] In embodiment no. 10 of this method, the patient is administered: (a) 400 mg of the antihuman PD-1 antibody or antigen binding fragment thereof, (b) 4 mg / kg of Immunoconjugate A, and (c) 1000 mg / m2of capecitabine, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is administered once every six weeks, Immunoconjugate A is administered once every 2 weeks, and capeitabine is administered twice daily for 14 consecutive days, every 3 weeks. For instance, the human patient is administered 400 mg of the anti-human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6- eek cycle, 4 mg / kg of Immunoconjugate A on days 1, 15, and 29 of a 6-week cycle, and 1000 mg / m2capecitabine twice daily on days 1-14 of a 3 -week cycle.

[0023] In embodiment no. 11 of this method, the patient is administered: (a) 400 mg of the antihuman PD-1 antibody or antigen binding fragment thereof, (b) 3 mg / kg of Immunoconjugate A, and (c) 1000 mg / m2of capecitabine, w herein the anti -human PD-1 antibody or antigen bindingfragment thereof is administered once every six weeks. Immunoconjugate A is administered once every 2 weeks, and capeitabine is administered twice daily for 14 consecutive days, every 3 weeks. For instance, the human patient is administered 400 mg of the anti-human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6- week cycle, 3 mg / kg of Immunoconjugate A on days 1, 15, and 29 of a 6-week cycle, and 1000 mg / m2capecitabine twice daily on days 1-14 of a 3-week cycle.

[0024] In embodiment no. 12 of this method, the patient is administered: (a) 400 mg of the antihuman PD-1 antibody or antigen binding fragment thereof, (b) 4 mg / kg of Immunoconjugate A, and (c) 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) of 5-FU, wherein the antihuman PD-1 antibody or antigen binding fragment thereof is administered once every six weeks, Immunoconjugate A is administered once every 2 weeks, and 5-FU is administered every 2 weeks. For instance, the human patient is administered 400 mg of the anti-human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6-week cycle, 4 mg / kg of Immunoconjugate A on days 1, 15, and 29 of a 6-week cycle, and 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) of 5-FU on day 1 of a 3-week cycle.

[0025] In embodiment no. 13 of this method, the patient is administered: (a) 400 mg of the antihuman PD-1 antibody or antigen binding fragment thereof, (b) 3 mg / kg of Immunoconjugate A, and (c) 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) of 5-FU, wherein the antihuman PD-1 antibody or antigen binding fragment thereof is administered once every six weeks. Immunoconjugate A is administered once every 2 weeks, and 5-FU is administered every 2 weeks. For instance, the human patient is administered 400 mg of the anti-human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6-week cycle, 3 mg / kg of Immunoconjugate A on days 1, 15, and 29 of a 6-week cycle, and 400 mg / m2(bolus) of 5-FU. plus 2400 mg / m2(continuous infusion) of 5-FU on day 1 of a 3-week cycle.

[0026] In embodiment no. 14 of this method, the gastroesophageal cancer being treated is selected from: metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, non-squamous cell gastroesophageal cancer, and esophageal adenocarcinoma.

[0027] In embodiment no. 15 of this method, the gastroesophageal cancer being treated is locally advanced or metastatic and selected from: metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, non-squamous cell gastroesophageal cancer, and esophageal adenocarcinoma.

[0028] In a second aspect, the present disclosure provides a kit comprising:(a) an anti-human PD-1 antibody or antigen binding fragment thereof;(b) a fluoropyrimidine; and(c) an Immunoconjugate of Formula (I).

[0029] In one embodiment of this second aspect, the kit further comprises instructions for administering the Immunoconjugate of Formula (I), an Immunoconjugate of Formula (I); the fluoropyrimidine, and the anti -human PD-1 antibody or antigen binding fragment thereof to a human patient.

[0030] In a third aspect, the present disclosure provides a therapeutic combination, comprising:(a) an anti-human PD-1 antibody or antigen binding fragment thereof;(b) a fluoropyrmidine; and(c) an Immunoconjugate of Formula (I) for treating gastroseophagal cancer in a human patient.

[0031] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof comprises three light chain CDRs of SEQ ID NO: 1, SEQ ID NO:2 and SEQ ID NO:3 and three heavy chain CDRs of SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.

[0032] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof comprises a VL region which comprises the amino acid sequence set forth in SEQ ID NO:4, and a VH region which comprises the amino acid sequence set forth in SEQ ID NO:9.

[0033] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof comprises a light chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO: 10.

[0034] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

[0035] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof is nivolumab.

[0036] In certain embodiments of the first, second, or third aspects, the anti-human PD-1 antibody or antigen binding fragment thereof is cemiplimab.

[0037] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof is dostarlimab.

[0038] In certain embodiments of the first, second, or third aspects, the Immunoconjugate of formula (I) is Immunoconjugate A.

[0039] In certain embodiments of the first, second, or third aspects, the fluoropyrimidine is 5- FU or capecitabine.DETAILED DESCRIPTION OF THE PRESENT DISCLOSUREDEFINITIONS AND ABBREVIATIONS

[0040] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0041] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0042] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes.” and “included,” is not limiting.

[0043] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest w hole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0044] An “antibody-drug conjugate,” or “ADC,” or “immunoconjugate,” refers to an antibody molecule or an antigen-binding fragment thereof that is covalently or non-covalently bonded, with or without a linker, to one or more biologically active molecule(s). The term “antibody” is used herein in the broadest sense and includes polyclonal and monoclonal antibodies, such as intact antibodies and functional (antigen-binding) fragments thereof. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multi-specific (e.g., bispecific) antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, and tandem tri-scFv.

[0045] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

[0046] The terms “administration” or “administer” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., 5-FU) into a patient, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other methods of physical delivery described herein or known in the art.

[0047] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability' to bind specifically to theantigen, e.g.. fragments that retain one or more CDR regions and the abi lity to bind specifically to the antigen. Antigen binding portions include, for example. Fab, Fab’, F(ab’)2, Fd, Fv, fragments including CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the antigen (e.g.. PD-1). Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. An antigen-binding fragment of a full-length antibody may be used in making an immunoconjugate of the present disclosure. Examples of antibody fragments include, but are not limited to, Fv, Fab. Fab'. Fab'-SH. F(ab')2; recombinant IgG (rlgG) fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); single domain antibodies (e.g., sdAb, sdFv, nanobodies); and multi-specific antibodies formed from antibody fragments. In certain embodiments, the fragments are single-chain antibody fragments comprising a variable heavy chain region and / or a variable light chain region, such as scFvs.

[0048] An "antigen" is a structure to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, an antigen is associated with a cell, for example, is present on or in a cell, for example, a cancer cell.

[0049] “Advanced solid tumor malignancy” and “advanced solid tumor” are used interchangeably to refer to a tumor for which curative resection is not possible. Advanced solid tumors include, but are not limited to, metastatic tumors in bone, brain, breast, liver, lungs, lymph node, pancreas, prostate, and soft tissue (sarcoma).

[0050] As used herein, the term “antibody” or “Ab,” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g.. bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a humantherapeutic. As used herein, the term “antibody’7encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site. In one embodiment, the term “antibody” or “Ab” does not encompass antibody fragments. In another embodiment, the term antibody” or “Ab” does encompass antibody fragments.

[0051] In general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See generally. Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0052] “Biotherapeutic agent” means a biological molecule, such as an antibody or fusion protein, that blocks ligand / receptor signaling in any biological pathway that supports tumor maintenance and / or growth or suppresses the anti -tumor immune response.

[0053] The term “carrier,” as used herein, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a patient.

[0054] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components orcompounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0055] As used herein, the term “C1D1” refers to the timing of administration of an Immunoconjugate of formula (I) and / or a Programmed Death 1 protein (PD-1) or an antigen binding fragment thereof. Specifically the term “Cl DI” refers to administration on day 1 of chemotherapy cycle 1, the term “C1D15” refers to administration on day 15 of chemotherapy cycle 1, and the term “C1D57” refers to administration on day 57 of chemotherapy cycle 1.

[0056] A “CDR” refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH P-sheel framework, or one of three hypervariable regions (LI, L2, or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable domains. CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved -sheet framework, and thus are able to adapt to different conformations. Both terminologies are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (AL Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable region numbering scheme (ALLazikani et al., supra). Such nomenclature is similarly well known to those skilled in the art. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art and shown below in Table 1. In some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In yet other embodiments, the CDRs are as defined by the AbM numbering system. In still other embodiments, the CDRs are as defined by the Chothia numbering system. In yet other embodiments, the CDRs are as defined by the Contact numbering system.Table 1. Correspondence between the CDR Numbering Systems

[0057] “Chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents (including platinum-containing chemotherapeutic agents), antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth. Chemotherapeutic agents useful in the treatment methods of the present disclosure include cytostatic and / or cytotoxic agents.

[0058] “Chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain contains sequences derived from a particular species (e.g.. human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0059] As used herein, the terms “combination therapy” and “therapeutic combination” refer to treatments in which at least one anti -human PD-1 antibody (or antigen-binding fragment thereof) and Immunoconjugate of Formula (I), and optionally additional therapeutic agents, each are administered to a patient in a coordinated manner, over an overlapping period of time. The period of treatment with the at least one anti -human PD-1 antibody (or antigen-binding fragment thereof) (the “anti-PD-1 treatment”) is the period of time that a patient undergoes treatment with the anti-human PD-1 antibody (or antigen-binding fragment thereof); that is, the period of time from the initial dosing with the anti -human PD- 1 antibody (or antigen-binding fragment thereof) through the final day of a treatment cycle. Similarly, the period of treatment with the Immunoconjugate of Formula (I) (the “Immunoconjugate of Formula (I) treatment”) is the period of time that a patient undergoes treatment with the Immunoconjugate of Formula (I); that is, theperiod of time from the initial dosing with the Immunoconjugate of Formula (I) through the final day of a treatment cycle. In the methods and therapeutic combinations described herein, the anti- PD-1 treatment overlaps by at least one day the Immunoconjugate of Formula (I) treatment. In certain embodiments, the anti-PD-1 treatment and the Immunoconjugate of Formula (I) treatment are coextensive. In embodiments, the anti-PD-1 treatment begins prior to the Immunoconjugate of Formula (I) treatment. In embodiments, the Immunoconjugate of Formula (I) treatment begins prior to the anti-PD-1 treatment. In embodiments, the anti-PD-1 treatment is terminated prior to termination of Immunoconjugate of Formula (I) treatment. In embodiments, the Immunoconjugate of Formula (I) treatment is terminated prior to termination of the anti-PD-1 treatment.

[0060] “Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and / or specificity. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 2 below.Table 2. Exemplary Conservative Amino Acid Substitutions

[0061] The term "DAR " or "Drug Antibody Ratio,’' as used herein, refers to the average number of linker / drug moieties attached to an antibody in a composition comprising more than one Antibody-Drug Conjugate molecule, wherein DAR is represented as a decimal from 0 to 10. Accordingly, in one embodiment, for an Antibody -Drug Conjugate of the present disclosure, the DAR is a decimal from 0 to 10, 0 to 9, 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, and from 0 to 1. In additional embodiments, for an Antibody-Drug Conjugate of the present disclosure, the DAR is a decimal from 1 to 8, 1 to 4, 2 to 5. 3 to 6, 4 to 7, 5 to 8, and 6 to 8. In other embodiments, for an Antibody -Drug Conjugates of the present disclosure, the DAR is a decimal from 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, and 6 to 8. In further embodiments, for an Antibody-Drug Conjugate of the present disclosure, the DAR is a decimal from 1 to 2, 2 to 3. 3 to 4, 4 to 5. 5 to 6, 6 to 7, and 7 to 8. Likewise, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR for the composition is an average of the DAR for all of the Antibody-Drug Conjugate molecules present in said composition. As such, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 0 to 8, from 0 to 7. from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, and from 0 to 1. In additional embodiments, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 1 to 4, 2 to 5, 3 to 6, 4 to 7, 5 to 8, and 6 to 8. In other embodiments, for a composition comprising an Antibody -Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 1 to 3, 2 to 4, 3 to 5. 4 to 6, 5 to 7. and 6 to 8. In further embodiments, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7. and 7 to 8. The term “composition” as used above, is understood to encompass pharmaceutical compositions.

[0062] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral route or parenteral route of administration. The term “enteral route” of administration refers to the administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal route, or intragastricroute. “Parenteral route” of administration refers to a route of administration other than enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal. subcutaneous, or topical administration. The therapeutic agents and compositions of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. A suitable route and method of administration may vary depending on a number of factors such as the specific therapeutic agent being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the patient, and can be readily selected by a person skilled in the art.

[0063] The term “fluoropyrimidine,” as used herein refers to a general class of organic compounds in which the substituent(s) around a pyrimidine ring include at least one fluorine atom. Fluoropyrimidines are antimetabolite drugs useful as anticancer agents. Non-limiting examples of fluoropyrimidines useful in the combination therapies of the present disclosure include 5-fluorouracil (5-FU), capeci tabine, carmofur (HCFU), doxifl uridine, and tegafur. In a specific embodment. the fluoropyrimidine is 5-FU. In another specific embodiment, the fluoropyrimidine is capecitabine.

[0064] “Homology” refers to sequence similarity between two polypeptide sequences when they are optimally aligned. When a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, e.g, if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position. The percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if 8 of 10 of the positions in two sequences are matched when the sequences are optimally aligned then the two sequences are 80% homologous. Generally, the comparison is made when two sequences are aligned to give maximum percent homology. For example, the comparison can be performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.

[0065] The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W„ et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) GenomeRes. 7:649-656; Wooton, J.C., et al., (1993) Comput. Chem. 17: 149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., “A model of evolutionary change in proteins.’’ in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M.. et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” M.O. Dayhoff (ed ), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul. S.F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S„ et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S„ et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S.F. “Evaluating the statistical significance of multiple distinct local alignments.” in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York.

[0066] “Human antibody” refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0067] “Humanized antibody” refers to forms of antibodies that contain sequences from nonhuman (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two. variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc). t pically that of a human immunoglobulin. The prefix “hum”, “hu” or “h” may be added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.

[0068] An "intact" antibody is one comprising an antigen-binding site as well as a CL and at least heavy chain constant regions, CHI, CH2 and CH3. The constant regions may includehuman constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0069] As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.

[0070] The term “isolated” as used in reference to an antibody or fragment thereof refers to the purification status and. in such context, means the named molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

[0071] “Kabat” as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health. Bethesda, Md.).

[0072] “Monoclonal antibody” or “mAb” or “Mab”. as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 1 16:731.

[0073] “PD-1 antagonist’’ means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cellor NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the treatment methods, compositons. and uses of the present disclosure in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP 079515, respectively.

[0074] “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab) is a humanized IgG4 mAb with the structure described in WHO Drug Information^ Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences and CDRs described in Table 3. Pembrolizumab has been approved by the U.S. FDA as described in the Prescribing Information for KEYTRUDA* (Merck & Co., Inc.. Rahway. NJ USA; initial U.S. approval 2014, updated February 2023). The term pembrolizumab includes mAb’s having a structure as described above (Id.) but which do not include the C-terminal lysine in the heavy chain.

[0075] "‘Pembrolizumab variant” as used herein means a monoclonal antibody that comprises heavy chain and light chain sequences that are identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six, five, four, three, two or one conservative amino acid substitutions that are located outside of the heavy chain CDRs, e.g, the variant positions are located in the framework regions or the constant region, and optionally has a deletion of the C- terminal lysine residues of the heavy chain. In other words, pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively. A pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity’ to PD-1 and ability' to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0076] The term “patient” as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g, cows), porcine (e.g., pigs), ovine (e.g., sheep), capra (e.g., goats), equine (e.g., horses), canine (e.g., domestic dogs).feline (e.g.. house cats), Lagomorpha (rabbits), rodents (e.g., rats or mice), Procyon lotor (e.g. raccoons). In particular embodiments, the patient is human.

[0077] The term ‘‘patient in need thereof’ as used herein refers to a patient diagnosed with, or suspected of having cancer. In one embodiment a patient in need thereof refers to a patient diagnosed with, or suspected of having gastroesophageal cancer.

[0078] The term “pharmaceutically acceptable carrier” refers to any inactive substance that is suitable for use in a formulation for the delivery’ of a therapeutic agent. A carrier may be an antiadherent, binder, coating, disintegrant, filler or diluent, preservative (such as antioxidant, antibacterial, or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifying agent, buffer, and the like. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), dextrose, vegetable oils (such as olive oil), saline, buffer, buffered saline, and isotonic agents such as sugars, polyalcohols, sorbitol, and sodium chloride.

[0079] The term “pharmaceutically acceptable salt” refers to a salt (including an inner salt such as a zwitterion) that possesses effectiveness similar to the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Thus, an embodiment of the present disclosure provides pharmaceutically acceptable salts of the compounds of the present disclosure. The term “salt(s)”. as employed herein, denotes any of the following: acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Salts of compounds of the present disclosure may be formed by methods known to those of ordinary' skill in the art, for example, by reacting an Immunoconjugate of the present disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by' lyophilization.

[0080] Exemplary' acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G.(eds.), Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley - VCH; S. Berge et al.. Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

[0081] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, / -butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogencontaining groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g, decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g, sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0082] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the present disclosure and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the present disclosure.

[0083] In addition, w hen an Immunoconjugate of the present disclosure contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary', tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole, and an acidic moiety, such as. but not limited to tetrazole or carboxylic acid, zwitterions ("inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds of the present disclosure may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the present disclosure.

[0084] “RECIST 1.1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.

[0085] "Responder patient” when referring to a specific anti-tumor response to a treatment described herein, means the patient exhibited an anti-tumor response.

[0086] The term ‘‘simultaneous administration” as used herein in relation to the administration of medicaments refers to the administration of medicaments such that the individual medicaments are present within a patient at the same time. In addition to the concomitant administration of medicaments (via the same or alternative routes), simultaneous administration may include the administration of the medicaments (via the same or an alternative route) at different times.

[0087] “Sustained response” means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.

[0088] “Treat” or “Treating” gastroesophageal cancer as used herein means to administer a combination therapy of an anti-human PD-1 antibody or antigen binding fragment thereof; 5- fluorouracil or capecitabine; and an Immunoconjugate of Formula (I) to a patient having gastroesophageal cancer, or diagnosed with gastroesophageal cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced tumor burden, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, comprising administration by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other methods of physical delivery described herein or know n in the art. Typically, the agent(s) of the treatment method are administered in an amount effective to alleviate one or more disease symptoms in the treated patient or population, whether by inducing the regression of or inhibiting the progression of such symptom(s) by any clinically measurable degree. The amount of the agent(s) of the treatment method that is effective to alleviate any particular disease symptom may vary' according to factors such as the disease state, age, and w eight of the patient, and the ability of the therapeutic combination to elicit a desired response in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. “Treatment” may include one or more of the following: inducing / increasing an antitumor immune response, decreasing the number of one or more tumor markers, halting or delaying the growth of a tumor or blood cancer or progression of disease such as cancer, stabilization of disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, decreasing the level of one or more tumor markers,ameliorating or abrogating the clinical manifestations of disease, reducing the severity or duration of the clinical symptoms, prolonging the survival of the treated patient relative to the expected survival in a similar untreated patient, and inducing complete or partial remission of a cancerous condition, wherein the disease is cancer, more specifically, gastroesophageal cancer.

[0089] The amount of a therapeutic agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom.

[0090] Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50: 1 S-10S (2009)). For example, with respect to tumor grow th inhibition, according to NCI standards, a T / C 42% is the minimum level of anti-tumor activity7. A T / C < 10% is considered a high anti -tumor activity level, with T / C (%) = Median tumor volume of the treated / Median tumor volume of the control x 100. In some embodiments, the treatment achieved by a therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow-, and includes the amount of time patients have experienced a CR or PR, as w ell as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1. 1 response criteria. The treatment regimen for a therapy of the disclosure that is effective to treat a cancer patient may vary' according to factors such as the disease state, age, and w eight of the patient, and the ability' of the therapy to elicit an anti-cancer response in the patient. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every patient, it should do so in a statistically significant number of patients as determined by any statistical test known in the art such as the Student's t-test. the chi2- test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere- Terpstra-test and the Wilcoxon-test.

[0091] The terms “treatment regimen”, “dosing protocol”, and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.

[0092] “Tumor” as it applies to a patient diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary7tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0093] “Tumor burden’’ also referred to as “tumor load”, refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art. such as, e.g., by measuring the dimensions of tumor(s) upon removal from the patient, e.g, using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging (MRI) scans.

[0094] The term “tumor size” refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the patient, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.

[0095] “Variable regions” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.”

[0096] Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, fromN-terminal to C- terminal. both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3. CDR3, and FR4. As referred to herein the light chain CDRs are CDRL1, CDRL2 and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2 and CDRH3, respectively. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health.Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0097] The term “variant” when used in relation to an antibody (e.g., an anti-Trop-2 antibody) or an amino acid region within the antibody may refer to a peptide or polypeptide comprising one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions as compared to a native or unmodified sequence. For example, a variant of an antibody may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native or previously unmodified antibody. Variants may be naturally occurring or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants. In specific embodiments, an antibody variant at least retains the antibody functional activity.

[0098] The term “variant” when used in relation to an antibody (e.g., an anti-PD-1 antibody, or an anti-TROP2 antibody) or an amino acid region within the antibody may refer to a peptide or polypeptide comprising one or more (such as. for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions as compared to a native or unmodified sequence. For example, a variant of an anti-PD-1 antibody may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native or previously unmodified anti-PD-1 antibody. Variants may be naturally occurring or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants. In specific embodiments, an antibody variant (e.g., an anti-PD-1 antibody variant) at least retains the antibody functional activity. In some embodiments, an anti-PD-1 antibody variant binds to PD-1 and / or is antagonistic to PD-1 activity.

[0099] Where aspects or embodiments of the disclosure are described in terms of a Markush group or other grouping of alternatives, the present disclosure encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present disclosure also envisages the explicit exclusion of one or more of any of the group members in the claims.

[0100] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any valuesdisclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0101] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word ‘'comprise,” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or "for example” is not meant to be exhaustive or limiting.

[0102] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0103] The following Abbreviations are used herein, and are defined as follows:ADC Anti body -Drug Conjugate AE Adverse Effect ALT Alanine transaminase APaT All patients as treated population ASCO American Society of Clinical Oncology AST Aspartate aminotransferase BICR Blinded independent central review CAPOX Capecitabine + oxaliplatinCD137 Cluster of differentiation 137 CDR Complimentarity determining region CI Confidence interval CNS Central nervous system COPD Chronic obstructive pulmonary diseaseCOVID-19 Coronavirus disease of 2019 CPS Central pain syndrome CR Complete response CRF Case report form eCRF Electronic case report form CT Computerized tomography CTCAE Common terminology criteria for adverse effects CTLA-4 Cytotoxic T-lymphocyte-associated protein 4CYP3A4 Cytochrome P450 3A4 DFS Disease-free survival DILI Drug-induced liver injury DLT Dose-limiting toxicity DMC Data Monitoring CommitteeDOR Duration of Response DPD dihydropyrimidine dehydrogenase ECHO Echocardiogram ECI Event of clinical interest ECOG Eastern Cooperative Oncology Group ECG Electrocardiogram EORTC European Organization for Research and Treatment of Cancer ePRO Electronic patient-reported outcomes FA Final analysis FAS Future biomedical research FBR Growth hormone secretagogue FOLIFIRI Irinotecan, 5-FU, and leucovorin FOLFOX Folinic acid, 5-FU, and oxaliplatin FR Framework region 5-FU 5 -fluorouracil GHS Globally harmonized system of classification and labeling of chemicals HBsAg Hepatitis B surface antigen HBV Hepatitis B virus HCV Hepatitis C virus HER2 Human epidermal growth factor-2 HER2 / neu Human epidermal growth factor-2 HIV Human immunodeficiency virus HR Hazard ratio HRQoL Health-related quality of life G-CSF Granulocyte colony stimulating factor GEJ Gastroesophageal junction GI Gastrointestinal IA(s) Interim analysis(ses) iCRO Imaging CRO IHC Immunohistocompatibility complex INR International normalized ratio IO Immune oncology irAE Immune-related adverse effect 1SOO International Society of Oral Oncology IV Intravenous LVEF Left ventricular ejection fraction mAh Monoclonal antibody MASCC Multinational Association of Supportive Care in Cancer MPK or mpk Milligram per kilogram MRI Magnetic resonance imaging MUGA Multi-gated acquisition NCI National Cancer Institute NCI-CTC Common toxicity criteria NSAE Neuronal surface antibody-mediated autoimmune encephalitis NSAID Non-steroidal anti-inflammatory drug OR Overall response ORR Objective response rate OS Overall survival OTC Over-the-counter PD Pharmacodynamics or progressive diseasePD-1 Programmed cell death protein 1PD-L1 Programmed death ligand 1PD-L2 Programmed death ligand 2PET Postiron Emission TomographyPFS Progression free survivalPK PharmacokineticsPOCBP Persons of childbearing potential PR Partial response PRO FAS Patient reported outcome PSA Prostate-specific antigen PT Prothrombin time PTT Partial thromboplastin time q2w Once every 2 weeks QoL Quality of Life QT QT interval QTc QTc interval QTcF QT interval corrected for heart rate RECIST Response Evaluation Criteria in Solid Tumors SAE Serious adverse effect SD Stable disease SGOT serum glutamic oxaloacetic transaminase SGPT Serum glutamic pyruvic transaminase SIM Site Imaging Manual SLAB Supplemental laboratory test(s) SoA Schedule of activities soc Standard of care T1DM Type-1 diabetes mellitus T / C Treatment-to-control ratio TCR T-cell receptor Trop-2 Tumor-associated calcium signal transducer 2 TTD Time to treatment discontinuation ULN Upper limit of normal VEGR Vascular endothelial growth factor VEGFR Vascular endothelial growth factor receptor VH immunoglobulin heavy chain variable region VL immunoglobulin light chain variable region

[0104] Additional abbreviations may be defined throughout this disclosure.

[0105] The present disclosure relates to a therapeutic combinations, wherein the therapeutic combinations comprise: (a) an anti -human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimidine; and (c) an Immunoconjugate of Formula (I).

[0106] The present disclosure relates to methods of treating gastroesophageal cancer, wherein the method comprises administering to a human patient in need thereof a combination therapy that comprises (a) an anti -human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimidine; and (c) an Immunoconjugate of Formula (I).

[0107] In preferred embodiments, the methods and the therapeutic combinations of the instant disclosure comprise 5-FU as the fluoropyrimidine. In other preferred embodiments, the methods and therapeutic combinations of the instant disclosure comprise capecitabine as the fluoropyrimidine.

[0108] In preferred embodiments, the Immunoconjugate of Formula (I) is Immunoconjugate A, which is described in US Patent Publication No. 20200347075. Immunoconjugate A has the structure:wherein each n is an integer or decimal from 1 to 8; and Ab is sacituzumab.PD-1 antagonists or anti-human PD-1 monoclonal antibodies useful in the present disclosure

[0109] Examples of mAbs that bind to human PD-1 , useful in the methods, compositions, kits, and uses of the present disclosure, are described in US 7,521,051, US 8,008,449, and US 8,354,509. Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the methods, compositions, kits, and uses of the present disclosure include: pembrolizumab (formerly known as MK-3475, SCH 900475 and lambrolizumab), a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Table 3, and the humanized antibodies h409Al l, h409A16 and h409A17, which are described in WO 2008 / 156712.

[0110] Additional examples of PD-1 antagonists useful in the methods, compositions, kits, and uses of the present disclosure include, but are not limited to: nivolumab (OPDIVO®, Bristol- Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO®, Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Sanofi-Aventis U.S. ELC., Bridgewater, NJ) and dostarlimab (JEMPEREI®, GlaxoSmithKline ELC. Philadelphia. PA).

[0111] Provided herein are PD-1 antagonists or anti-human PD-1 monoclonal antibodies that can be used in any of the methods, compositions, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks binding of PD-L1 to PD-1 and preferably also blocks binding of PD-L2 to PD-1.

[0112] Any monoclonal antibodies that bind to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and block the interaction between PD-1 and its ligand PD-L1 or PD-L2 can be used. In some embodiments, the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1. In other embodiments, the antihuman PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L2. In yet other embodiments, the anti -human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.

[0113] In certain embodiments, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostarlimab, pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD), PDR001 (U.S. Pat. No. 9,683,048), tislelizumab BGB-A317 (U.S. Pat. No. 8,735,553), and INCMGA00012 or MGA012 (MacroGenics, Rockville, MD). In one embodiment, the anti -human PD-1 monoclonal antibody is pembrolizumab. In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In another embodiment, the anti -human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti -human PD-1 monoclonal antibody is cemiplimab. In yet another embodiment, the anti -human PD-1 monoclonal antibody is pidilizumab. In one embodiment, the anti -human PD-1 monoclonal antibody is AMP-514. In another embodiment, the anti-human PD-1 monoclonal antibody is PDR001. In yet another embodiment, the antihuman PD-1 monoclonal antibody is BGB-A317. In still another embodiment, the anti -human PD-1 monoclonal antibody is MGA012.

[0114] In some embodiments, an anti -human PD-1 antibody or antigen binding fragment thereof for use in the methods and uses disclosed herein comprises three light chain CDRs of CDRL1, CDRL2 and CDRL3 and / or three heavy chain CDRs of CDRH1, CDRH2 and CDRH3.

[0115] In one embodiment, CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 1 or a variant of the amino acid sequence as set forth in SEQ ID NO: 1, CDRL2 has the amino acid sequence as set forth in SEQ ID NO:2 or a variant of the amino acid sequence as set forth in SEQID N0:2. and CDRL3 has the amino acid sequence as set forth in SEQ ID NO:3 or a variant of the amino acid sequence as set forth in SEQ ID NO: 3.

[0116] In one embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, CDRH1 has the amino acid sequence as set forth in SEQ ID NO:6 or a variant of the amino acid sequence as set forth in SEQ ID NO: 6, CDRH2 has the amino acid sequence as set forth in SEQ ID NO:7 or a variant of the amino acid sequence as set forth in SEQ ID NO:7, and CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 8 or a variant of the amino acid sequence as set forth in SEQ ID NO: 8.

[0117] In one embodiment of the anti-human PD-1 antibody or antigen binding fragment thereof, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.

[0118] In an alternative embodiment of the anti-human PD-1 antibody or antigen binding fragment thereof, CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 11 or a variant of the amino acid sequence as set forth in SEQ ID NO: 11 , CDRL2 has the amino acid sequence as set forth in SEQ ID NO: 12 or a variant of the amino acid sequence as set forth in SEQ ID NO: 12, and CDRL3 has the amino acid sequence as set forth in SEQ ID NO: 13 or a variant of the amino acid sequence as set forth in SEQ ID NO: 13.

[0119] In one embodiment of the anti -human PD- 1 antibody or antigen binding fragment thereof, CDRH1 has the amino acid sequence as set forth in SEQ ID NO: 16 or a variant of the amino acid sequence as set forth in SEQ ID NO: 16, CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 17 or a variant of the amino acid sequence as set forth in SEQ ID NO: 17, and CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 18 or a variant of the amino acid sequence as set forth in SEQ ID NO: 18.

[0120] In an alternative embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18.

[0121] In a further embodiment, CDRL1 has the amino acid sequence as set forth in SEQ ID NO:21 or a variant of the amino acid sequence as set forth in SEQ ID NO:21, CDRL2 has the amino acid sequence as set forth in SEQ ID NO:22 or a variant of the amino acid sequence as set forth in SEQ ID NO:22, and CDRL3 has the amino acid sequence as set forth in SEQ ID NO:23 or a variant of the amino acid sequence as set forth in SEQ ID NO:23.

[0122] In yet another embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, CDRH1 has the amino acid sequence as set forth in SEQ ID NO:24 or a variant of the amino acid sequence as set forth in SEQ ID NO:24, CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 25 or a variant of the amino acid sequence as set forth in SEQ ID NO:25. and CDRH3 has the amino acid sequence as set forth in SEQ ID NO:26 or a variant of the amino acid sequence as set forth in SEQ ID NO: 26.

[0123] In another embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO:21, SEQ ID NO:22, and SEQ ID NO:23 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26.

[0124] In a sub embodiment of the anti -human PD-1 embodiments above, the anti -human PD-1 antibody or antigen binding fragment is an antibody.

[0125] Some anti-human PD-1 antibody and antigen binding fragments disclosed herein comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NON or a variant of the amino acid sequence as set forth in SEQ ID NON, and the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 9 or a variant of the amino acid sequence as set forth in SEQ ID NO:9. In further embodiments, the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 14 or a variant of the amino acid sequence as set forth in SEQ ID NO: 14, and the heavy' chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 19 or a variant of the amino acid sequence as set forth in SEQ ID NO: 19. In further embodiments, the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:27 or a variant of the amino acid sequence as set forth in SEQ ID NO:27 and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:28 or a variant of the amino acid sequence as set forth in SEQ ID NO:28, the amino acid sequence as set forth in SEQ ID NO: 29 or a variant of the amino acid sequence as set forth in SEQ ID NO:29, or the amino acid sequence as set forth in SEQ ID NO:30 or a variant of the amino acid sequence as set forth in SEQ ID NO:30. In such embodiments, a light chain variable region or heavy chain variable region sequence is identical to the reference sequence except having one, two, three, four or five amino acid substitutions. In some embodiments, the substitutions are in the framework region (i.e., outside of the CDRs). In some embodiments, one, two, three, four or five of the amino acid substitutions are conservative substitutions.

[0126] In one embodiment of the methods, kits or uses disclosed herein, the anti-human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising orconsisting of the amino acid sequence as set forth in SEQ ID NO:4 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 14 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 19. In one embodiment of the compositions, methods, kits, and uses disclosed herein, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:28 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27. In a further embodiment, the anti-human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:29 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27. In another embodiment, the antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:30 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27.

[0127] In another embodiment, the methods, kits or uses disclosed herein comprise an antihuman PD-1 antibody or antigen binding protein that has a VL domain and / or a VH domain with at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VL domains or VH domains described above, and exhibits specific binding to PD-1. In another embodiment, the anti -human PD-1 antibody or antigen binding protein of the present methodsm comprises VL and VH domains having up to 1. 2, 3. 4. or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0128] In any of the embodiments above, the PD-1 antagonist may be a full-length anti-PD-1 antibody or an antigen binding fragment thereof that specifically binds human PD-1. In certain embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. Any isotype of IgG can be used, including IgGi, IgGz, IgGa, and IgG4. Different constant domains may be appended to the VL and VH regions provided herein. For example, if a particular intended use of an antibody (or fragment) disclosed herein were to call for altered effector functions, a heavy chain constant domain other than IgGi may be used. Although IgGl antibodies provide for long half-life and for effector functions, such as complement activationand antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody. In such instances an IgG4 constant domain, for example, may be used.

[0129] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 10. In alternative embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 15 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:20. In further embodiments, the PD-1 antagonist is an anti- PD-1 antibody comprising a light chain comprising or consisting of a sequence of ammo acid residues as set forth in SEQ ID NO:32 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:33 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In yet additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:34 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In some compositions, methods, kits, and uses disclosed herein, the PD-1 antagonist is pembrolizumab or a pembrolizumab biosimilar. In some compositions, methods, kits, and uses disclosed herein, the PD-1 antagonist is nivolumab or a nivolumab biosimilar. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is cemiplimab. In another such embodiment, the agent is dostarlimab.

[0130] Ordinarily, amino acid sequence variants of the anti-PD-1 antibodies and antigen binding fragments disclosed herein will have an amino acid sequence having at least 75% amino acid sequence identity with the amino acid sequence of a reference antibody or antigen binding fragment (e.g., heavy chain, light chain, VH, VL, or humanized sequence), more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95, 98, or 99%. Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the anti-PD-1 residues, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. None of N-terminal, C-terminal, or internal extensions, deletions, orinsertions into the antibody sequence shall be construed as affecting sequence identity or homology.

[0131] Sequence identity refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences. The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al.. (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17: 149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.). pp. 345- 352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3." M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S.. et al..(1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul, S.F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S„ et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S„ et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S.F. "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed ), (1997) pp. 1-14, Plenum, New York.

[0132] Likewise, either class of light chain can be used in the compositions and methods herein. Specifically, kappa, lambda, or variants thereof are useful in the present compositions and compositions, methods, kits, and uses disclosed herein.Table 3. Exemplary PD-1 Antibody SequencesTable 4. Additional PD-1 Antibodies and Antigen Binding Fragments Useful in theMethods and Uses disclosed herein.

[0133] In embodiments of the compositions, methods, kits, and uses disclosed herein, the antihuman PD-1 antibody (or antigen-binding fragment thereof) is an anti-PD-1 monoclonal antibody. In particular aspects of these embodiments, the anti -human PD-1 antibody (or antigenbinding fragment thereof) is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP -224. In specific aspects of these embodiments, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is selected from nivolumab and pembrolizumab. In a more specific aspect, the anti -human PD-1 antibody (or antigen-binding fragment thereof) is nivolumab. In a further specific aspect, the anti-human PD-1 antibody (or antigen-binding fragment thereof) is pembrolizumab.

[0134] In embodiments of the compositions, methods, kits, and uses disclosed herein, the antihuman PD-1 antibody is pembrolizumab. In other such embodiments, the anti -human PD-1 antibody is nivolumab. In other such embodiments, the anti-human PD-1 antibody ispidilizumab. In other such embodiments, the anti -human PD-1 antibody is tislelizumab. In other suchembodiments, the anti-human PD-1 antibody is AMP-514. In other such embodiments, the antihuman PD-1 antibody is cemiplimab. In other such embodiments, the anti-human PD-1 antibody is dostarlimab.The Immunoconjugate of Formula (I)

[0135] Immunoconjugates useful in the present disclosure are those immuoconjugates of Formula (I):wherein Ab is an antibody that binds to Trop-2; and and each n is an integer from 1 to 10, and the DAR is 0.1 to 10.

[0136] In a class of this embodiment, the Ab is linked via one or more thiol group(s) to form the conjugate.

[0137] In certain embodiments, immunoconjugates useful in the present disclosure are those Immunoconjugates of Formula (I):wherein each n is an integer from 1 to 10 and the DAR is 0. 1 to 10; andAb is an antibody that binds to Trop-2 comprising:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(li) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0138] In certain embodiments, immunoconjugates useful in the present disclosure are those Immunoconjugates of Formula (I):wherein each n is an integer from 1 to 10, and the DAR is 0.1 to 10; andAb is an antibody that binds to Trop-2 comprising:(i) a heavy chain variable region having the amino acid sequence of SEQ ID No.: 37; and(ii) a light chain variable region having the amino acid sequence of SEQ ID No.:38.

[0139] In certain embodiments, immunoconjugates useful in the present disclosure are those Immuoconj gates of Formula (I):wherein each n is integer from 1 to 10, and the DAR is 0. 1 to 8; andAb is an antibody that binds to Trop-2 comprising:(i) a heavy chain having the amino acid sequence of SEQ ID No. : 35; and(ii) a light chain having the amino acid sequence of SEQ ID No. : 36.

[0140] In preferred embodiments, the Immunoconjugate of Formula (I) is Immunoconjugate A, which is described in US Patent Publication No. 20200347075. Immunoconjugate A is an Immunoconjugate of Formula (I):wherein each n is an integer 1 to 8, and the DAR is 0. 1 to 8; andAb is sacituzumab.

[0141] In other preferred embodiments, a composition comprising the Immunoconjugates ofFormula (I) is administered whereinthe average n of the composition is a decimal from 0 to 8; andAb is sacituzumab.

[0142] In another embodiment of the present disclosure is a method of of treating gastroesophageal cancer in a patient, said method comprising administering to the patient:(a) an amount of an anti -human PD- 1 antibody or antigen binding fragment thereof;(b) an amount of a fluoropyrimidine; and(c) an amount of an immunoconjugate comprising an anti-Trop-2 monoclonal antibody conjugated to a linker-drug moiety of Formula (II):.(11),Wherein:' wx represents the site of attachment of the drug-linker moiety to a cysteine of the antibody; wherein the number of linker-drug moieties per antibody is from 1 to 8, and wherein the amounts administered of (a), (b), and (c) are together effective to treat gastroesophageal cancer.

[0143] In one class of this embodiment, the anti-Trop-2 monoclonal antibody comprises:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0144] In another class of this embodiment, the anti-Trop-2 monoclonal antibody comprises:(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38.

[0145] In yet another class of this embodiment, the anti-Trop-2 monoclonal antibody comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0146] In still another class of this embodiment, the anti-Trop-2 monoclonal antibody is sacituzumab and n is 1 to 8.

[0147] Another embodiment is a method of treating gastroesophageal cancer in a patient, said method comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof;(b) an amount of a fluoropyrimidine; and(c) a composition comprising Immunoconjugates of Formula (I) having a DAR:(I), wherein:Ab is an antibody that binds to Trop-2; each n is an integer from I to 10. representing the number of drug linkers bound to a particular Ab, and the DAR is the drug-antibody ratio and is an integer from 1 to 10, representing the average of n of the composition.In a class of this embodiment, the amounts of (a), (b) and (c) administered are together effective to treat gastroesophageal cancer.

[0148] In one class of this embodiment, the antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0149] In another class of this embodiment, antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38.

[0150] In yet another class of this embodiment, antibody that binds to Trop-2 comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0151] In still another class of this embodiment, antibody that binds to Trop-2 is sacituzumab and n is 1 to 8.

[0152] In one class of this embodiment, the DAR is a decimal from 1 to 8. In a subclass, the DAR is a decimal from 5 to 8. In another subclass, the DAR is a decimal from 6 to 8. In yet another subclass, the DAR is a decimal from 7 to 8. In still another subclass, the DAR is a decimal from 6 to 7.

[0153] Y et another embodiment is a method of treating gastroesophageal cancer in a patient, said method comprising administering to the patient an amount of a composition comprising an Immunoconjugate of Formula (I) having a DAR:(I), wherein:Ab is an antibody that binds to Trop-2; n is an integer from 1 to 10, representing the number of drug linkers bound to a particular Ab, and the DAR is the drug-antibody ratio and is an integer from 1 to 10, representing the average of n of the composition; separately, sequentially or simultaneously with: (a) an anti-human PD-1 antibody or antigen binding fragment thereof; and (b) a fluoropyrimdine.

[0154] In one class of this embodiment, the amounts in the composition of the (a) anti-human PD-1 antibody or antigen binding fragment thereof; (b) the fluoropyrimidine, and (c) the Immunoconjugate of Formula (I) are together effective to treat gastroesophageal cancer.

[0155] In yet another embodiment of the present disclosure is provided a method of treating gastroesophageal cancer in a patient in need thereof. In a specific embodiment, the gastroesophageal cancer is locally advanced. In a specific embodiment, the gastroesophageal cancer is metastatic.

[0156] In some embodiments of the present disclosure, the anti-Trop-2 antibody of the Immunoconjugates of Formula (I) is sacituzumab (or hRS7), which is described in US Patent Publication No. 2012 / 0237518. This antibody can also be obtained by screening through carrier design, construction of an antibody library displaying antibodies as disclosed in CN103476941 A, or can be obtained by screening a G-MAB® library of Sorrento Therapeutics, Inc.

[0157] Table 5 shows the SEQ ID NOs for the amino acid sequences of the heavy and light chain complementarity-determining regions (HCDRs and LCDRs). heavy and light chain variable domains (VH and VL), and heavy' and light chains (HC and LC) of sacituzumab.Table 5. List of sacituzumab (“Abl”) Amino Acid Sequences

[0158] In certain embodiments, the Immunoconjugate of Formula (I) comprises at least 1, 2, 3.4, 5, 6, 7. 8, 9, or 10 linker / drug moieties per antibody (i.e.. n is from 1 to 10). In certain embodiments, the Immunoconjugate of Formula (I) comprises one or more (e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2) linker / drug moieties.

[0159] In a particular embodiment, the Immunoconjugate of Formula (I) comprises from about 6 to about 8 linker / drug moieties per antibody (i.e. , n is from about 6 to about 8). In a specific embodiment, the Immunoconjugate of Formula (I) is Immunoconjugate A, and n is from 6 to 8.

[0160] The Immunoconjugates of Formula (I) comprise antibodies or fragments thereof that are specific for human Trop-2 and thus can serve as excellent targeting moieties for delivering the conjugated payloads to cells (e.g., Trop-2-positive cells). In certain embodiments, an immunoconjugate used in a treatment regimen of the present disclosure is any anti-Trop-2 immunoconjugate that is described in US Patent Publication No. 20200347075.

[0161] Compositions comprising a plurality of Immunoconjugates of Formula (I) having a DAR wherein the DAR is the drug-antibody ratio and is a decimal from 1 to 10, representing the average number of drug linkers bound to Ab may be administered as a component of the present method or may comprise part of the present pharmaceutical composition, or a component of the present kit.

[0162] In one class are compositions wherein the DAR is a decimal from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2. and from 0 to 1. In additional embodiments, are compositions wherein the DAR is a decimal from 1 to 4. 2 to 5, 3 to 6. 4 to 7, 5 to 8, 6 to 8, and 7 to 8. In other embodiments, are compositions wherein the DAR is a 6. 1, 6.2.6.3. 6.4. 6.5. 6.6. 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.Uses of the Combination Therapies of the Present DisclosureTreatment or Prevention of Gastroesophageal Cancer

[0163] The combination therapies disclosed herein are potentially useful in treating gastroesophageal cancer. The terms “cancer”, “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0164] Accordingly, in one aspect, the present disclosure relates to methods of methods for treating gastroesophageal cancer in a patient, the method comprising administering to the patient a combination therapy that comprises: (a) an anti-human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimdine; and (c) an Immunoconjugate of Formula (I, wherein the amounts administered are together effective to treat gastroesophageal cancer.

[0165] In a specific embodiment, the amount administered is effective to treat gastroesophageal cancer in a human patient. In another specific embodiment, the amount administered is effective to inhibit cancer cell replication or cancer cell metastasis in the patient.

[0166] In one embodiment, the gastroesophageal cancer is relapsed. In another embodiment, the gastroesophageal cancer is refractory. In yet another embodiment, the gastroesophageal cancer is relapsed and refractory.

[0167] In one embodiment, the patient has previously received treatment for the gastroesophageal cancer. In another embodiment, the patient has not previously received treatment for cancer.

[0168] In one embodiment, the patient has previously received surgical treatment for the gastroesophageal cancer.

[0169] In one embodiment, the patient has previously received systemic treatment for the gastroesophageal cancer. In another embodiment, the patient has not previously received systemic treatment for the gastroesophageal cancer.

[0170] In one embodiment, the patient has previously received radiation therapy for the gastroesophageal cancer. In another embodiment, the patient has not previously received radiation therapy for the gastroesophageal cancer.

[0171] The compositions, methods, kits, and uses provided herein are useful for the treatment of gastroesophageal cancer.

[0172] The term "cancerous cell" as used herein, includes a cell afflicted by any one of the above-identified conditions.

[0173] In particular embodiments, the gastroesophageal cancer is classified as stage 111 cancer or stage IV cancer. In some instances of these embodiments, the gastroesophageal cancer is not surgically resectable.ADMINISTRATION AND DOSAGE

[0174] The present disclosure relates to methods of treating gastroesophageal cancer, said method comprising administering to a patient in need thereof a combination therapy that comprises: (a) an anti -human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimidine; and (c) an Immunoconjugate of Formula (I), wherein the amounts administered are together effective to treat or prevent the gastroesophageal cancer. In one embodiment of this method, the patient is a human patient.

[0175] The anti-human PD-1 antibody or antigen binding fragment thereof, the fluoropyrimidine, and the Immunoconjugate of Formula (I), will each (with a pharmaceutically acceptable carrier or excipient(s)). t pically be formulated into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients may be chosen for a particular function that they may serve in the composition. In embodiments, the anti -human PD-1 antibody or antigen binding fragment thereof, 5-FU, capecitabine. and the Immunoconjugate of Formula (1) may be formulated into a dosage form that allows for systemic use, z.e., distribution throughout the body of the patient; examples of such systemic administration include oral administration, intravenous administration, and subcutaneous administration. In additional embodiments, the the anti -human PD-1 antibody or antigen binding fragment thereof, the fluoropyrimidine, and the Immunoconjugate of Formula (I) may be formulated into a dosage form that allows for targeted or isolated use, i.e., administration of the the anti -human PD-1 antibody or antigen binding fragment thereof, the fluoropyrimidine, and the Immunoconjugate of Formula (I) only to the portion of the patient’s body to be treated; examples of such targeted administration include intratumoral injection.

[0176] In some embodiments, at least one of the therapeutic agents (the anti-human PD-1 antibody or antigen binding fragment thereof, the fluoropyrimidine, and the Immunoconjugate of Formula (I)) in the combination therapy is administered using the same dosage regimen (dose,frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and / or shorter treatment duration.

[0177] In embodiments of the compositions, methods, kits, and uses disclosed herein, the the anti -human PD-1 antibody or antigen binding fragment thereof is administered by intravenous infusion or subcutaneous injection, and the Immunoconjugate of Formula (I) is administered by intravenous infusion or subcutaneous injection. In specific embodiments, the anti -human PD-1 antibody or antigen binding fragment thereof, and the Immunoconjugate of Formula (I) are each administered by intravenous infusion.

[0178] When administering a combination therapy of the present disclosure to a patient, the agents comprising the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various agents in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, the anti-human PD-1 antibody or antigen binding fragment thereof may be present in fixed amounts (dosage amounts) in a single dosage unit.

[0179] In one embodiment, the Immunoconjugate of Formula (I) is administered during a time when the rest of the components of the combination therapy exert their prophylactic or therapeutic effect, or vice versa.

[0180] In another embodiment, the anti -human PD-1 antibody or antigen binding fragment thereof; the fluoropynmidine; and the Immunoconjugate of Formula (1) are administered in doses commonly employed when such agents are used as monotherapy for treating cancer.

[0181] In another embodiment, the anti -human PD-1 antibody or antigen binding fragment thereof; the fluoropyrimidine; and the Immunoconjugate of Formula (I) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating cancer.

[0182] In still another embodiment, the anti-human PD-1 antibody or antigen binding fragment thereof; the fluoropyrimidine; and the Immunoconjugate of Formula (I) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating cancer.

[0183] The anti -human PD-1 antibody or antigen binding fragment thereof; the fluoropyrimidine,; and the Immunoconjugate of Formula (I) can act additively or synergistically.A synergistic combination may allow the use of lower dosages of one, two or three of these agents, and / or less frequent administration of one, two or three of these agents. A lower dosage or less frequent administration of these agents may lower the toxicity of therapy without reducing the efficacy of therapy.

[0184] In one embodiment, the administration of anti -human PD-1 antibody or antigen binding fragment thereof; the fluoropyrimidine; and the Immunoconjugate of Formula (I) may inhibit the resistance of cancer to any one or more of these agents.

[0185] In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient shows no symptoms of the diseases or disorders. In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient is cured of the diseases or disorders. In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient shows resistance to the therapy. In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient shows side effects that would require discontinuation of the therapy.

[0186] In some embodiments, the patient is fasting for at least 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours before one or more components of a combination therapy is administered. In some embodiments, the patient needs to fast for at least 1 hour, 2 hours. 3 hours, 4 hours, 6 hours, 8 hours, 12 hours after one or more components of a combination therapy is administered.

[0187] A combination therapy of the present disclosure may be used prior to or following surgery to remove a tumor and may be used prior to, during, or after radiation treatment.

[0188] In some embodiments, a combination therapy of the present disclosure is administered to a patient who has not previously been treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naive. In other embodiments, the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with the biotherapeutic or chemotherapeutic agent, i.e.. is treatment-experienced.

[0189] Products provided as therapeutic combinations may include a composition comprising an anti -human PD-1 antibody or antigen binding fragment thereof; a composition comprising a fluoropyrimidine, and a composition comprising an Immunoconjugate of Formula (I) in separate form, e.g., in the form of a kit or in any form designed to enable separate administration either concurrently or on separate dosing schedules.

[0190] In some embodiments, the fluropyrimidine is 5-FU, and is administered intravenously, on a weekly, biweekly, triweekly, every 4 weeks, every 5 weeks, every 6 weeks, monthly,bimonthly. or quarterly basis at about 10, about 20, about 50. about 80. about 100. or about 200 mg / m2.

[0191] In some specific methods, the dose of 5-FU is from about 10 mg / m2to about 200 mg / m2, from about 25 mg / m2to about 200 mg / m2, from about 100 mg / m2to about 3000 mg / m2, from about 200 mg / m2to about 3000 mg / m2, from about 400 mg / m2to about 3000 mg / m2. In other specific embodiments, 5-FU is provided in 2 doses - a first dose administered via bolus injection and a second dose administered as a continuous infusion. In some embodiments the bolus dose is from about 100 mg / m2to about 600 mg / m2, from about 200 mg / m2to about 500 mg / m2. and from about 300 mg / m2to about 400 mg / m2. In some embodiments, the dose administered via continuous infusion is from about 1500 mg / m2to about 3000 mg / m2. In some embodiments, the bolus dose is about 100 mg / m2, about 200 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, and about 600 mg / m2, In a specific embodiment, 5-FU is administered in a bolus dose of 400 mg / m2, followed by a continuous infusion at a dose of 2400 mg / m2.

[0192] In another embodiment, the 5-FU is administered intravenously at a bolus dose of from about 100 to 3000 mg / m2. In certain embodiments, 5-FU is administered intravenously as a bolus dose is from about 100 mg / m2to about 600 mg / m2, from about 200 mg / m2to about 500 mg / m2, and from about 300 mg / m2to about 400 mg / m2. In a specific embodiments, 5-FU is administered intravenously at a bolus dose of about 100 mg / m2, about 200 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, or about 600 mg / m2. In a specific embodiment, 5-FU is administered intravenously at a bolus dose of 400 mg / m2.

[0193] In another embodiment, the 5-FU is administered intravenously at a continuous dose of from about 100 to 3000 mg / m2. In certain embodiments, 5-FU is administered intravenously as a continuous dose is from about 200 mg / m2to about 2000 mg / m2, and from about 300 mg / m2to about 1500 mg / m2. In a specific embodiments, 5-FU is administered intravenously at a dose of about 1000 mg / m2, about 1250 mg / m2, about 1500 mg / m2, about 1750 mg / m2, about 2000 mg / m2, about 2100 mg / m2, about 2200 mg / m2, about 2300 mg / m2, about 2400 mg / m2, about 2500 mg / m2. about 2600 mg / m2. about 2700 mg / m2, about 2800 mg / m2, about 2900 mg / m2, or about 3000 mg / m2. In a specific embodiment, 5-FU is administered intravenously at a continuous dose of 2400 mg / m2.

[0194] In another embodiments, 5-FU is provided in 2 doses - a first dose administered via bolus injection, followed by. or simultaneously with, a second dose administered as a continuous infusion.

[0195] In a specific embodiment, 5-FU is administered as a bolus dose of 400 mg / m2followed by a continuous dose of 2400 mg / m2.

[0196] In certain embodiment of the methods, compositions, kits and uses described herein, the 5-FU is administered to a human patient on day 1 of a 2-week cycle.

[0197] In a specific embodiment of the methods, compositions, kits and uses described herein, 5-FU is administered to a human patient as a bolus dose of 400 mg / m2followed by a continuous dose of 2400 mg / m2on day 1 of a 2-week cycle.

[0198] In another specific embodiment of the methods, compositions, kits and uses described herein, 5-FU and is administered to a human patient at a dose 80 mg / m2on days 1, 8 and 15 of a 4-week cycle.

[0199] In some embodiments, the 5-FU is administered by IV infusion.

[0200] In some embodiments, the fluoropyrimidine is capecitabine, and is administered intravenously, on a weekly, biweekly, triweekly, every 4 weeks, every 5 weeks, every 6 weeks, monthly, bimonthly, or quarterly basis at about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, or about 1500 mg / m2.

[0201] In some specific methods, the dose of capecitabine is from about 500 to about 1500 mg / m2, from about 750 mg / m2to about 1250 mg / m2, and from about 900 to about 1000 mg / m2. In a specific embodiment, capecitabine is administered at a dose of 1000 mg / m2.

[0202] In another embodiment, the capecitabine is administered orally at a dose of from about 500 to about 1500 mg / m2. In certain embodiments, capecitabine is administered orally at a dose from about 750 mg / m2to about 1250 mg / m2, and from about 900 mg / m2to about 1000 mg / m2. In a specific embodiment, capecitabine is administered orally at a dose of 1000 mg / m2.

[0203] In certain embodiment of the methods, compositions, kits and uses described herein, the capecitabine is administered to a human patient on days 1-14 of a 3-week cycle.

[0204] In a specific embodiment of the methods, compositions, kits and uses described herein, capecitabine is administered to a human patient at an oral dose of 1000 mg / m2, twice daily, on days 1-14 of a 3-week cycle.

[0205] In some embodiments, the capecitabine is administered orally.

[0206] In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is administered subcutaneously or intravenously, on a weekly, biweekly, triweekly, every’ 4 weeks, every' 5 weeks, every' 6 weeks, monthly, bimonthly, or quarterly basis at about 10, about 20, about 50, about 80, about 100, about 200, about 300, about 400, about 500, about 1000 or about 2500 mg / patient.

[0207] In some specific methods, the dose of the anti-PD-1 antibody (e.g, anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is from about 0.01 mg / kg to about 50 mg / kg, from about 0.05 mg / kg to about 25 mg / kg, from about 0. 1 mg / kg to about 10 mg / kg, fromabout 0.2 mg / kg to about 9 mg / kg. from about 0.3 mg / kg to about 8 mg / kg. from about 0.4 mg / kg to about 7 mg / kg, from about 0.5 mg / kg to about 6 mg / kg, from about 0.6 mg / kg to about 5 mg / kg, from about 0.7 mg / kg to about 4 mg / kg, from about 0.8 mg / kg to about 3 mg / kg, from about 0.9 mg / kg to about 2 mg / kg. from about 1.0 mg / kg to about 1.5 mg / kg. from about 1.0 mg / kg to about 2.0 mg / kg. from about 1.0 mg / kg to about 3.0 mg / kg. from about 3.0 mg / kg to about 5.0 mg / kg, or from about 2.0 mg / kg to about 4.0 mg / kg.

[0208] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is from about 10 mg to about 500 mg, from about 25 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 150 mg to about 250 mg, from about 175 mg to about 250 mg, from about 200 mg to about 250 mg, from about 300 mg to about 400 mg, from about 350 mg to about 450 mg, from about 150 mg to about 240 mg, from about 175 mg to about 240 mg, or from about 200 mg to about 240 mg. In some embodiments, the dose of the anti-PD-1 antibody (e.g, anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. In a specific embodiment, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is about 400 mg.

[0209] In another embodiment, the PD-1 antagonist in the therapy is the anti-PD-1 antibody pembrolizumab, or a pembrolizumab variant, which is administered in a liquid medicament at a dose selected from the group consisting of 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, or 10 mg / kg Q3W. In other embodiments, the PD-1 antagonist in the therapy is pembrolizumab, or a pembrolizumab variant, which is administered in a liquid medicament at a flat dose such as 200 mg Q3W, or 400 mg Q6W.

[0210] In some embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 antibody (e.g. anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg pembrolizumab once every7three or six weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every' three weeks. In a specific embodiment, the human patient is administered 2 mg / kg pembrolizumab once every three weeks. In another specific embodiment, the human patient is administered 400 mg pembrolizumab once every' six weeks.

[0211] In certain embodiments of the methods, compositions, kits and uses described herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab and the human patient is administered 200 mg pembrolizumab once every three weeks.

[0212] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab and the human patient is administered 400 mg pembrolizumab once every six weeks.

[0213] In some embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab. and the human patient is administered about 200 mg, about 240 mg, about 400 mg. about 480 mg, or about 2 mg / kg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every' six weeks. In one embodiment, the human patient is administered about 400 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered 480 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered 2 mg / kg pembrolizumab once every' six weeks.

[0214] In some embodiments, pembrolizumab is provided as a liquid medicament that comprises 25 mg / ml pembrolizumab, 7% (w / v) sucrose, 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer pH 5.5. In other embodiments, pembrolizumab is provided as a liquid medicament that comprises about 125 to about 200 mg / mL of pembrolizumab, or an antigen binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof; about 7% (w / v) sucrose; and about 0.02 % (w / v) polysorbate 80.

[0215] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg pembrolizumab once every' three weeks. In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 400 mg pembrolizumab once every six weeks.

[0216] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes. In other embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0217] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient is from 320 mg to 420 mg, from 340 mg to 420 mg, from 345 mg to 415 mg, from 350 mg to 410 mg, from 355 mg to 405 mg, from 360 mg to 400 mg, from 365 mg to 395 mg, from 370 mg to 390 mg, from 375 mg to 385 mg, or from 379 mg to 381 mg. In one embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 280 mg to about 450 mg. In a further embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 300 mg to about 450 mg. In yet a further embodiment, pembrolizumab is administered subcutaneously at a dose of about 320 mg to about 450 mg.

[0218] In certain embodiments, pembrolizumab is administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 130 mg / mL. In certain embodiments, pembrolizumab administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 165 mg / mL. In certain embodiments, pembrolizumab is administered subcutaneously to the patient in two injections. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in one pre-filled syringe. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in two pre-filled syringes.

[0219] In one embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection at a dose that is at least about 1.6 times higher than a 200 mg or a 2 mg / kg dose. In one embodiment, the subcutaneous dose is administered once every' three weeks. In one embodiment, the subcutaneous dose is administered once every six weeks. In one embodiment, the bioavailabihty of the pembrolizumab subcutaneous dose is at least 63%. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 64%. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 66%.

[0220] In other embodiments of the methods, compositions, kits, and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab, the human patient is administered about 240 mg or about 3 mg / kg nivolumab, and nivolumab is administered once every two weeks. In one specific embodiment, the human patient is administered about 240 mg nivolumab once every two weeks. In one specific embodiment, the human patient is administered about 3 mg / kg nivolumab once every’ two weeks. In other embodiments of the methods, compositions, kits and uses described herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab, the human patient is administered about 480 mg nivolumab once every four weeks.

[0221] The Immunoconjugates of Formula (I), and a pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients may be chosen for a particular function. In embodiments, the Immunoconjugate of Formula (I) may be formulated into a dosage form that allows for systemic use, i.e., distribution of Immunoconjugate of Formula (I) throughout the body of the patient; examples of such systemic administration include subcutaneous administration and intravenous administration. In additional embodiments, the Immunoconjugate of Formula (I) may be formulated into a dosage form that allows for targeted or isolated use, i.e., administration of the Immunoconjugate of Formula (I) only to the portion of the patient’s body to be treated; examples of such targeted administration include intratumoral injection. In certain embodiments, the doses are provided intravenously or subcutaneously. A total dose for a treatment interval is generally at least 0.25 mg / kg body weight, more generally at least 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.00 mg / kg,2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.00 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg. 5.25 mg / kg, 5.50 mg / kg. 5.75 mg / kg, 6.00 mg / kg, 6.25 mg / kg, 6.50 mg / kg, 6.75 mg / kg, and 7.00 mg / kg. In other embodiments, Immunoconjugates of Formula (I) are administered subcutaneously or intravenously, on a weekly, biweekly, “every' 3 weeks,” “every' 4 weeks,” monthly, “every 6 weeks,” bimonthly, or quarterly basis at 2.00 mg / kg, 2.25 mg / kg. 2.50 mg / kg, 2.75 mg / kg, 3.00 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg. 4.00 mg / kg, 4.25 mg / kg. 4.50 mg / kg, 4.75 mg / kg. 5.00 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg, or 6.00 mg / kg. In a specific embodiments, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg,4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg, every 2 weeks. In specific embodiments, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg. 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg,5.25 mg / kg, or 5.50 mg / kg, every 2 weeks, every 3 weeks, every 4 weeks or every 6 weeks. In a specific embodiments, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 2 weeks, every 3 weeks, every 4 weeks, or every 6 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 2 weeks. In another specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 2 weeks, every 3 weeks, every 4 weeks, or every' 6 yveeks. In another specific embodiment, theImmunoconjugate of Formula (1) is administered at 4.00 mg / kg every 2 weeks. In another specific embodiments, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 2 weeks, every' 3 weeks, every' 4 weeks, or every' 6 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 2 weeks.

[0222] In one embodiment, in the combination therapies of the present disclosure, an Immunoconjugate of Formula (I) is administered at a dose of 0.25 mg / kg to 10 mg / kg. In another embodiment, an Immunoconjugate of Formula (I) is administered at a dose of 1 mg / kg to 6 mg / kg. In some embodiments, the Immunoconjugate of Formula (I) may 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 as a single dose, or in any combination thereof for multiple doses. In certain embodiments, the Immunoconjugate of Formula (I) is administered at a dose of 4, 4.25,4.5, 4.75, 5, 5.25, 5.5, 5.75, or 6 mg / kg. In other embodiments, the Immunoconjugate of Formula (I) is administered at a dose of 3.5, 3.75. 4.0, 4.25, 4.5, 4.75, 5, 5.25, or 5.5 mg / kg. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of about 3.0 mg / kg. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of about 4.0 mg / kg. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of about 5.0 mg / kg.

[0223] 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 one specific embodiment, the Immunoconjugate of Formula (I) is administered in two-week cycles. In another specific embodiment, the Immunoconjugate of Formula (I) is administered in three-week cycles. In another specific embodiment, the Immunoconjugate of Formula (I) is administered in four- week cycles. In still another specific embodiment, the Immunoconjugate of Formula (1) is administered in six-week cycles. The treatment regimen may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more cycles of administration (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the Immunoconjugate of Formula (I) is administered on one, two, three, four, five, six, or seven days of the cycle. The days of administration may be consecutive or may have one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof, between them. In particular embodiments, the Immunoconjugate of Formula (I) is administered on Day 1 only of each cycle (e.g., a two-week cycle). In particular embodiments, the Immunoconjugate of Formula (I) is administered on Days 1 and 8 of each cycle (e.g., a three-week cycle). In particular embodiments, the Immunoconjugate of Formula (I) is administered on Days 1, 8, and 15 of each cycle (e.g., a four- week cycle or a six-week cycle). In a specific embodiment, the Immunoconjugate of Formula (I)is administered on the first day of a 2-week cycle. In another specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 3-week cycle. In another specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 4- week cycle. In another embodiment, the Immunoconjugate of Formula (I) is administered on days 1. 15. and 29 of a six-week cycle. In other embodiments, the Immunoconjugate of Formula (I) is administered at 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg, every’ 2 weeks, every' 3 weeks, every' 4 weeks, or every 6 weeks. In a specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 2 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 3 weeks. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every' 2 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 3 weeks. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 2 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 3 weeks.

[0224] The Immunoconjugate of Formula (I) may be administered initially according to a dosage regimen described herein and subsequently according to a different dosage regimen described herein (e.g., to increase or decrease the frequency of administration). In some embodiments, the Immunoconjugate of Formula (I) is administered weekly during the first 1, 2, 3, 4, 5, or 6, 7, 8, 9, 10, 11, or 12 weeks, then every 3 weeks thereafter. In certain embodiments, the Immunoconjugate of Formula (I) is administered weekly during the first 2, 3, 4, 5, or 6 weeks, and then every 3 weeks. In certain embodiments, the Immunoconjugate of Formula (I) is administered weekly during the first 1, 2, 3. 4. 5, or 6 weeks, and then every 4 weeks.

[0225] The Immunoconjugate of Formula (I) may be administered via parenteral administration. As used herein, “parenteral administration” of an immunoconjugate includes any route of administration characterized by physical breaching of a tissue of a patient and administration of the immunoconjugate through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ.Parenteral administration thus includes, but is not limited to, administration of an immunoconjugate by injection of the immunoconjugate, by application of the immunoconjugate through a surgical incision, by 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, intrastemal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, andintrasynovial injection or infusions; and kidney dialytic infusion techniques. In a specific embodiment, the Immunoconjugate of Formula (I) is administered intravenously. In another specific embodiment the Immunoconjugate of Formula (I) is administered subcutaneously. Regional perfusion is also contemplated. In some embodiments, the infusion may be administered by one route (e.g., intravenously) for initial doses and then be administered by another route for subsequent doses.

[0226] In certain embodiments, the Immunoconjugate of Formula (I) is administered by intravenous (IV) infusion. The infusion may take place 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 minutes). In particular embodiments, the infusion time is 30 minutes. Infusion times may be extended as necessary to accommodate individual patient tolerance of treatment. Where the immunoconjugate is administered in more than one dose, 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.

[0227] In certain embodiments, the Immunoconjugate of Formula (I) and the anti -human PD-1 antibody or antigen binding fragment thereof are administered in six-week cycles, whrerein the Immunoconjugate of Formula (I) is administered on days 1. 15, and 29 of each six -week cycle, and the anti -human PD-1 antibody or antigen binding fragment thereof is administered on day 1 of each six-week cycle.

[0228] In certain embodiments, the anti -human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400 mg, and the Immunoconjugate of Formula (I) is administered at a dose of about 3 mg / kg to about 4 mg / kg.

[0229] In one embodiment, provided is a method treating gastroesophageal cancer, said method comprising administering to a patient in need thereof a combination therapy that comprises: (a) an anti -human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimidine; and (c) an Immunoconjugate of Formula (I); wherein the an anti-human PD-1 antibody or antigen binding fragment thereof is administered on day 1 of a six-week cycle, and the Immunoconjugate of Formula (I) is administered on days 1, 15, and 29 of a six-week cycle (“Combination Regimen 1”).

[0230] In a specific embodiment, for Combination Regimen 1, the anti -human PD-1 antibody or antigen binding fragment thereof is administered at a single dose of 400 mg on day 1 of each six-week cycle; the fluoropyrimidine is capecitabine, and is administered twice daily at a dose of 1000 mg / m2(per administration) on days 1-14 and days 22-35 of a six week cycle; and theImmunoconjugate of Formula (1) is administered at a dose of 4 mg / kg on each of days 1. 15. and 29 of each 6-week cycle.

[0231] In another specific embodiment, for Combination Regimen 1, the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a single dose of 400 mg on day 1 of each six-week cycle; the fluoropyrimidine is capecitabine. and is administered twice daily at a dose of 1000 mg / m2(per administration) on days 1-14 and days 22-35 of a six week cycle; and the Immunoconjugate of Formula (I) is administered at a dose of 3 mg / kg on each of days 1, 15, and 29 of each 6-week cycle.

[0232] In another specific embodiment, for Combination Regimen 1, the anti -human PD-1 antibody or antigen binding fragment thereof is administered at a single dose of 400 mg on day 1 of each six-week cycle; the fluoropyrimidine is 5-FU, and is administered at a dose of 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) on days 1, 15, and 29 of a six week cycle; and the Immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg on each of days 1. 15. and 29 of each 6-week cycle.

[0233] In another specific embodiment, for Combination Regimen 1, the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a single dose of 400 mg on day 1 of each six-week cycle; the fluoropyrimidine is 5-FU, and is administered at a dose of 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) on days 1, 15, and 29 of a six week cycle: and the Immunoconjugate of Formula (I) is administered at a dose of 3 mg / kg on each of days 1, 15, and 29 of each 6-week cycle.

[0234] In a specific embodiment, for Combination Regimen 1, the anti-human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

[0235] In a specific embodiment, for Combination Regimen 1, the Immunoconjugate of Formula (I) is Immunconjugate A.

[0236] In another embodiment, Combination Regimen 1 is administered in from 1 to 18 cycles.

[0237] In a specific embodiment, Combination Regimen 1 is administered to a patient to treat metastatic or locally advanced gastroesophageal cancer.

[0238] In a specific embodiment. Combination Regimen 1 is administered to a patient to treat metastatic or locally advanced gastroesophageal cancer that has been previously treated.

[0239] In some embodiments, at least one of the therapeutic agents (the an anti -human PD-1 antibody or antigen binding fragment thereof, the fluoropyrimidine, and the Immunoconjugate of Formula (I)) in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition. In other embodiments, the patient receives a lowertotal amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g, smaller doses, less frequent doses, and / or shorter treatment duration.

[0240] In some embodiments, at least one of the therapeutic agents (the anti -human PD-1 antibody or antigen binding fragment thereof, the fluoropyrimidine, and the Immunoconjugate of Formula (I)) in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g, smaller doses, less frequent doses, and / or shorter treatment duration.Additional Therapeutic Agents

[0241] The therapeutic combinations, and combination therapies disclosed herein may be used in combination with one or more other additional therapeutic agents, including but not limited to, additional anti-cancer agents, wherein said additional anti-cancer agents are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g.. cellular proliferative disorders). In one embodiment, a therapeutic combination disclosed herein is combined with one or more additional anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of cancer. Such additional therepeutic agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a combination therapy of the present disclosure.

[0242] Accordingly, in one aspect, the present disclosure provides pharmaceutical compositions comprising: (a) an anti-human PD-1 antibody or antigen binding fragment thereof: (b) a fluoropyrimidine; (c) an Immunoconjugate of Formula (I), and (d) a pharmaceutically acceptable carrier. In one embodiment, the amounts of (a), (b), and (c) present in the pharmaceutical composition are together effective to treat cancer.

[0243] In one embodiment, provided herein is a pharmaceutical composition comprising:(a) an anti -human PD-1 antibody or antigen binding fragment thereof;(b) a fluoropyrimidine;(c) a plurality’ of Immunoconj ugates of F ormula (I) :(I), wherein:Ab is an antibody that binds to Trop-2; andeach n is an integer from 1 to 10, and the DAR represents the average number of linker / payload moi eties joined to each antibody for the plurality of Immunoconjugates of Formula (I); and(d) a pharmaceutically acceptable carrier.

[0244] In one class of this embodiment, the amounts of (a), (b), and (c) present in the composition are together effective to treat gastroesophageal cancer.

[0245] In a specific embodiment, for the pharmaceutical composition, the antibody that binds to Trop-2 is sacituzumab.

[0246] In another specific embodiment, for the pharmaceutical composition, the anti-human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

[0247] In a specific embodiment, for the pharmaceutical composition, the fluoropyrimidine is 5-FU or capecitabine.

[0248] Also provided herein are combination therapies comprising administering to a patient: a pharmaceutical composition comprising: (a) an anti -human PD-1 antibody or antigen binding fragment thereof; (b) a fluoropyrimidine; (c) an Immunoconjugate of Formula (I):wherein:Ab is an antibody that binds to Trop-2; and each n is from 1 to 10 and the DAR is from x to y; and (d) an additional therapeutic agent.

[0249] In one embodiment, the amounts administered of (a), (b), (c), and (d) are together effective to treat cancer.

[0250] In certain embodiments, the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

[0251] In certain embodmiments, the fluoropyrimidine is 5-FU.

[0252] In certain embodmiments, the fluoropyrimidine is capecitabine.

[0253] In certain embodiments, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0254] When a combination therapy of the instant disclosure is co-administered with an additional therapeutic agent, the additional therapeutic agent can be administered in repeated cycles of I, 2, 3, 4. 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15. or 16 weeks. In one specific embodiment, the additional therapeutic agent is administered in three-week cycles. In another specific embodiment, the additional therapeutic agent is administered in four-week cycles. In still another specific embodiment, the additional therapeutic agent is administered in six-week cycles. In certain embodiments, the additional therapeutic agent is administered on one, two, three, four, five, six, or seven days of the cycle. The days of administration may be consecutive or may have one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof, between them. In particular embodiments, the additional therapeutic agent is administered on Day 1 only of each cycle (e.g. , a two- week cycle, a three-week cycle, or a 4- week cycle). In particular embodiments, the additional therapeutic agent is administered on Day 1 of a three-week cycle. In another specific embodiment, the additional therapeutic agent is administered on the first day of a 4-week cycle. In particular embodiments, the additional therapeutic agent is administered on Days 1, 8, and 15 of a three-week cycle.

[0255] The additional therapeutic agent(s) may be one or more agents selected from the group consisting of STING agonists, poly ADP ribose polymerase (PARP) inhibitors, mitogen- activated protein kinase (MEK) inhibitors, cyclin-dependent kinase (CDK) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, tryptophan 2,3 -dioxygenase (TDO) selective inhibitors, anti-viral compounds, antigens, adjuvants, anti-cancer agents, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alky lating agents,anti-tumor antibiotics, anti-metabolites, retinoids, and immunomodulatory agents including but not limited to anti-cancer vaccines. It will be understood the descriptions of the above additional therepeutic agents may be overlapping. It will also be understood that the treatment combinations are subject to optimization, and it is understood that the best combination to use of the (a) antihuman PD-1 antibody or antigen binding fragment thereof; (b) the fluoropyrimidine; (c) Immunoconjugate of Formula (I); and (d) one or more additional therapeutic agents, will be determined based on the individual patient needs.

[0256] When the therapeutic combination disclosed herein is used contemporaneously with one or more additional therapeutic agents, the active components of the therapeutic combination may be administered either simultaneously with, or before or after, one or more additional therapeutic agent(s). The active components of the therapeutic combination may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).

[0257] The weight ratio of the active components of the combination therapies of the instant disclosure may be varied and will depend upon the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. The the combination therapies of the instant disclosure will generally include a therapeutically effective dose of each active component. In such combinations, the active components of the combination therapies of the instant disclosure may be administered separately or in conjunction. In addition, the administration of one component may be prior to, concurrent with, or subsequent to the administration of additional therapeutic agent(s). In one embodiment, the Combinations therapies of the instant disclosure will comprise a dose of each active component, such the amounts administered are together effective to treat cancer.

[0258] In one embodiment, this disclosure provides: (a) an anti-human PD-1 antibody or antigen binding fragment thereof: (b) a fluoropyrimidine; (c) an Immunoconjugate of Formula (I) or pharmaceutically acceptable salt thereof; and (d) at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of gastroesophageal cancer.

[0259] Anti-viral compounds that may be used in combination with the therapeutic combinations disclosed herein include hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors. HCV polymerase inhibitors. HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.

[0260] Antigens and adjuvants that may be used in combination with the therapeutic combinations disclosed herein include B7 costimulatory molecule, interleukin-2, interferon- / ,GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim, levamisol, vaccinia virus, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surface active substances such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants, such as aluminum hydroxide or aluminum phosphate, can be added to increase the ability of the vaccine to trigger, enhance, or prolong an immune response. Additional materials, such as cytokines, chemokines, and bacterial nucleic acid sequences, like CpG, a toll-like receptor (TLR) 9 agonist as well as additional agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR7 / 8, TLR9, and TLR 8 / 9 including lipoprotein, lipopolysaccharide (LPS), monophosphoryllipid A, lipoteichoic acid, imiquimod, resiquimod, and in addition retinoic acid-inducible gene I (RIG-I) agonists such as poly I:C, used separately or in combination are also potential adjuvants.

[0261] Chemotherapeutic agents that may be used in combination with the therapeutic combinations disclosed herein include abiraterone acetate, altretamine, anhydrovinblastine, aroplatin, asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase). auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4- methoxyphenyljbenzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L- valyl-L-prolyl- I -Lproline-t-but lamide (SEQ ID NO: 45), cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'deoxy-8'-norvin-caleukoblastine, dinaciclib, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5 -fluorouracil, finasteride, flutamide, hy droxy urea and hydroxyurea and taxanes, ifosfamide, liarozole, lonidamine, lomustine, MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin. sertenef. streptozocin, mitomycin, methotrexate, taxanes, nilutamide, olaparib, onapristone, oxaliplatin, prednimustine, procarbazine, RPR109881, selumetinib, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine, and pharmaceutically acceptable salts thereof.

[0262] Examples of vascular endothelial grow th factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark AVASTIN by Genentech / Roche), axitinib (described in PCT International Patent Publication No. W001 / 002369), Brivanib Alaninate ((S)-((R)- 1 -(4-(4-Fluoro-2-methy 1- lH-indol-5-yloxy)-5-methy lpyrrolo[2, 1 - f][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide, and described in International Patent Publication No. W002 / 068470),pasireotide (also known as SO 230, and described in International Patent Publication No. W002 / 010192), and sorafenib.

[0263] Examples of topoisomerase II inhibitors, include but are not limited to, etoposide, and teniposide.

[0264] Examples of alkylating agents, include but are not limited to, 5-azacytidine. decitabine. temozolomide, dactinomycin (also known as actinomycin-D, melphalan, altretamine, carmustine, bendamustine, busulfan, platinum-based chemotherapeutic agents (e.g., aroplatin, cisplatin, carboplatin, and oxaliplatin), lomustine, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, streptozocin, thiotepa, and pharmaceutically acceptable salts thereof. In one embodiment, the additional thereapeutic agent is a platinum-based chemotherapeutic agent. In a specific embodiment, the additional therapeutic agent is cisplatin. In another specific embodiment, the additional therapeutic agent is carboplatin. In specific embodiments, when co-administered with carboplatin. the dose of carboplatin is from about AUC 1 mg / mL / min to AUC 10 mg / mL / min, administered intravenously. In a specific embodiment, when co-administered with carboplatin, the dose of carboplatin is AUC 5 mg / mL / min, administered intravenously. In other embodiments, when co-administered with cisplatin, the dose of cisplatin is from about 10 mg / m2to 150 mg / m2, administered intravenously. In a specific embodiment, when co-administered with cisplatin, the dose of cisplatin is 75 mg / m2, administered intravenously.

[0265] Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin, bleomycin, daunorubicin liposomal (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0266] Examples of anti-metabolites include, but are not limited to. claribine. 5-fluorouracil. 6- thioguanine, pemetrexed (sold under the tradename ALIMTA®), cytarabine (also known as arabinosylcytosine (Ara-C)), cytarabine liposomal (also know n as Liposomal Ara-C, sold under the tradename DEPOCYT™), decitabine (sold under the tradename DACOGEN®), hydroxyurea and fludarabine, floxuridine. cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin.

[0267] Examples of retinoids include, but are not limited to, alitretinoin, tretinoin, isotretinoin, and bexarotene.ADDITIONAL EMBODIMENTS

[0268] Additional embodiments of the disclosure include the compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may becombined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.Kits

[0269] The present disclosure also provides articles of manufacture, e.g, kits, comprising one or more containers (e.g., single-use or multi-use containers) containing: (a) a pharmaceutical composition of an anti -human PD-1 antibody or antigen binding fragment thereof, at a dose described herein; (b) a pharmaceutical composition of a fluoropyrimidine; (c) a pharmaceutical composition of an Immunoconjugate of Formula (I) at a dose described herein, and (d) instructions for use according to a treatment regimen described herein. The an anti-human PD-1 antibody or antigen binding fragment thereof, fluoropyrimidine, and Immunoconjugate of Formula (I), can be packaged together or separately in suitable packing such as a vial or ampule made from non-reactive glass or plastic. In one embodiment, the kit also contains a pharmaceutical composition of an additional therapeutic agent.

[0270] In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. A kit of this disclosure may be used for administration of different dosage forms, for example, oral and parenteral, for administration of the separate compositions at different dosage intervals, or for titration of the separate compositions against one another. To assist with compliance, a kit of the disclosure typically comprises directions for administration.

[0271] In one embodiment, the present disclosure provides a kit comprising:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof;(b) an amount of a fluoropyrimidine; and(c) an amount of an Immunoconjugate of Formula (I):wherein:Ab is an antibody that binds to Trop-2; and each n is an integer from 1 to 10, and the DAR is from x to y, wherein the amounts of (a), (b), and (c) present in the kit are together effective to treat gastroesophageal cancer.

[0272] In one embodiment, for a kit of the present disclosure, the fluoropyrimidine is 5-FU or capecitabine.

[0273] In another embodiment, for a kit of the present disclosure, the Immunoconjugate of Formula (I) contained in the kit is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-Trop-2 antibody (sacituzumab). and n is an integer or decimal from 1 to 10.

[0274] In another embodiment, for a kit of the present disclosure, the anti-human PD-1 antibody or antigen binding fragment thereof contained in the kit is pembrolizumab.GENERAL METHODS

[0275] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 1989 2ndEdition, 2001 3rdEdition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA. Vol. 217, Academic Press. San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0276] Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 7, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described see. e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available see. e.g., Coligan. et al. (2001) Current Protocols in Immunology. Vol. 4, John Wiley, Inc., New York).

[0277] Monoclonal, polyclonal, and humanized antibodies can be prepared {see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New Y ork, NY ;Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp. 139-243; Carpenter, et al. (2000) Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272: 10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6.329,511).

[0278] An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309- 314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15: 146- 156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. {2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).

[0279] Purification of antigen is not necessary for the generation of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce ahybridoma (see, e.g.. Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra, Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

[0280] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g.. Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice. John Wiley and Sons, Hoboken. NJ; Givan (2001) Flow Cytometry. 2nded , Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes. Inc., Eugene, OR; Sigma- Aldrich (2003) Catalogue, St. Louis, MO).

[0281] Standard methods of histology of the immune system are described (see, e.g., Muller- Harmelink (ed.) (1986) Human Thymus: Histopathology: and Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0282] Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g.. GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys. Inc., San Diego, CA); DeCypher® (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68: 177-181; von Heijne (1983) Eur. J. Biochem. 133: 17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).EXAMPLES

[0283] The following examples illustrate representative embodiments of the present disclosure and are not meant to be limiting in any way.EXAMPLE 1 Preparation of Immunoconjugate A

[0284] Immunoconjugate A can be made using the methodology described in US Patent Publication No. US Patent Publication No. 20200347075, wherein Immunoconjugate A is referred to as “BT001021.”EXAMPLE 2Study of Immunoconjugate A with Pembrolizumab and Chemotherapy in Participants with IL Locally Advanced Unresectable / Metastatic Gastroesophageal AdenocarcinomaINTRODUCTION

[0285] This study aims to establish a dose combination of Immunoconjugate A with pembrolizumab plus fluoropyrimidine chemotherapy (platinum sparing) and then evaluate the safety / efficacy of this combination in the IL treatment of participants with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinomas (including gastric adenocarcinoma. GEJ adenocarcinoma, and esophageal adenocarcinoma).HYPOTHESES, OBJECTIVES, AND ENDPOINTS

[0286] This is an estimation study, and no formal hypothesis testing will be performed.

[0287] In participants >18 years of age with a diagnosis of locally advanced or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma:STUDY DESIGNRationale for EndpointsEfficacy Endpoints

[0288] This study will use ORR based on RECIST 1.1 criteria as assessed by BICR as the primary endpoint. ORR is an acceptable measure of clinical benefit for this study that demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has an acceptable risk / benefit profile. The use of BICR and RECIST 1.1 to assess ORR is typically considered acceptable by regulatory authorities. Images will besubmited to an iCRO and read by an independent central review blinded to treatment assignment to minimize bias in the response assessments.

[0289] The secondary efficacy endpoints will include PFS and DOR per RECIST 1. 1 as assessed by BICR, and OS. These endpoints are commonly accepted endpoints by both regulatory authorities and the oncology community.

[0290] RECIST 1.1 will be used when assessing scans for efficacy measures. Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is needed to adequately represent the tumor burden.Safety Endpoints

[0291] Safety parameters frequently used for evaluating investigational-systemic anticancer treatments are included as safety endpoints including, but not limited to, the incidence of, causality, and outcome of AEs / SAEs, and changes in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 5.0.

[0292] In addition, the occurrence of DLTs during the Safety Lead-in Phase will be evaluated as one of the criteria to assess the safety profile of the investigational arm during Dose Escalation / Safety Lead-in and support continued enrollment in that arm throughout the study.Patient-reported Outcomes

[0293] Symptomatic improvement is considered a clinical benefit and accepted by health authorities as additional evidence of the risk-benefit profile of any new study intervention. In this study, HRQoL and disease-related symptoms will be investigated via the following assessment tools: EORTC QLQ-C30, and EORTC QLQ-STO22. and EQ-5D-5L questionnaires. Health utilities will be evaluated using the EQ-5D-5L PRO instrument. These measures are not pure efficacy or safety’ endpoints because they are affected by both disease progression and treatment tolerability.EORTC QLQ-C-30

[0294] EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for assessing HRQoL in oncology7studies. The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea / vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale. For the global health status or QoL and function scales, a higher value indicates a beter level of function; forsymptom scales and items, a higher value indicates increased severity of symptoms. TTD and mean change from baseline in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as tertiary objectives.EORTC QLQ-STO22

[0295] The EORTC QLQ-STO22 is a disease-specific questionnaire developed and validated to address measurements specific to gastric cancer. It is one of multiple disease-specific modules developed by the EORTC Quality of Life Group designed for use in clinical studies, to be administered in addition to the EORTC QLQ C30, to assess disease-specific treatment measurements. It contains 22 items with symptoms of dysphagia (3 items), pain or discomfort (4 items), reflux symptoms (3 items), eating restrictions (4 items), anxiety (3 items), dry mouth, hair loss, taste, and body image.EQ-5D-5L

[0296] The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will provide data to develop health utilities for use in health economic analyses [Rabin, R. and de Charro, F. 2001], The 5 health state dimensions in the EQ-5D-5L include the following: Mobility, Self-Care, Usual Activities, Pain / Discomfort, and Anxiety / Depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to / extreme problems). The EQ-5D- 5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates their general state of health at the time of the assessment. This instrument has been used extensively in cancer studies and published results from these studies support its validity and reliability.Pharmacokinetic EndpointsPharmacokinetics

[0297] To characterize the PK profile of Immunoconjugate A, and support the proposed dosing regimen, an integrated analysis of Immunoconjugate A PK data obtained in this study and from other studies may be performed to estimate PK parameters.

[0298] The PK profile of pembrolizumab when administered in combination with Immunoconjugate A will be characterized.Planned Exploratory Biomarker Research

[0299] The mechanism of action of many antitumor agents is not completely understood and much remains to be learned regarding how best to leverage new drugs in treating patients. Thus, to aid future patients, it is important to investigate the determinants of response or resistance to cancer treatments. These efforts may identify novel predictive / pharmacodynamic biomarkers and generate information that may better guide single-agent and combination therapy withantineoplastic drugs. To identify novel biomarkers, biospecimens (e.g.. blood components, tumor material, etc) will be collected to support analyses of cellular components (e.g., protein, DNA, RNA, metabolites) and other circulating molecules. Investigations may include, but are not limited to the following:Germline genetic analyses (e.g., SNP analyses, whole exome sequencing, whole genome sequencing)

[0300] This research may evaluate whether genetic variation within a clinical study population correlates with response to the treatment(s) under evaluation. If genetic variation is found to predict efficacy, the data might inform optimal use of therapies in the patient population. Furthermore, it is important to evaluate germline DNA variation across the genome to interpret tumor-specific DNA mutations.Genetic (DNA) tumor analyses

[0301] The application of new technologies, such as next generation sequencing, has provided scientists the opportunity to identify important tumor-specific DNA changes (e.g., mutations, methylation status, microsatellite instability, etc). Key molecular changes of interest to oncology drug development may also include the mutational burden of tumors and the clonality of T-cells in the tumor microenvironment. Microsatellite instability may also be evaluated as this is an important biomarker for some cancers (e.g., colorectal cancer). Genome-wide approaches may be used for this effort. Note that to understand tumor-specific mutations, it is necessary to compare the tumor genome with the germline genome. Circulating tumor DNA may also be evaluated from biospecimens (e.g., blood, urine, etc).Tumor and / or blood RNA analyses

[0302] Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue and / or in blood may be performed to define gene signatures that might correlate to clinical response to treatment with antitumor therapies. Specific gene sets (e.g., those capturing interferon-gamma transcriptional pathways) may be evaluated and new signatures may be identified. Expression of individual genes may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal profiling. Circulating tumor RNA may also be evaluated from biospecimens (e.g., blood, urine, etc).Immunohistochemical (IHC) and / or proteomic analyses using tumor

[0303] Tumor samples from this study may undergo histopathological (e.g., PD-L1 IHC), proteomic, and / or immunological analyses. These approaches could identify novel protein biomarkers that could aid in patient selection for antitumor therapy.Beginning and End-of-Study Definition

[0304] The overall study begins when the first participant (or their legally acceptable representative) provides documented informed consent. The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up. For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last.STUDY POPULATIONInclusion Criteria

[0305] An individual is eligible for inclusion in the study if the individual meets all of the following criteria:Type of Participant and Disease Characteristics1. Has histologically and / or cytologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic IL gastroesophageal adenocarcinoma (gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma).Note: Participants who are eligible for radiotherapy or neoadjuvant therapy are not eligible.2. Is not expected to require tumor resection during the treatment course.3. Has gastroesophageal adenocarcinoma that is not HER2 / neu positive.Note: A Participant with gastroesophageal adenocarcinoma that is known to be HER2 / neu positive are not eligible. If HER2 / neu status is unknown, sites should follow local standards if HER2 / neu testing is required as SOC.4. Has measurable disease per RECIST 1. 1 as determined by the local site investigator / radiology assessment and verified by BICR. A lesion(s) situated in a previously irradiated area can be considered a target lesion(s) if progression has been demonstrated and the lesion(s) is considered measurable per RECIST 1. 1 criteria.Demographics5. Is an individual of any sex / gender. at least 18 years of age inclusive, at the time of providing the informed consent.Assigned Male Sex at Birth6. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:Immunoconjugate A: 100 daysChemotherapy: 180 daysPembrolizumab: No contraception requirements• Refrains from donating spermPLUS either:• Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinentOR• Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below:Uses a penile / extemal condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method, as a condom may break or leak.Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use a penile / extemal condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.- Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.Assigned Female Sex at Birth7. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:• Is not a POCBPORIs a POCBP and:Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The participant agrees not to donate eggs (ova, oocytes) to others or freeze / store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for each study intervention is: ° Immunoconjugate A: 190 days ° Chemotherapy: 270 days ° Pembrolizumab: 120 days- The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention.- If a urine test cannot be confirmed as negative (e.g.. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention.- Medical history', menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.Informed Consent8. The participant (or legally acceptable representative) has provided documented informed consent for the study. The participant (or legally acceptable representative) may also provide consent for FBR. However, the participant may participate in the study without participating in FBRAdditional Categories9. Has provided an archival tumor tissue sample or most recently obtained core, or incisional, or excisional biopsy of a tumor lesion (not previously irradiated) obtained as part of clinical practice. Details pertaining to tumor tissue submission can be found in the Laboratory Manual.10. Participants who have AEs due to previous anticancer therapies must have recovered to <Grade 1 or baseline (except alopecia and vitiligo). Participants with endocrine-related AEs who are adequately treated with hormone replacement are eligible.11. Adequate organ function as defined in the following table (Table 6). Specimens must be collected within 10 days before the start of study intervention.Table 6 Adequate Organ Function Laboratory Values12. Has ECOG performance status of 0 or 1 within 3 days prior to the first dose of substudy intervention.13. Be willing and able to comply with study procedures, laboratory tests, and other requirements of the study.14. Has a life expectancy of at least 6 months.Exclusion Criteria

[0306] An individual must be excluded from the study if the individual meets any of the following criteria:Medical Conditions1. Has had previous therapy for locally advanced unresectable or metastatic gastric / GEJ / esophageal adenocarcinoma.Note: Participants may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization and progression occurred at least 6 months after completion of therapy.2. Has experienced weight loss >20% over 3 months before the first dose of study intervention.3. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and / or blepharitis, or comeal disease that prevents / delays comeal healing.4. Has Grade >2 peripheral neuropathy.5. Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (e g., Crohn’s disease, ulcerative colitis, or chronic diarrhea).6. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >480 ms, and / or other serious cardiovascular and cerebrovascular diseases within 6 months preceding study intervention.7. Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment. If the participant is receiving diuretic drugs for other reasons, it is acceptable. Consult with the Sponsor if the participant has more than trivial / trace fluid accumulation.8. History of HIV infection. HIV testing is not required unless mandated by local health authority.Prior / Concomitant Therapy9. Received prior treatment with a TROP2-targeted ADC.10. Received prior treatment with a topoisomerase 1 inhibitor-based ADC and / or a topoisomerase 1 inhibitor-based chemotherapy.11. Received pnor systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.12. Has received prior therapy with an anti-PD-1. anti-PD-Ll, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory TCR (e g., CTLA-4, 0X40, CD137).13. Received prior radiotherapy within 2 weeks of start of study intervention, or has radiation related toxicities. requiring corticosteroids. Participants must not have had radiation pneumonitis.Note: Tw o weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last palliative radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.14. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.15. Is currently receiving a strong and / or moderate inducer / inhibitor of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period before starting Immunoconjugate Ais 2 weeks.Note: A list of strong inhibitors or induces of CYP3A4 can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers.Prior / Concurrent Clinical Study Experience16. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.Diagnostic Assessments17. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.18. Known additional malignancy that is progressing or has required active treatment within the past 3 years.Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (Tl-T2a, Gleason score <6, and PSA <10 ng / mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.Known active CNS metastases and / or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e., without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention. Severe hypersensitivity (>Grade 3) to pembrolizumab or Immunoconjugate A and / or any of their excipients or other biologic therapy. Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (e.g.. thyroxine, insulin, or physiologic corticosteroid) is allowed. History of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. Active infection requiring systemic therapy. Has concurrent active hepatitis B (defined as HBsAg reactive and / or detectable HBV DNA) and / or hepatitis C (defined as anti-HCV Ab positive and detectable HCV RNA) infection or a known history of hepatitis B and / or C infection. Testing for Hepatitis B and C is not required unless mandated by local health authority. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. Has a contraindication to SOC therapy should be excluded based on the following:- Has a history of a GI condition or procedure that in the opinion of the investigator may affect oral study medication absorption.Has a history of a severe and unexpected reaction to a fluoropyrimidine-containing treatment.- Has severe dyspnea at rest related to advanced disease stage or oxygen-dependent complications.Has hypokalemia, hypomagnesemia, or hypocalcemia.- Had active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks or tumor bleeding within 2 weeks prior to the first dose of study intervention.Other Exclusions27. Has GI obstruction, poor oral intake (CAPOX participants), or difficulty in taking oral medication (CAPOX participants). G-tubes, J-tubes and nasogastric tubes will not be permitted for treatment administration of capecitabine. Participants with existing esophageal stent are not eligible.28. Has poorly controlled diarrhea (e g., watery stool, uncontrollable bowel movement with supportive medication, Grade >2 and number of defecations, >5 / day).29. Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary.30. History of allogeneic tissue / solid organ transplant.31. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.Lifestyle ConsiderationsMeals and Dietary Restrictions

[0307] Participants should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, nausea, or vomiting.

[0308] Participants randomized to Arm 2 (Immunoconjugate A) should avoid foods that affect CYP3A4 activity while receiving study intervention.

[0309] Participants randomized to Arm 2 (Immunoconjugate A) should be advised to modify their diet to avoid foods that may cause damage to the mucosa (e.g., pretzels and chips) and foods that are acidic.Caffeine, Alcohol, and Tobacco Restrictions

[0310] Participants randomized to Arm 2 (Immunoconjugate A) should be advised to avoid alcohol (i.e., beverages and mouthwash) and tobacco.Photosensitivity

[0311] Investigators are advised to counsel participants receiving 5-FU about the risk of photosensitivity and to take sun protection measures accordingly.Measures to Minimize Bias: Randomization and BlindingIntervention Assignment

[0312] Intervention will be allocated by nonrandom assignment during the Safety- Lead-in and through random assignment during the Efficacy Phase. Allocation across study arms will occurcentrally using an 1RT system. The assigned treatment arm for a participant will not change during the study; there is no crossover between treatment arms.

[0313] At the start of the study, enrollment will initially open for Arm 2 [pembrolizumab plus Immunoconjugate A plus fluoropyrimidine (capecitabine or 5-FU)]. Once Safety Lead-in has been completed, Efficacy Phase enrollment will begin in Arm 1 and Arm 2. To minimize selection bias, arms that are eligible for the Efficacy Phase will be randomized.BlindingStudy Intervention Compliance

[0314] If there are interruptions in the study intervention schedule or infusion / inj ection was stopped, the details of and reason for any interruption or infusion / inj ection cessation of study intervention will be documented in the participant’s medical record.

[0315] When participants are dosed at the site, they will receive study intervention directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents and recorded in the CRF.Concomitant Therapy

[0316] If there is a clinical indication for any medications or vaccinations prohibited, the investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. The final decision on any supportive therapy or vaccination rests with the investigator and / or the participant’s primary physician. However, the decision to continue the participant on study intervention requires the mutual agreement of the investigator and the Sponsor.

[0317] The following medications and vaccinations are prohibited during the study:• Live or live-attenuated vaccines within 30 days before the first dose of study intervention and while participating in the study, and for 30 days after the last dose of study intervention.• Systemic glucocorticoids except when used for the following purposes:To modulate symptoms of an AE that is suspected to have an immunologic etiology For the prevention of emesisTo premedicate for IV contrast allergies- To treat asthma or COPD exacerbations (only short-term oral or IV use in doses >10 mg / day prednisone equivalent)For chronic systemic replacement not to exceed 10 mg / day prednisone equivalent To premedicate for study intervention administration• Other glucocorticoid use except when used for the following purposes:For topical use or ocular use- Intraarticular joint useFor inhalation in the management of asthma or COPDStrong inhibitors or inducers of CYP3A4. For additional information refer to https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducersFor each chemotherapy agent used in the study, any medication prohibited in the approved product labelIf the investigator determines that a participant requires any of the following prohibited medications and vaccinations for any reason during the study, study intervention must be discontinued:• Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not specified in this protocol• Investigational agents other than those specified in this protocol• Radiation therapyNote: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s discretion.• Investigational vaccines (i.e., those not licensed or approved for Emergency Use) are not allowed.Note: Any licensed COVID- 19 vaccine (including for Emergency Use) in a particular country is allowed in the study as long as they are mRNA vaccines, replication-incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy.• For participants receiving 5-FU, or capecitabine:Brivudine, Sorivudine analogs, and other inhibitors of the enzyme dihydropyrimidine dehydrogenaseConcomitant Medications to be Used With Caution• Caution is advised when oxaliplatin treatment is coadministered with other medicinal products known to cause QT interval prolongation. In case of combination with such medicinal products, the QT interval should be closely monitored. Cimetidine, metronidazole and interferons may increase levels of 5-FU. Reliable sources such as crediblemeds.org can be used to assist in identification of medicinal products known to cause QT interval prolongation.• Participants who are taking phenytoin in conjunction with 5-FU should be examined regularly due to a potential elevation in phenytoin plasma levels. Hepatotoxic effects (increase in alkaline phosphatase, transaminase, or bilirubin levels) are frequently observed under the treatment with 5-FU and levamisole.• For participants receiving oxaliplatin:- Caution is advised if medicinal products associated with rhabdomyolysis are administered concomitantly with oxaliplatin.

[0318] The exclusion criteria describe other medications that are prohibited in this study.

[0319] Blood transfusions are allowed at any time during the study, except to meet eligibilitycriteria.

[0320] All treatments that the investigator considers necessary for a participant’s welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medications will be recorded on the eCRF including all presenptions, OTC products, herbal supplements, and IV medications, and fluids. If changes occur during the study period, documentation of drug dosage, frequency, route, and date should also be included on the eCRF.

[0321] All concomitant medications received within 28 days prior to the first dose of study intervention and up to 30 days after the last dose of study intervention should be recorded. All concomitant medications administered during SAEs or ECIs are to be recorded.Rescue Medications and Supportive CareImmunoconjugate A

[0322] The use of antiemetic therapy should follow Multinational Association of Supportive Care in Cancer and European Society for Medical Oncology guidelines; however, strong inhibitors or inducers of CYP3A4 are not permitted.

[0323] Prior to treatment with Immunoconjugate A, participants should receive prophylactic treatment to mitigate the onset and severity of stomatitis / oral mucositis in accordance with published ASCO and MASCC / ISOO guidelines.

[0324] It is highly recommended that participants use daily prophylactic steroid-containing mouthwash (e.g., dexamethasone oral solution 0.1 mg / mL 10 mL or equivalent [per institutional guidelines]) 4 times per day.• In the absence of a steroid-containing mouthwash, rinsing with bland solutions (e.g., normal saline, sodium bicarbonate, or tap water) at least 4 times per day or mucoadhesive hydrogel (e.g., MuGard) or calcium phosphate rinses (e.g., Caphosol) are recommended.• Oral nystatin suspension or other topical antifungal agent can be used following the steroid- containing mouthwash per investigator discretion and following institutional guidelines.

[0325] Participants should also follow additional preventative measures:• Brushing with a soft toothbrush 2 times per day and flossing daily.• If a participant is considered high-risk for developing stomatitis, consider early dental assessment for aggressive prophylactic care (e.g., treatment of caries and extraction of compromised teeth).• Cry otherapy or ice chip therapy, where patients hold ice chips in their mouth for 30 minutes before and during the infusion.Chemotherapy

[0326] For supportive care measures for the management of AEs that may result from treatment with chemotherapy, refer to the approved product labels for these agents.

[0327] For all agents and all administration, antiemetic therapy should follow MASCC guidelines and should include a 5-HT3 receptor antagonist, dexamethasone (or equivalent) and / or aprepitant as per the MASCC guidelines.

[0328] In addition, all participants should receive the appropriate corticosteroid premedications as per the local approved label.Dose Modification (Escalation / Other)

[0329] During treatment with study intervention, all participants should be closely monitored for treatment-related AEs and actively treated with supportive care. Dose modifications in response to treatment-related AEs / toxicities are permitted in order to keep the participant on study intervention, when appropriate. Dose modifications must follow official current prescription information and local therapeutic guidelines. Details on the modifications for each study intervention are provided in the sections below.

[0330] If a participant experiences a >10% weight change, the dose(s) of study intervention (Immunoconjugate A / chemo therapies) should be recalculated.

[0331] Dose modifications (dose escalation or dose reduction) of pembrolizumab is not allowed in this study.

[0332] AEs will be graded using NCI CTCAE Version 5.0. Investigators will decide the probability of the event being related to one or more drugs as to whether dose modification of one or more drugs is required. This is an open-label protocol with a novel combination of Immunoconjugate A, pembrolizumab, and fluoropyrimidine chemotherapy. Because of the multiple agents included in this protocol, overlapping toxicities may occur and the determination of the contribution of agents to specific toxicities may be challenging. Dose modifications can be handled individually or in concert depending on determined relatedness.

[0333] Participants w ho interrupt or discontinue one of the study medications (pembrolizumab, Immunoconjugate A, or chemotherapy) due to toxicity may continue with the other drug(s) in the combination until the criteria for treatment discontinuation are met (e.g., unacceptable toxicity, disease progression).Immunoconjugate A

[0334] Recommended dose-modification guidelines for Immunoconjugate A are provided in Table 7. Dosing delays for Immunoconjugate A due to an AE should not exceed 28 days of the last administered dose, unless otherwise discussed with the Sponsor.

[0335] If a dose reduction for an AE associated with Immunoconjugate A is needed, the dose can be reduced in 1 mg / kg increments (Table 7). Once the dose is selected, one dose reduction is allowed (i.e.. from 4 mg / kg to 3 mg / kg). If the participant experiences an AE that requires a second dose reduction, but the participant is deriving clinical benefit, the decision to reduce and continue the participant on study intervention requires the mutual agreement of the investigator and the Sponsor.

[0336] Once the Immunoconjugate A dose has been reduced because of toxicity, all subsequent cycles are to be administered at that lower dose level, unless further dose reduction is required. Reescalation is not permitted. If toxicity continues after all permitted dose reductions, then Immunoconjugate A should be permanently discontinued.

[0337] Participants should receive appropriate supportive care measures as deemed necessary' by the treating investigator. If the proposed dose-modification plan is inconsistent with the guidelines provided inTable 6, the investigator should discuss the management details with the Sponsor.

[0338] Immunoconjugate A may be interrupted for situations other than treatment-related AEs, such as medical or surgical events and / or unforeseen circumstances not related to study intervention. Study intervention is to be restarted within 14 days of the originally scheduled dose and within 28 days of the last administered dose, unless otherwise discussed with the Sponsor.The reason for study intervention interruption is to be documented in the participant’s study record.Table 7 Dose Modification and Toxicity) Management Guidelines for Adverse Events Associated With Immunoconjugate AManagement of Immunoconjugate A Infusion Reactions

[0339] Immunoconjugate A may cause severe or fatal infusion-related reactions, including severe hypersensitivity' or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion.

[0340] Premedication to prevent hypersensitivity and / or infusion reactions is required before each dose of Immunoconjugate A. Participants should be premedicated 1.5 hours (±30 minutes) before an infusion of Immunoconjugate A. For the first 4 administrations, participants should be premedicated with diphenhydramine (or equivalent Hl receptor antagonist [per approved product label]), acetaminophen (or equivalent [per approved product label]), and a corticosteroid (dexamethasone 10 mg IV [or equivalent]). In addition, an H2 receptor antagonist, if available, is also recommended for the first 4 administrations of Immunoconjugate Aper the approved product label and / or institutional standards. After the fourth infusion, in the absence of prior infusion- related or hypersensitivity AEs, participants should be premedicated with diphenhydramine (or equivalent [per approved product label]) and acetaminophen (or equivalent [per approved product label]) with the addition of a corticosteroid and an H2 receptor antagonist at thediscretion of the investigator. Dose modification and toxicity management of infusion reactions following Immunoconjugate A administration are provided in Table 8.

[0341] Premedication for Immunoconjugate A should be administered after completion of the pembrolizumab infusion. In the event of an infusion reaction that occurs following pembrolizumab administration, Immunoconjugate A should be held until the infusion reaction has resolved.Table 8 Infusion Reaction Dose Modification and Treatment Guidelines for Immunoconjugate AImmune-Related Events and Dose Modification (Withhold, Treat, Discontinue)Dose Modification and Toxicity Management for Immune-related AEs Associated With Pembrolizumab

[0342] AEs associated with pembrolizumab exposure may represent an immune-related response. These irAEs may occur shortly after the first dose or several months after the last dose of pembrolizumab treatment and may affect more than one body system simultaneously.Therefore, early recognition and initiation of treatment is critical to reduce complications. Based on existing clinical study data, most irAEs were reversible and could be managed with interruptions of pembrolizumab. administration of corticosteroids, and / or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation.

[0343] Dose Modification and Toxicity Management Guidelines for irAEs Associated With Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 9.Table 9 Dose Modification and Toxicity Management Guidelines for Immune-relatedAdverse Events Associated With Pembrolizumab Monotherapy, Coformulations, or IO CombinationsDose Modification and Toxicity Management of Infusion Reactions Related toPembrolizumab Monotherapy, Coformulations, or IO Combinations

[0344] Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs andsymptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab monotherapy, coformulations, or IO combinations associated infusion reactions are provided in Table 10.Table 10 Pembrolizumab Monotherapy, Coformulations, or 10 Combinations InfusionReaction Dose Modification and Treatment GuidelinesOther Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0345] Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for situations other than treatment-related AEs such as medical or surgical events and / or unforeseen circumstances not related to study intervention. However, study intervention is to be restarted within 6 weeks or 42 days of the originally scheduled dose and within 84 days of the previously administered dose, unless otherwise discussed with the Sponsor. The reason for study intervention interruption is to be documented in the participant's study record.Chemotherapy Dose Modification

[0346] Dose delays and treatment restarts will be made at the discretion of the site investigator according to institutional guidelines or local standard practice. If any adjustments to the chemotherapy dose modification guidelines are required per local guidelines, a Sponsor consultation is strongly recommended. If a dose reduction for toxicity occurs with any agent, the dose may not be reescalated.

[0347] Dose modifications will be needed for fluoropyrimidine only in investigational arm (Arm 2) and are recommended for CAPOX / mFOLFOX6 in SOC arm (Arm 1) as mentionedbelow. CTCAE Version 5.0 must be used to grade the severity of AEs. All dose modifications should be based on the AE requiring the greatest dose modification.

[0348] In participants with unrecognized DPD deficiency, acute, life-threatening toxicity may occur when participants are treated with fluoropyrimidine. We recommend DPD testing as appropriate per local guidelines. Participants who require dose modification on Cycle 1 are not eligible for the study.

[0349] Supportive care measures as per investigators’ choice (e.g., G-CSF, erythropoietin, blood or platelet transfusion) should be used according to local standards to manage chemotherapy -induced myelosuppression. including to prevent severe infections linked to febrile neutropenia. To minimize dose reductions, interruptions, and discontinuations of chemotherapy, it is recommended these supportive care measures be used before implementing dose modifications, when clinically appropriate. Prophylactic use is acceptable.CAPOX (Capecitabine / Oxaliplatin)

[0350] CAPOX treatment will comprise the following:• Capecitabine (1000 mg / m2, bid on Day 1 to Day 14 and Day 22 to Day 35 of every cycle)• Oxaliplatin(130 mg / m2, IV infusion, q3w)

[0351] For capecitabine, older participants are more susceptible to the effects of fluoropyrimidine-based therapies with increased Grade 3 / 4 adverse effects, especially when used in combination. For oxaliplatin, participants >65 years have a higher incidence of GI toxicity’, myelosuppression, syncope and fatigue. No dose adjustments are needed, but caution should be exercised.

[0352] Dose modifications for CAPOX are outlined in Table 11 and Table 12.Table 11 Recommended Dose Modification (Reduction) Guidelines for CAPOXDrug-related Adverse Eventsbid=twice dailyTable 12 Recommended Dose Modification Guidelines for CAPOX Drug-related Adverse Events (mandatory for capecitabine only arm)mFOLFOX6

[0353] mFOLFOX6 treatment will comprise the following:• Oxaliplatin (85 mg / m2, IV infusion, q2w)• 5-FU (400 mg / m2, bolus IV infusion followed by 2400 mg / m2continuous IV infusion, q2w)• Leucovorin (400 mg / m2. IV infusion, q2w) or levoleucovorin (200 mg / m2, IV infusion, q2w)Refer to Table 13 for dose modification criteria for mFOLFOX6.Table 13 Recommended Dose Modification Guidelines for mFOLFOX6 Drug-related Adverse Events (mandatory for 5-FU only arm)Management of Overlapping Toxicities

[0354] Because of the multiple agents included in this protocol, overlapping toxicities may occur and the determination of the contribution of agents to specific toxicities may be challenging. Dose modifications can be handled individually or in concert depending on determined relatedness. AEs commonly observed, as well as less common serious findings, are described in the IB for Immunoconjugate A and pembrolizumab, and approved labeling for chemotherapies (CAPOX / mFOLFOX6). Safety7will be continuously monitored though the study as well as by an internal DMC.

[0355] Attribution of such AEs to an individual study intervention may be difficult. The management actions (i.e., dose reduction, withholding, or discontinuation) for toxicities with uncertain attribution should apply to Immunoconjugate A (Arm 2 only), pembrolizumab (Arm 2 only) and chemotherapies (CAPOX / mFOLFOX6) in Arml and fluoropyrimidine (capecitabine or 5-FU) in Arm 2. and the investigator should follow the most conservative dose modification guidelines, and the approved labeling for chemotherapies. If the toxicity does not improve, the investigator should consider discontinuing each study intervention.

[0356] Some possible overlapping toxicities in this combination are listed below.Immunoconi ugate Ain combination with chemotherapy:• Myelosuppression: anemia, neutropenia, thrombocytopenia• GI toxicity: nausea, vomiting, constipation, diarrhea, mucositis• Dermatologic toxicity7: alopecia, rash• NeuropathiesImmunoconj ugate Ain combination with pembrolizumab:• Pneumonitis / ILD• Hepatic toxicity• Infusion related reactions / hypersensitivityModified Toxicity Probability Interval in the Safety Lead-in

[0357] Participants will be closely followed for DLTs for the first 28 days after the first dose of study intervention (the DLT evaluation period). The dose will be evaluated on an ongoing basis as up to 10 participants complete the DLT evaluation period. In Table 11 the columns indicate the numbers of participants treated at the current dose level, and the rows indicate the numbers of participants experiencing a DLT. The entries of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. Initially, 3 DLT evaluable participants will be enrolled at the starting dose. Dose recommendations for the next participants will depend on the observed number of DLTs in the first 3 DLT evaluable participants and the mTPI table. For example, if 2 of 3 participants at a dose level develop a DLT. the dose will be deescalated to the next lower dose level, but may be reescalated at a later time if the lower dose is well tolerated. If 3 of 3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose should be deescalated, if allowed per protocol, and the current dose will not be explored further. The Safety Lead-in Phase ends when 10 participants are enrolled and treated with the identified dose level.

[0358] A “D” or “DU” decision at the lowest dose level will stop the evaluation of the combination under study. An “E” decision at the highest dose level will result in staying at that level. During dose finding, it may be acceptable to deescalate or escalate to an intermediate dose that was not predefined and not previously studied if evaluation of toxicity at such a dose is desired.

[0359] The totality of the data will be considered prior to determining the dose level in the Efficacy Evaluation.Table 14 Dose-finding Framework of m Pl DesignDefinition of Dose-limiting Toxicity

[0360] The DLT window of observation will be during Cycle 1. The occurrence of any of the toxicities listed in Table 15 will be considered a DLT if assessed by the investigator to be possibly, probably, or definitely related to study intervention administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.Table 15 Dose-limiting ToxicitiesDISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT WITHDRAWALDiscontinuation of Study Intervention

[0361] Discontinuation of study intervention does not represent withdrawal from the study.

[0362] As certain data on clinical events beyond study intervention discontinuation may be important to the study, they must be collected through the participant’s last scheduled follow-up, even if the participant has discontinued study intervention. Therefore, all participants who discontinue study intervention before completion of the protocol-specified treatment period will still continue to be monitored in this study and participate in the study visits and procedures.

[0363] Participants may discontinue study intervention at any time for any reason or be discontinued from the study intervention at the discretion of the investigator should any untoward effect occur. In addition, a participant may be discontinued from study intervention by the investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or for administrative and / or other safety reasons.

[0364] A participant must be discontinued from study intervention, but continue to be monitored in the study for any of the following reasons:• The participant or participant’s legally acceptable representative requests to discontinue study intervention.• Any prolonged interruption of study interv ention beyond the permitted periods, for irAE management or other allowed dose interruptions, require Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the participant will continue to be monitored in the study and the reason for discontinuation of study intervention will be recorded in the medical record.• The participant has a medical condition or personal circumstance which, in the opinion of the investigator and / or Sponsor, placed the participant at unnecessary risk from continued administration of study intervention.• The participant has a confirmed positive serum pregnancy test.• Radiographic disease progression (after obtaining informed consent and assent (when applicable) addendum and Sponsor communication, the investigator may elect to continue treatment beyond iCRO-verified disease progression).• Any progression or recurrence of malignancy, or any occurrence of another malignancy that requires active treatment.Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection do not have to discontinue study intervention.

[0365] For participants who are discontinued from study intervention, but continue to be monitored in the study, all visits and procedures, as outlined in the SoA, should be completed.

[0366] Discontinuation from study intervention is “permanent.” Once a participant is discontinued from study intervention, they shall not be allowed to restart study intervention.STUDY ASSESSMENTS AND PROCEDURES• Study procedures and their timing are summarized in the SoA.• Adherence to the study design requirements, including those specified in the SoA, is essential and required for study conduct.• The investigator is responsible for ensuring that procedures are conducted by appropriately- qualified (by education, training, and experience) staff. Delegation of study-site personnel responsibilities will be documented in the Investigator Trial File Binder (or equivalent).• All study-related medical (or dental) decisions must be made by an investigator who is a qualified physician (or dentist when appropriate).• All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable.• Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) and obtained before providing documented informed consent or assent, when applicable, may be used for screening or baseline purposes provided the procedures meet the protocol-specified criteria and were performed within the time frame defined in the SoA.• Additional evaluations / testing may be deemed necessary by the investigator and or the Sponsor for reasons related to participant safety. In some cases, such evaluation / testing may be potentially sensitive in nature (e g., HIV, hepatitis C), and thus local regulations may require that additional informed consent or assent, when applicable, be obtained from the participant. In these cases, such evaluations / testing will be performed in accordance with those regulations.• The maximum amount of blood collected from each participant over the duration of the study will not exceed the volume mentioned in the laboratory manual.• Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.Timing of Dose Administration

[0367] Study intervention is to be administered at the study visits outlined in the SoA. After Cycle 1 , study intervention may be administered up to 3 days before or after the scheduled day of administration. Participants will continue receiving study intervention until one of the criteria for treatment discontinuation are met.

[0368] For in-clinic dosing, study intervention will be administered after all procedures and assessments have been performed. For cohorts that will evaluate pembrolizumab in combination with Immunoconjugate A, administer treatments in the following order:• Pembrolizumab• Immunoconjugate A• ChemotherapyAdministration of Pembrolizumab

[0369] Pembrolizumab will be administered using a 30 minute IV infusion q6w. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 25 to 40 minutes). The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, preparation of the infusion fluid, and administration.

[0370] Pembrolizumab will be dosed on Day 1 of each 6-week cycle. After C 1D1, pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each subsequent cycle for administrative reasons.Administration of Immunoconjugate A

[0371] Immunoconjugate Awill be administered by IV infusion on Days 1, 15, and 29 of each 6-week cycle. The duration of the Immunoconjugate Ainfusions should be 90 minutes (±15 minutes) and infusion related AEs will be monitored. The infusion duration may be adjusted to be longer than 105 minutes at the discretion of investigator, but the infusion of Immunoconjugate A needs to be completed within the time frame specified in the Pharmacy Manual. After at least 4 administrations and in the absence of either infusion-related AEs or anaphylactic reactions, the infusion of Immunoconjugate A may be shortened at the discretion of investigator, but cannot be shorter than 60 minutes.

[0372] All participants are to be premedicated. Premedication for Immunoconjugate A should be administered after completion of the pembrolizumab infusion. Participants are to be closely monitored during and after the infusions for the development of hypersensitivity reactions and / or infusion reactions.

[0373] Participants should be observed for at least 60 minutes after the first 4 infusions of Immunoconjugate A. If no infusion-related or hypersensitivity AEs are observed during the first 4 infusions, at the investigator’s discretion, participants can be monitored for 30 minutes following the completion of subsequent infusions of Immunoconjugate A (with the exception of close monitoring due to clinical symptoms).

[0374] Emergency rescue medications (including epinephrine) and appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.Efficacy / Immunogenicity AssessmentsTumor Imaging and Assessment of Disease

[0375] Throughout this section, the term 'scan’ refers to any medical imaging data used to assess tumor burden and may include cross-sectional imaging (such as CT or MRI), medical photography, or other methods as specified in this protocol.

[0376] In addition to survival, efficacy will be assessed based on evaluation of scan changes in tumor burden over time, until the participant is discontinued from the study or goes into survival follow-up. The process for scan collection and transmission to the iCRO can be found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or when mandated bylocal practice. The same scan technique should be used in a participant throughout the study to optimize the reproducibility of the assessment of existing and new tumor burden and improve the accuracy of the response assessment based on scans.

[0377] Note: For the purposes of assessing tumor scans, the term “investigator"’ refers to the local investigator at the site and / or the radiological reviewer at the site or at an offsite facility.

[0378] If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is medically contraindicated.

[0379] Bone scans may be performed to evaluate bone metastases. Any supplemental scans performed to support a positive or negative bone scan, such as plain x-rays acquired for correlation, should also be submitted to the iCRO.

[0380] Other imaging modalities that may be collected, submitted to the iCRO, and included in the response assessment include PET-CT scans. Other types of medical imaging (such as ultrasound) should not be submitted to the iCRO and will not be included in response assessment. Further details will be found in the SIM.

[0381] At screening, participant eligibility will require radiographic documentation of at least one lesion that meets the requirements for selection as a target lesion, as defined by RECIST 1.1 verified by BICR, prior to participant allocation / randomization.

[0382] All scheduled scans for participants will be submitted to the iCRO. In addition, a scan that is obtained at an unscheduled time point, for any reason (including suspicion of progression or other clinical reason), should also be submitted to the iCRO if it shows disease progression, or if it is used to support a response assessment. All scans acquired within the protocol-specified window of time around a scheduled scan visit are to be classified as pertaining to that visit.

[0383] When the investigator identifies disease progression, the iCRO will verify this progression and email the results to the study site and Sponsor. In clinically stable participants, scans are to continue until disease progression has been verified by BICR. If investigator- assessed progression was not verified by BICR, each subsequent scan must be submitted to the iCRO. Once progression is verified by BICR, subsequent scans (if acquired) should not be submitted to the iCRO.Initial Tumor Scans

[0384] Initial tumor scans at Screening must be performed within 28 days prior to the date of allocation / randomization. The screening scans must be submitted to the iCRO for verification of eligibility. Tumor scans performed as part of routine clinical management are acceptable for screening if they are of acceptable diagnostic quality, are performed within 28 days before randomization, and can be assessed by the iCRO.

[0385] Bone scans are required at screening for participants with a history of bone metastases and / or for those participants with indicative clinical signs / symptoms such as bone pain or elevated alkaline phosphatase levels. Bone scan refers to imaging methods used to assess bone metastasis. The specific methods permitted for this study are described in the SIM. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening assessment. The site must review screening scans to confirm the participant has measurable disease per RECIST 1.1.

[0386] If brain scans are required to document the stability of existing metastases, the brain scan should be acquired during screening. The specific methods permitted for this study are described in the SIM.Tumor Scans During the Study

[0387] The first on-study scan should be performed at 6 weeks (42 days +7 days) from the date of allocation / randomization. Subsequent tumor scans should be performed every 6 weeks (42 days ±7 days) or more frequently if clinically indicated. After Week 54 participants will have scans performed every 9 weeks (63 days ±7 days). Scan timing should follow calendar days and should not be adjusted for delays in cycle starts.

[0388] Scans are to be performed until disease progression is identified by the investigator and verified by the BICR, or until any of these conditions are met:• the start of a new anticancer treatment• pregnancy• death• withdraw al of consent• the end of the study

[0389] Objective response should be confirmed by a repeat scan performed at least 4 weeks after the first indication of a response is observed. Participants will then return to the regular scan schedule, starting with the next scheduled time point. Participants who receive additional scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 weeks later; scans may resume at the subsequent scheduled time point.

[0390] On-study brain and / or bone scans should be performed if clinically indicated or to confirm CR (if other lesions indicate CR and brain and / or bone lesions existed at baseline). End-of- treatment and Follow-up Tumor Scans

[0391] If participants discontinue study intervention, tumor scans should be performed at the time of discontinuation (±4-week window) unless previous scans w ere obtained within 4 weeksof discontinuation. If participants discontinue study intervention due to documented disease progression, this is the final required tumor scan.

[0392] If participants discontinue study intervention without documented disease progression, every effort is to be made to monitor disease status by acquiring tumor scans using the same schedule calculated from the date of allocation / randomization.

[0393] Scans are to be continued until one of the following conditions are met:• disease progression as defined by RECIST 1. 1 verified by BICR• the start of a new anticancer treatment• pregnancy• death• withdrawal of consent• the end of the studyRECIST 1.1 Assessment of Disease

[0394] RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.

[0395] Upon investigator-assessed disease progression, the indicative scan(s) are to be submitted immediately to iCRO for BICR verification of progression. After submission of scan(s), the iCRO will email the assessment to the site and Sponsor.

[0396] If disease progression is not verified, the process continues as follows:• If participant is clinically stable, continue study intervention per protocol continue scans per protocol schedule (the next scheduled scan should be >4 weeks from most recent scan acquired) send scans to iCRO- continue local assessment do not change investigator assessment of progression if subsequent scan(s) indicate progression, request verification from iCRO• If the participant is not clinically stable, best medical practice is to be applied

[0397] Before stopping study intervention or imaging or starting new anticancer therapy in a participant who is clinically stable, communication with the Sponsor is required.

[0398] If disease progression is verified, the process continues as follows:• investigator judgment will determine action• if the participant is clinically stable and study intervention is to continue, communication with the Sponsor is required and a reconsent addendum must be signed• obtain scans locally per original protocol schedule• do not send scans to iCRO• For the purpose of this decision process, lack of clinical stability is defined as:- unacceptable toxicity clinical signs or symptoms indicating clinically significant disease progression decline in performance status rapid disease progression or threat to vital organs or critical anatomical sites (e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative medical intervention.

[0399] RECIST=Response Evaluation Criteria In Solid TumorsPatient-reported Outcomes

[0400] The PRO questionnaires will be administered by trained site personnel and completed electronically by participants in the following order: EORTC QLQ-C30 first, EORTC QLQ- STO22 then EQ-5D-5L. The questionnaires should be administered before dosing at every cycle (q6w), at the Treatment Discontinuation Visit, and at the 30-day Safety Follow-up Visit.

[0401] If the Treatment Discontinuation Visit occurs 30 days from the last dose of study intervention, at the time of the mandatory Safety Follow-up Visit, the ePROs do not need to be repeated.

[0402] It is best practice and strongly recommended that ePROs are administered to randomized participants before drug administration. AE evaluation, and disease status notification. If the participant does not complete the ePROs at a scheduled time point, the MISS_MODE form must be completed to capture the reason the assessment was not performed.Safety Assessments

[0403] Details regarding specific safety procedures / assessments to be performed in this study are provided. The total amount of blood / tissue to be drawn / collected over the course of the study (from prestudy to poststudy visits), including approximate blood / tissue volumes drawn / collected by visit and by sample ty pe per participant, can be found in the Laboratory Manual.- I l l -Physical Examinations

[0404] A complete physical examination will be conducted by an investigator or medically qualified designee (consistent with local requirements) per institutional standard.Full Physical Examination

[0405] The investigator or qualified designee will perform a complete physical examination during the Screening period. Clinically significant abnormal findings should be recorded as medical history. After the first dose of study intervention, new clinically significant abnormal findings should be recorded as AEs.Directed Physical Examination

[0406] For cycles that do not require a full physical examination, the investigator or qualified designee will perform a directed physical examination as clinically indicated prior to study intervention administration. New clinically significant abnormal findings should be recorded as AEs.Vital Signs

[0407] The investigator or qualified designee will assess vital signs at screening. Vital signs will include heart rate, systolic and diastolic blood pressure, temperature, respiratory7rate. The height is measured at screening only and weight will be monitored per vital signs.Electrocardiograms

[0408] A standard 12-lead ECG will be obtained and reviewed by an investigator or medically qualified designee (consistent with local requirements) at screening. At screening, a single 12- lead ECG with QTcF measurement will be obtained for all participants. Clinically significant abnormal findings should be recorded as medical history. Assessments may be repeated during the study, as clinically indicated.

[0409] Note: A 6-lead ECG is allowed per institutional standard.

[0410] For participants receiving Immunoconjugate Ain combination with Pembrolizumab and chemotherapy, ECGs will be performed as follows:• On C1D1, before the first dose of Immunoconjugate A, a 12-lead ECG with QTcF measurement will be performed in triplicate in a supine position with the participant having rested for at least 5 minutes. The ECG tracings should be obtained as closely as possible in succession and no more than 5 minutes apart.• A single 12-lead ECG with QTcF measurement will be obtained before every third infusion of Immunoconjugate A(i.e., Day 1 of each cycle). The predose ECG may be obtained within the 3 days preceding the scheduled dose.

[0411] Note: Clinically significant abnormal findings are to be evaluated, including repeated ECGs if necessary. Additional time points may be performed as clinically indicated.Echocardiogram or Multi-gated Acquisition Scan

[0412] A MUGA scan (using technetium-based tracer) or an ECHO will be performed to assess LVEF. MUGA or ECHO scans should be performed locally in accordance with the institution’s standard practice. Whichever modality is used for an individual participant at baseline should be used for any subsequent LVEF assessments for that participant. Investigator assessment will be based upon institutional reports.Clinical Safety Laboratory Assessments• The investigator or medically qualified designee (consistent with local requirements) must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study in the AE section of the CRF. The laboratory reports must be filed with the source documents. Clinically significant abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant’s condition.• All protocol-required laboratory assessments, must be conducted in accordance with the laboratory7manual and the SoA.• If laboratory values from nonprotocol-specified laboratory assessments performed at the institution’s local laboratory require a change in study participant management or are considered clinically significant by the investigator (e g., SAE or AE or dose modification), then the results must be recorded in the appropriate CRF (e.g., SLAB).• For any laboratory tests with values considered clinically significantly abnormal during participation in the study or within 30 days after the last dose of study intervention, even7attempt should be made to perform repeat assessments until the values return to normal or baseline or if anew baseline is established as determined by the investigator.Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)

[0413] Details regarding specific laboratory procedures / assessments to be performed in this study are provided below. The total amount of blood / tissue to be drawn / collected over the course of the study (from prestudy to poststudy visits), including approximate blood / tissue volumes drawn / collected by visit and by sample type per participant can be found in the Laboratory Manual. Refer to the Schedule of Activities for the timing of laboratory7assessments.Pregnancy Testing• Pregnancy testing:Pregnancy testing (urine or serum) should be conducted at every' protocol treatment cycle, as per So A.- Pregnancy testing (urine or serum) should be conducted for the time required to eliminate systemic exposure after the last dose of each study intervention and should correspond with the time frame for the participant’s contraception. The length of time required to continue pregnancy testing for each study intervention is:° Immunoconjugate A: 190 days° pembrolizumab: 120 days° Chemotherapy: 270 daysAdditional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation, to establish the absence of pregnancy at any time during the participant’s participation in the study.Performance AssessmentsEastern Cooperative Oncology Group Performance Status

[0414] The investigator or qualified designee will assess ECOG status at screening, before the administration of each dose of study intervention and during the follow up period as specified in the So A.Adverse Events, Serious Adverse Events, and Other Reportable Safety Events

[0415] Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative).

[0416] The investigator and any designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE as well as other reportable safety’ events. Investigators need to document if an SAE was associated with a medication error, misuse, or abuse.

[0417] Investigators remain responsible for following up AEs, SAEs, and other reportable safety’ events for outcome. The investigator, who is a qualified physician, will assess events that meet the definition of an AE or SAE as well as other reportable safety events with respect to seriousness, intensity / toxicity, and causality.Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event Information

[0418] All AEs, SAEs. and other reportable safety events that occur after the participant provides documented informed consent, but before intervention, must be reported by the investigator if the participant is receiving placebo run-in or other run-in treatment, if the event causes the participant to be excluded from the study, or is the result of a protocol-specified intervention, including, but not limited to washout or discontinuation of usual therapy, diet, or a procedure.• All AEs from the time of intervention randomization through 30 days after cessation of study intervention must be reported by the investigator.• All AEs meeting serious criteria, from the time of intervention randomization through90 days after cessation of study intervention or 30 days after cessation of study intervention if the participant initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.• All pregnancies and exposure during breastfeeding, from the time of intervention randomization through the time required to eliminate systemic exposure after cessation of study intervention, or 30 days after cessation of study intervention if the participant initiates new anticancer therapy must be reported by the investigator.• Additionally, any SAE brought to the attention of an investigator at any time outside the time specified above must be reported immediately to the Sponsor if the event is considered related to study intervention.

[0419] All initial and follow-up AEs, SAEs. and other reportable safety events will be recorded and reported to the Sponsor or designee.

[0420] Exception: A positive pregnancy test at the time of initial screening is not a reportable event unless the participant has received study intervention.Table 16 Reporting Periods and Time Frames for Adverse Events and Other ReportableSafety! EventsAnalysis Endpoints

[0421] Efficacy and safety endpoints that will be evaluated for within- and / or between- treatment differences are listed below.Efficacy EndpointsPrimary• Objective Response Rate (ORR)

[0422] The ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by BICR. Participants without response assessment will be counted as nonresponders.Secondary• Progression-free survival (PFS)

[0423] PFS is defined as the time from the date of allocation / randomization to the date of the first documentation of disease progression per RECIST 1.1 by BICR or death from any cause, whichever occurs first.• Duration of Response (DOR)

[0424] For participants who demonstrate confirmed CR or PR per RECIST 1.1 as assessed by BICR, DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death from any cause, whichever occurs first.• Overall Survival (OS)

[0425] OS is defined as the time from the date of allocation / randomization to the date of death from any cause. Participants without documented death at the time of the analysis will be censored at the date of the last known alive date.Safety Endpoints

[0426] Safety endpoints include AEs, SAEs. and study intervention discontinuation due to AEs. In addition, safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, laboratory test results, and vital signs, and ECGs.

[0427] DLTs will be assessed for participants in the Safety Lead-in Phase.Analysis PopulationEfficacy Analysis Populations

[0428] The FAS population will serve as the primary population for the analysis of efficacy data in this study. The FAS population consists of all allocated / randomized participants with a baseline scan that showed measurable disease by BICR. and who were administered at least 1 dose of study intervention.

[0429] Participants within the same dose level treated in the Safety Lead-in Phase and the Efficacy Phase will be pooled for the efficacy analyses.Safety Analysis Populations

[0430] Safety Analyses will be conducted in the APaT population, which consists of all randomized / allocated participants who received at least one dose of study intervention. Participants will be included in the treatment group corresponding to the study intervention they actually received for the analysis of safety data using the APaT population.

[0431] The DLTe population includes APaT participants that meet the criteria for DLT evaluability (e.g., finished DLT evaluation period without a DLT or experienced a DLT in the DLT evaluation period).

[0432] Analyses of laboratory test results, vital signs, and ECG measurements will include only participants with at least one measurement obtained after at least one dose of study intervention. If the analysis will assess change from baseline, a baseline measurement is also required.

[0433] Participants within the same dose level treated in the Safety Lead-in Phase and the Efficacy Phase will be pooled for the safety analyses.PRO Analysis Populations

[0434] The PRO analyses are based on the PRO FAS population, defined as all allocated / randomized participants who have at least one PRO assessment available for the specific endpoint and have received at least one dose of the study intervention.

[0435] Participants within the same dose level treated in the Safety Lead-in Phase and the Efficacy Phase will be pooled for PRO analyses.Statistical MethodsStatistical Methods for Efficacy AnalysesObjective Response Rate

[0436] The assessment of the ORR by BICR is a primary endpoint. The point estimate of ORR will be provided in each treatment arm, together with 95% Cl using exact binomial method proposed by Clopper and Pearson.

[0437] The Miettinen and Nurminen’s method will be used to evaluate Arm 2 and Arm 1. The difference in ORR and its corresponding 95% CI from the Miettinen and Nurminen’s method will also be reported.Duration of Response (DOR)

[0438] The secondary efficacy endpoint of DOR as assessed by BICR will be summarized by treatment arm. If sample size permits, DOR will be summarized descriptively using Kaplan- Meier medians and quartiles. Range and median DOR will be reported. Only the subset of participants who show a confirmed CR or PR will be included in this analysis. Censoring rules for DOR are summarized in Table 17.

[0439] For each DOR analysis, a corresponding summary of the reasons responding participants are censored will also be provided. If a participant meets multiple criteria for censoring, the censoring criterion that occurs earliest will be applied.Table 17 Censoring Rules for DORProgression-Free Survival (PFS)

[0440] The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each treatment group along with descriptive summaries such as medians and quartiles. A Cox proportional hazard model with Efron's method of tie handling will be used to assess the magnitude of the treatment difference (i.e., the HR) betw een the treatment arms. The HR and its 95% CI from the Cox model with Efron's method of tie handling and with a single treatment covariate will be reported. Censoring rules for PFS are summarized in Table 18.Table 18 Censoring Rules for Primary and Sensitivity Analysis of PFSOverall Survival (OS)

[0441] The nonparametric Kaplan-Meier method will be used to estimate the survival curves in each arm, along with descriptive summaries such as medians and quartiles. A Cox proportional hazard model with Efron's method of tie handling will be used to assess the magnitude of the treatment difference (i.e., the HR) between the treatment arms. The HR and its 95% CI from the Cox model with Efron's method of tie handling and with a single treatment covariate will be reported. Participants without documented death at the time of analysis will be censored at the date of the last known alive date.Analysis Strategy for Key Efficacy Variables

[0442] A summary of the primary analysis strategy for the key efficacy endpoints is provided in Table 19.Table 19 Analysis Strategy for Key Efficacy Variables

[0443] Additional efficacy analyses may be performed by adjusting for prognostic factors, such as ECOG, PDL1 status, etc.Statistical Methods for Safety AnalysesOverall Safety Assessment

[0444] Safety and tolerability will be assessed by clinical review of AEs and other relevant parameters, including laboratory test results, vital signs, and ECG measurements.

[0445] The overall safety endpoints include the number of participants with any AE, drug- related AE, serious AE, serious and drug-related AE, Grade 3-5 AE, who discontinue from study intervention due to an AE, or with an AE resulting in death are considered safety topics of special interest in this study. Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.

[0446] The safety evaluation will include a summary by treatment group of the number and percentage of participants with each type of AE. For overall safety endpoints, specific AEs and safety topics of special interest that meet predefined threshold rules, point estimates and 95% Cis for the differences between treatment groups in the percentages of participants with events will be provided using the stratified M&N method [Miettinen. O. and Nurminen, M. 1985], Based on the umbrella platform design, it is possible that new investigational agent(s) may be added later to the study, and some group(s) may not be randomized or concurrent.

[0447] For continuous safety measures, such as change from baseline in laboratory values, vital signs, and ECG parameters, summary statistics for baseline, on-treatment, and change from baseline values will be provided by treatment group.

[0448] In Safety Lead-in Phase, the estimate of the DLT rate and the 90% Bayesian credible interval based on a prior distribution of Beta (1,1) for the estimate will be provided.Interim Analyses

[0449] An internal DMC (iDMC) will monitor all safety information to ensure participant safety as well as review IAS result in accordance with a separate charter. The iDMC will serve asthe primary reviewers of the treatment-level results and will make recommendations for discontinuation of study intervention based on safety and risk / benefit considerations. The iDMC is composed of members of Sponsor staff, none of whom otherwise are directly associated with conduct of this study. The iDMC responsibilities and review schedules will be outlines in the DMC charter.Safety Interim Analyses

[0450] The investigational arm will have a Safety Lead-in Phase to evaluate the safety and tolerability of the combination of investigational agents with different Immunoconjugate A dose level which includes up to 10 DLT evaluable participants per dose level.

[0451] At the end of Safety Lead-in, the Sponsor will evaluate the Safety Lead-in data before randomization into Efficacy Phase commences.Efficacy Interim Analyses

[0452] After the dose level is selected from the Safety Lead-in Phase, participants will be randomized into the Arm 1 or Arm 2 (60 for Arm 1; approximately 50 for Arm 2) in Efficacy Phase. Participants within the same dose level treated in the Safety Lead-in Phase and the Efficacy Phase will be pooled for the efficacy analyses. Two efficacy interim analyses (lAs) may be performed.

[0453] IA1 may be performed when 40 participants per arm (includes participants from Safety Lead-in Phase for the selected dose level) have been followed up at least 6 months from study entry. There is no enrollment pause for this IA1.

[0454] IA2 may be performed when 60 participants enrolled per arm (includes participants from Safety’ Lead-in Phase for the selected dose level) and have been folloyved up at least 6 months from study entry.

[0455] If Arm 2 shows promising efficacy and safety results at lAs, then the study may be expanded to enroll additional 40 participants in each arm (that is, a total up to 100 participants per arm). The final analysis will be performed when 100 participants enrolled in each arm and have been followed up at least 6 months from study entry. The final decision regarding expansion of the study will not be based solely on efficacy, but will instead be based on evaluation by the Sponsor of the totality of the data and analysis of risks and benefits.

[0456] At lAs and FA for ORR, secondary efficacy endpoints (PFS, OS) will be evaluated if the number of events warrants. Post the FA for ORR, additional analysis may be performed for PFS and OS with additional follow-up.Sample Size and Power Calculations

[0457] In this Substudy C. approximately up to 130 participants may be enrolled in the Safety Lead-in Phase and Efficacy Phase. A maximum of 10 DLT-evaluable participants for each of the two dose levels will be allocated to the Safety Lead-in Phase. After the dose level is selected from the Safety Lead-in Phase, participants will be randomized into the Arm 1 or Arm 2 (60 for Arm 1; approximately 50 for Arm 2) in Efficacy Phase. Participants within the same dose level treated in the Safety Lead-in Phase and the Efficacy Phase will be pooled for the efficacy analyses. Two efficacy interim analyses (IAS) may be performed.

[0458] If Arm 2 shows promising efficacy and safety7results at IAs, then the study may be expanded to enroll additional 40 participants in each arm (that is, a total up to 100 participants per arm).

[0459] Since this study does not have formal hypotheses to be tested, no power calculations will be incorporated.

[0460] The sample size will be:Up to 20 participants in Safety Lead-in Phase;110 participants in Efficacy Phase (investigational arm + reference arm);80 participants if expanded (investigational arm + reference arm).

[0461] Tables 20 - 22 shows the two-sided 95% CI for ORR with 40 / 60 / 100 participants for different observed response rate based on the method of Clopper and Pearson.Table 20 Two-sided 95% CI for Observed ORR with 40 ParticipantsTable 21 Two-sided 95%> CI for Observed ORR with 60 ParticipantsTable 22 Two-sided 95% CI for Observed ORR with 100 Participants

[0462] While preferred embodiments of the present disclosure 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 occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the methods and uses disclosed herein.

Claims

WHAT IS CLAIMED IS:

1. A method of treating gastroesophageal cancer in a patient in need thereof, comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof;(b) an amount of a fluropyrimidine; and(c) an amount of an Immunoconjugate of Formula (I):wherein:Ab is an antibody that binds to Trop-2; and n is from 1 to 10. and wherein the amounts of (a), (b) and (c) administered are together effective to treat gastroesophageal cancer.

2. The method of claim 1. wherein the fluoropyrimidine is 5-FU or capecitabine.

3. The method of claim 1 or 2, wherein n is from 6 to 8.

4. The method of any of claims 1-3, wherein the antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising an HCDR 1 comprising the amino acid sequence of SEQ ID No.: 39, an HCDR2 comprising the amino acid sequence of SEQ ID No.: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID No.: 41, and(li) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID No.: 42; an LCDR2 comprising the amino acid sequence of SEQ ID No.: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID No.: 44.

5. The method of any of claims 1-4, wherein the antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID No.: 37, and(ii) a light chain variable region comprising the amino acid sequence of SEQ ID No.: 38.

6. The method of any of claims 1-5, wherein the antibody that binds to Trop-2 comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID No.:

35. and(ii) a light chain comprising the amino acid sequence of SEQ ID No.: 36.

7. The method of any of claims 1-6, wherein the antibody that binds to Trop-2 is sacituzumab.

8. The method of any of claims 1-7, wherein the Immunoconjugate of Formula (I) is administered to the patient at a dose from 1 mg / kg to 6 mg / kg.

9. The method of any of claims 1-8, wherein the wherein the anti-human PD-1 antibody or antigen binding fragment thereof is selected from nivolumab, cemiplimab, dostarlimab, pidilizumab, tislelizumab and pembrolizumab.

10. The method of any of claims 1-9, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is administered to the patient at a dose of 50 mg to 500 mg.

11. The method of any of claims 1-10, wherein the Immunoconjugate of Formula (I) and the anti -human PD-1 antibody or antigen binding fragment thereof are administered in six- week cycles, whrerein the Immunoconjugate of Formula (I) is administered on days 1, 15, and 29 of each six -week cycle, and the anti-human PD-1 antibody or antigen binding fragment thereof is administered on day 1 of each six-week cycle.

12. The method of any of claims 1-11, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400 mg, and the Immunoconjugate of Formula (I) is administered at a dose of 3.0 mg / kg to about 5.0 mg / kg.

13. The method of any of claims 1-12, wherein:(i) anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab, and is administered at a dose of 400 mg on day 1 of a six-week cycle;(ii) the fluoropyrimidine is 5-FU, and is is administered at a dose of 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) on days 1, 15, and 29 of a six week cycle; and(iii) the Immunoconjugate of Formula (I) is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-Trop-2 antibody (sacituzumab), and n is an integer from 1 to 8, and is administered at a dose of 3 mg / kg on days 1, 15, and 29 of a 6-week cycle.

14. The method of any of claims 1-12, wherein:(i) anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab, and is administered at a dose of 400 mg on day 1 of a six-week cycle;(ii) the fluoropyrimidine is 5-FU, and is administered at a dose of 400 mg / m2(bolus) plus 2400 mg / m2(continuous infusion) on days 1, 15, and 29 of a six week cycle; and(iii) the Immunoconjugate of Formula (I) is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-Trop-2 antibody (sacituzumab). and n is an integer from 1 to 8, and is administered at a dose of 4 mg / kg on days 1, 15, and 29 of a 6-week cycle.

15. The method of any of claims 1-12, wherein:(i) anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab, and is administered at a dose of 400 mg on day 1 of a six-week cycle;(ii) the fluoropyrimidine is capecitabine. and is administered at at dose of administered twice daily at a dose of 1000 mg / m2on days 1-14 and days 22-35 of a six week cycle; and(iii) the Immunoconjugate of Formula (I) is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-Trop-2 antibody (sacituzumab), and n is an integer from 1 to 8, and is administered at a dose of 4 mg / kg on days 1, 15, and 29 of a 6-week cycle.

16. The method of any of claims 1-12. wherein:(i) anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab, and is administered at a dose of 400 mg on day 1 of a six-week cycle;(ii) the fluoropyrimidine is capecitabine, and is administered at at dose of administered twice daily at a dose of 1000 mg / m2on days 1-14 and days 22-35 of a six week cycle; and(iii) the Immunoconjugate of Formula (1) is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-Trop-2 antibody (sacituzumab). and n is an integerfrom 1 to 10, and is administered at a dose of 4 mg / kg on days 1, 15, and 29 of a 6-week cycle.

17. The method of any of claims 13-16, wherein the number of cycles administered is from 1 to 18.

18. The method of any of claims 1-17, wherein the gastroesophageal cancer is selected from: locally advanced or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, non-squamous cell gastroesophageal cancer, and esophageal adenocarcinoma.

19. A pharmaceutical composition comprising:(a) an anti -human PD-1 antibody or antigen binding fragment thereof;(b) a fluoropyrimidine;(c) a plurality of Immunoconjugates of Formula (I):(I),wherein:Ab is an antibody that binds to Trop-2; and n represents the average number of linker / payload moieties joined to each antibody for the plurality of Immunoconjugates of Formula (I); and(d) a pharmaceutically acceptable carrier, wherein the amounts of (a), (b), and (c) present in the composition are together effective to treat gastroesophageal cancer.

20. The pharmaceutical composition of claim 19, wherein the antibody that binds to Trop-2 is sacituzumab.

21. The pharmaceutical composition of claim 19 or 20, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

22. The pharmaceutical composition of of any of claims 19-21, wherein the fluoropyrimidine is 5-FU or capecitabine.

23. A kit comprising:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof;(b) an amount of a fluoropyrimidine; and(c) an amount of an Immunoconjugate of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and each n is an integer from 1 to 10,wherein the amounts of (a), (b), and (c) present in the kit are together effective to treat gastroesophageal cancer.

24. The kit of claim 23, further comprising instructions for administering the Immunoconjugate of Formula (I), the fluoropyrimidine, and the anti-human PD-1 antibody or antigen binding fragment thereof to a human patient.

25. The kit of claim 23 or 24, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

26. The kit of any of claims 23-25, wherein the Immunoconjugate of Formula (I) is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-Trop-2 antibody (sacituzumab). and n is an integer from 1 to 8.

27. The kit of any of claims 23-26, wherein the fluoropyrimidine is 5-FU or capecitabine.

Images