WO2024039925A1 - Méthodes de traitement associées pour cancer à mutation tp53 - Google Patents

Méthodes de traitement associées pour cancer à mutation tp53 Download PDF

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WO2024039925A1
WO2024039925A1 PCT/US2023/068368 US2023068368W WO2024039925A1 WO 2024039925 A1 WO2024039925 A1 WO 2024039925A1 US 2023068368 W US2023068368 W US 2023068368W WO 2024039925 A1 WO2024039925 A1 WO 2024039925A1
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administered
btki
antibody
mutation
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Salim YAZJI
James BREITMEYER
Gunnar Kaufmann
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Oncternal Therapeutics, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Receptor-tyrosine kinase like orphan receptor 1 is a conserved embryonic protein whose expression becomes progressively reduced during embryonic development in mammals.
  • ROR1 is found to be re-expressed at high levels on many solid and hematologic cancers including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and marginal zone lymphoma (MZL), but not on normal adult tissues.
  • MCL mantle cell lymphoma
  • CLL chronic lymphocytic leukemia
  • MZL marginal zone lymphoma
  • a method of treating a cancer or tumor in an individual comprising administering to the individual an ROR1 antagonist and/or a Bruton’s tyrosine kinase inhibitor (BTKi), wherein the tumor or cancer comprises a mutation in a TP53 gene or is a high-risk subtype.
  • the ROR1 antagonist is an antibody or antigen binding fragment thereof.
  • the antibody or antigen binding fragment thereof binds to an epitope of ROR1 as set forth in SEQ ID NO: 13 or 14.
  • the antibody or antigen biding fragment thereof comprises: a) a heavy chain CDR1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 1; b) a heavy chain CDR2 (HCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 2; c) a heavy chain CDR3 (HCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 3; d) a light chain CDR1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 4; e) a light chain CDR2 (LCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 5; and/or f) a light chain CDR3 (LCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1
  • the antibody or antigen biding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 8.
  • the antibody or antigen biding fragment thereof is zilovertamab or an R0R1 binding fragment thereof.
  • the R0R1 antagonist is administered at a dose of between 200 milligrams and 800 milligrams.
  • the ROR1 antagonist is administered at a dose of 200 milligrams.
  • the ROR1 antagonist is administered at a dose of 400 milligrams.
  • the ROR1 antagonist is administered at a dose of 600 milligrams.
  • the BTKi comprises ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, orelabrutinib, rilzabrutinib, or tolebrutinib.
  • the BTKi comprises branebrutinib, elsubrutinib, remibrutinib, vecabrutinib, remibrutinib, spebrutinib tirabrutinib, AC0058TA, LOXO-305, DTRMWXHS-12, M7583, SN-1011, TG-1701.
  • the BTKi comprises ibrutinib.
  • the BTKi comprises nemtabrutinib.
  • the BTKi is administered at a dose of between about 280 and about 700 milligrams. In certain embodiments, the BTKi is administered at a dose of about 420 milligrams.
  • the BTKi is administered at a dose of about 560 milligrams. In certain embodiments, the ROR1 antagonist and the BTKi are administered separately.
  • the tumor or the cancer comprises a blood cancer. In certain embodiments, the tumor or the cancer comprises a leukemia or a lymphoma. In certain embodiments, the tumor or the cancer comprises a B cell leukemia or B cell lymphoma. In certain embodiments, the tumor or the cancer comprises chronic lymphocytic leukemia (CLL). In certain embodiments, the tumor or the cancer comprises small cell lymphocytic leukemia (SLL). In certain embodiments, the tumor or the cancer comprises marginal zone lymphoma (MZL).
  • CLL chronic lymphocytic leukemia
  • SLL small cell lymphocytic leukemia
  • MZL marginal zone lymphoma
  • the cancer or tumor is relapsed. In certain embodiments, the cancer or refractory to one or more previous treatments.
  • the MCL is a high-risk subtype according to the simplified mantle cell lymphoma international prognostic index.
  • the mutation is in an exon of the TP53 gene. In certain embodiments, the mutation is in an intron of the TP53 gene. In certain embodiments, the mutation is a nonsense mutation in the TP53 gene. In certain embodiments, the mutation is a missense mutation in the TP53 gene. In certain embodiments, the mutation results in an amino acid insertion, deletion, or substitution in a protein encoded by the TP53 gene.
  • the cancer or tumor is relapsed. In certain embodiments, the cancer or tumor is refractory to one or more previous treatments. In certain embodiments, the test is performed on a biopsy sample of the tumor or the cancer of the individual. In certain embodiments, the method halts progression of the cancer. In certain embodiments, the method halts progression of the cancer for at least 12 months. In certain embodiments, the method halts progression of the cancer at least 24 months. In certain embodiments, the method halts progression of the cancer for at least 36 months. In certain embodiments, the method halts progression of the cancer for at least 48 months.
  • FIGs. 1A-1D illustrate a waterfall plot of best percentage (%) tumor reduction from baseline.
  • the CLL patients were either treatment- naive or relap sed/refractory.
  • the CLL patients were either treatment-naive or relap sed/refractory.
  • the CLL patients were either treatment-naive or relap sed/refractory.
  • SPD sum of the products of the diameters. The number under the bars represent baseline SPD.
  • FIGs. 2A-2B illustrate the comparison of clinical response rates between the combination treatment (zilovertamab + ibrutinib) and a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment based on historical data.
  • FIG. 2A shows the clinical response rates over time of the combination treatment (zilovertamab + ibrutinib).
  • FIG. 2B shows the clinical response rates over time of a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment alone.
  • FIGs. 3A-3B illustrate the comparison of clinical response rates based on prior regiment in MCL patients between the combination treatment (zilovertamab + ibrutinib) and ibrutinib treatment based on historical data.
  • FIG. 3A shows the clinical response rates of the combination treatment (zilovertamab + ibrutinib).
  • FIG. 3B shows the clinical response rates of ibrutinib treatment alone.
  • FIG. 4 illustrates the comparison of clinical response rates based on p53 mutation status in MCL patients treated with the combination treatment (zilovertamab + ibrutinib).
  • FIGs. 5A-5B illustrate the comparison of Progression-free Survival (PFS) in MCL patients (Parts 1&2) between the combination treatment (zilovertamab + ibrutinib) and a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment based on historical data.
  • FIG. 5A shows the PFS of the combination treatment (zilovertamab + ibrutinib).
  • FIG. 5B shows the PFS of a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment alone.
  • FIGs. 6A-6B illustrate the comparison of PFS in MCL patients (Parts 1&2) based on prior systemic treatment between the combination treatment (zilovertamab + ibrutinib) and ibrutinib treatment based on historical data.
  • FIG. 6A shows the PFS of the combination treatment (zilovertamab + ibrutinib).
  • FIG. 6B shows the PFS of a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment alone.
  • FIGs. 7A-7B illustrate the comparison of PFS in MCL patients (Parts 1&2) based on MIPI subgroups between the combination treatment (zilovertamab + ibrutinib) and a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment based on historical data.
  • FIG. 7A shows the PFS of the combination treatment (zilovertamab + ibrutinib).
  • FIG. 7B shows the PFS of a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment alone.
  • FIG. 8 illustrates the comparison of PFS in MCL patients (Parts 1&2) based on p53 mutation status between the combination treatment (zilovertamab + ibrutinib) and a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment based on historical data.
  • FIGs. 9A-9C illustrate the comparison of PFS in treatment naive and relapsed/refractory CLL patients (Parts 1&2, Part 3).
  • FIG. 9A shows PFS comparison in CLL patients (Parts 1 & 2).
  • FIG. 9B shows PFS comparison in CLL patients (Part 3).
  • FIG. 9C shows the comparison of PFS in treatment naive and relapsed/refractory CLL patients (pooled analysis of Parts 1, 2 & 3).
  • FIGs. 10A-10C illustrate the comparison of PFS in CLL patients by p53 mutation status.
  • FIG. 10A shows PFS comparison in CLL patients (Parts 1 & 2).
  • FIG. 10A shows PFS comparison in CLL patients (Parts 1 & 2).
  • FIG. 10B shows PFS comparison in pooled CLL patients (Parts 1, 2 & 3).
  • PFS is defined as the time from the first dose to the time of disease progression of death from any cause, whichever comes first; a - Pooled analysis includes all Part 1 and 2 CLL patients + Part 3 CLL patients randomized to treatment with zilovertamab + ibrutinib.
  • FIG. 10C shows PFS comparison in pooled CLL patients (Parts 1, 2 & 3) and compares it to the PFS in subjects with a p53 mutation treated with either ibrutinib or zanuburtinib alone.
  • FIG. 11 illustrates PFS in CLL patients by prior systemic treatment.
  • FIGS. 12A-12B illustrate the comparison of Landmark PFS in R/R CLL patients (Parts 1&2) by prior systemic treatment between the combination treatment (zilovertamab + ibrutinib) and ibrutinib treatment based on historical data.
  • FIG. 12A shows the Landmark PFS of the combination treatment (zilovertamab + ibrutinib).
  • FIG. 12B shows the PFS of a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib) treatment alone.
  • BTKI Kinase Inhibitor BTKI
  • a method of treating a cancer or tumor in an individual comprising administering to the individual an-RORl antagonist wherein the tumor or cancer comprises a mutation in a TP53 gene or a high-risk subtype.
  • the individual has been administered or is being concurrently administered a Bruton’s tyrosine kinase inhibitor (BTKi).
  • BTKi Bruton’s tyrosine kinase inhibitor
  • BTKi Bruton’s tyrosine kinase inhibitor
  • the individual has been administered or is being concurrently administered an R0R1 antagonist.
  • a method of treating a cancer or tumor in an individual comprising administering to the individual an-RORl antagonist and/or a Bruton’s tyrosine kinase inhibitor (BTKi), wherein the tumor or cancer comprises a mutation in a TP53 gene or a high-risk subtype.
  • BTKi tyrosine kinase inhibitor
  • a cell includes one or more cells, including mixtures thereof.
  • a and/or B is used herein to include all of the following alternatives: “A”, “B”, “A or B”, and “A and B .”
  • Bruton s tyrosine kinase
  • BTK tyrosine-protein kinase
  • BTK Bruton's tyrosine kinase
  • variants or homologs thereof that maintain BTK activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to BTK).
  • the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring BTK protein.
  • the BTK protein is substantially identical to the protein identified by the UniProt reference number Q01687 or a variant or homolog having substantial identity thereto.
  • the term “BTK inhibitor” or “BTKi” as provided herein refers to a substance capable of inhibiting BTK activity compared to a control.
  • the inhibited activity of BTK can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or less than that in a control. In some instances, the inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more in comparison to a control.
  • a BTKi inhibits BTK activity e.g., by at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction, activity or amount of BTK relative to the absence of the BTKi.
  • R0R1 refers to the any of the recombinant or naturally-occurring forms of tyrosine kinase-like orphan receptor 1 (R0R1) or variants or homologs thereof that maintain ROR1 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to ROR1).
  • the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring ROR1 protein.
  • the ROR1 protein is substantially identical to the protein identified by Accession No. NP_005003.1 or a variant or homolog having substantial identity thereto.
  • the ROR1 protein comprises the amino acid sequence of SEQ ID NO: 12.
  • the ROR1 protein consists of the amino acid sequence of SEQ ID NO: 12.
  • the ROR1 protein comprises or consists of the amino acid sequence of SEQ ID NO: 13.
  • the ROR1 protein comprises or consists of the amino acid sequence of SEQ ID NO: 14.
  • ROR1 antagonist refers to a substance capable of inhibiting ROR1 activity compared to a control.
  • the inhibited activity of ROR1 can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or less than that in a control. In some instances, the inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more in comparison to a control.
  • a ROR1 antagonist inhibits ROR1 activity e.g., by at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction, activity or amount of ROR1 relative to the absence of the ROR1 antagonist. In some instances, the ROR1 antagonist is an antibody or small molecule.
  • the term “antagonist” may alternatively be used herein as inhibitor.
  • tumor protein p53 and “p53” used interchangeably herein, refer to a potent tumor suppressor protein.
  • TP 53 refers to the gene encoding the tumor suppressor protein.
  • TP 53 is negatively regulated or mutated in many cancers. Absence or inactivation of TP53 may contribute to cancer.
  • a “wild type” TP53 is TP53 found in normal (i.e., non-cancerous cells) or TP53 that does not have a mutation correlated to a cancer.
  • the TP53 status of a sample may be assessed as for example described in U.S. Pat. No. 6,090,566 issued to Vogelstein et al., or using standard techniques such as described herein or known in the art.
  • a p53 protein may include, without limitation, polypeptides containing sequences substantially identical to that set forth in for example UniProt Accession No. P04637.
  • a TP 53 molecule may include, without limitation, nucleic acid molecules encoding polypeptides containing sequences substantially identical to that set forth in for example UniProt Accession No. P04637.
  • the amino acid sequence of p53 is the sequence of SEQ ID NO: 11.
  • p53 comprises an amino acid sequence of SEQ ID NO: 11.
  • mutation refers to any genetic alteration that compromises wildtype function or expression of an mRNA, protein, or polypeptide encoded by the gene. Such alterations include missense or non-sense mutations, gene deletions or translocations, insertion of one or more nucleic acids and the like. Mutations are not limited to exon sequences and can occur in introns, 3’ or 5’ untranslated regions, regulatory regions (including promoters and enhancers) of genes.
  • an “epitope” refers to the binding determinant of an antibody or fragment described herein minimally necessary for specific binding of the antibody or fragment thereof to a target antigen.
  • the target antigen is a polypeptide the epitope will be a continuous or discontinuous epitope.
  • a continuous epitope is formed by one region of the target antigen, while a discontinuous epitope may be formed from two or more separate regions.
  • a discontinuous epitope for example, may form when a target antigen adopts a tertiary structure that brings two amino acid sequences together and forms a three-dimensional structure bound by the antibody.
  • the epitope When the target antigen is a polypeptide the epitope will generally be a plurality of amino acids linked into a polypeptide chain.
  • a continuous epitope may comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids. While an epitope may comprise a contiguous polymer of amino acids, not every amino acid of the polymer may be contacted by an amino acid residue of the antibody. Such non-contacted amino acids will still comprise part of the epitope as they may be important for the structure and linkage of the contacted amino acids.
  • the skilled artisan may determine if any given antibody binds an epitope of a reference antibody, for example, by cross-blocking experiments with a reference antibody.
  • antibodies that bind the same epitope of the described antibodies. In certain embodiments, described herein, are antibodies that are competitively blocked by the described antibodies. In certain embodiments, described herein, are antibodies that compete for binding with the described antibodies.
  • antibody is used according to its commonly known meaning in the art. Antibodies exist, e.g., as intact immunoglobulins or as a number of well -characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)’2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond.
  • the F(ab)’2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)’2 dimer into an Fab’ monomer.
  • the Fab’ monomer is essentially Fab with part of the hinge region. While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology.
  • antibody also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., scFv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).
  • mAb monoclonal antibodies
  • Techniques for the production of single chain antibodies can be adapted to produce antibodies of this disclosure.
  • transgenic mice, or other organisms such as other mammals may be used to express humanized antibodies.
  • phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).
  • a single-chain variable fragment is typically a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of 10 to about 25 amino acids.
  • the linker may usually be rich in glycine for flexibility, as well as serine or threonine for solubility.
  • the linker can either connect the N- terminus of the VH with the C-terminus of the VL, or vice versa.
  • Suitable antibodies e.g., recombinant, monoclonal, or polyclonal antibodies
  • many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2d ed. 1986)).
  • the genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody.
  • Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. Nos.
  • transgenic mice or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Pat. Nos.
  • phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552- 554 (1990); Marks et al., Biotechnology 10:779-783 (1992)).
  • Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121 :210 (1986)).
  • Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Pat. No. 4,676,980, WO 91/00360; WO 92/200373; and EP 03089).
  • Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293.
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain.
  • humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and a second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments.
  • Human constant region DNA sequences can be isolated in accordance with well- known procedures from a variety of human cells.
  • numbered with reference to or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence refer to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.
  • An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue.
  • residues corresponding to a specific position in a protein e.g., ROR1
  • a protein e.g., ROR1
  • the identity and location of residues corresponding to specific positions of said protein are identified in other protein sequences aligning to said protein.
  • a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138.
  • the position in the aligned selected protein aligning with glutamic acid 138 is said to correspond to glutamic acid 138.
  • a three- dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared.
  • an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is said to correspond to the glutamic acid 138 residue.
  • Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, 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. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows: 100 times the fraction X/Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B.
  • terapéuticaally effective dose or amount as used herein is meant a dose that produces effects for which it is administered (e.g., treating or preventing a disease).
  • dose and formulation will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Editor (2003), and Pickar, Dosage Calculations (1999)).
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a standard control.
  • a therapeutically effective dose or amount may ameliorate one or more symptoms of a disease.
  • a therapeutically effective dose or amount may prevent or delay the onset of a disease or one or more symptoms of a disease when the effect for which it is being administered is to treat a person who is at risk of developing the disease.
  • ibrutinib also known as Imbruvica®, PCI 32765 or the like, refers in the usual and customary sense, to l-[(3R)-3[4-Amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin- l-yl]piperidin-l-yl]prop-2-en-l-one (CAS Registry number 936563-96-1).
  • the BTK inhibitor is any one of the compounds disclosed in U.S. Pat. Nos. 7,514,444; 8,008,309; 8,497,277; 8,476,284; 8,697,711, and 8,703,780 which are incorporated by reference herein in their entirety and for all purposes.
  • idelalisib also known as CAL101, GS-1101, Zydelig® or the like, refers in the usual and customary sense to 5-Fluoro-3-phenyl-2-[(lS)-l-(7H-purin-6-ylamino)propyl]- 4(3H)-quinazolinone (CAS Registry number 870281-82-6).
  • the BTK inhibitor is any one of the compounds disclosed in U.S. Pat. Nos. 9,469,643; 9,492,449; 8,139,195;
  • R406 refers, in the usual and customary sense, to 6-((5-fluoro-2- ((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one benzenesulfonate.
  • Fostamatinib refers in the usual and customary sense, to 6-((5- fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2- b][l,4]oxazin-3(4H)-one benzenesulfonate (CAS Registry number 901119-35-5 or 1025687-58-4 (disodium salt)).
  • Fostamatinib is a prodrug of R406.
  • the BTK inhibitor is any one of the compounds disclosed in U.S. Pat. No. 7,449,458 which is incorporated by reference herein in its entirety and for all purposes.
  • acalabrutinib also known as ACP-196 or the like, refers in the usual and customary sense to 4-[8-amino-3-[(2S)-l-but-2-ynoylpyrrolidin-2-yl]imidazo[l,5-a]pyrazin-l- yl]-N-pyridin-2-ylbenzamide (CAS Registry number 1420477-60-6).
  • the BTK inhibitor is any one of the compounds disclosed in US Pat. Application Nos. 20140155385, 20160151364, 20160159810 which are incorporated by reference herein in their entirety and for all purposes.
  • the BTK inhibitor is any one of the compounds disclosed in U.S. Pat. Nos. 8,940,725 and 8,557,803 and US Patent Application No. 20150094299 which are incorporated by reference herein in their entirety and for all purposes.
  • BGB-3111 also known as zanubrutinib and the like, refers in the usual and customary sense to 2-(4-phenoxyphenyl)-7-(l-prop-2-enoylpiperidin-4-yl)-l, 5,6,7- tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide (CAS Registry number 1633350-06-7).
  • the BTK inhibitor is any one of the compounds disclosed in US Patent Nos. 9,447,106 and 9,556,188 which are incorporated by reference herein in their entirety and for all purposes.
  • CC-292 also known as AVL-292, spebrutinib or the like, refers in the usual and customary sense to N-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4- yl]amino]phenyl]prop-2-enamide (CAS Registry number 1202757-89-8).
  • the BTK inhibitor is any one of the compounds disclosed in U.S. Pat. No. 8,338,439 which is incorporated by reference herein in its entirety and for all purposes.
  • cirmtuzumab refers to a humanized monoclonal antibody capable of binding the extracellular domain of the human receptor tyrosine kinase-like orphan receptor 1 (ROR1).
  • ROR1 human receptor tyrosine kinase-like orphan receptor 1
  • cirmtuzumab is any one of the antibodies or fragments thereof disclosed in U.S. Patent No. 9,758,591, which is incorporated by reference herein in its entirety and for all purposes.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas.
  • Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g.
  • ER positive triple negative
  • ER negative chemotherapy resistant
  • herceptin resistant HER2 positive
  • doxorubicin resistant tamoxifen resistant
  • ductal carcinoma lobular carcinoma, primary, metastatic
  • ovarian cancer pancreatic cancer
  • liver cancer e.g., hepatocellular carcinoma
  • lung cancer e.g.
  • non-small cell lung carcinoma non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma.
  • squamous cell carcinoma e.g., head, neck, or esophagus
  • colorectal cancer leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma.
  • Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairycell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia
  • “Patient” or “subject in need thereof’ refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a composition or pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • relapse refers to the recurrence of a disease (e.g., cancer) after an initial response period, e.g., after prior therapy, e.g., cancer therapy (e.g., complete response or partial response).
  • the initial response period may involve the level of malignant cells falling below a certain threshold, for example, below 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1%.
  • Recurrence may involve the level of malignant cells reaching values above a certain threshold level, for example, above 20%, 1%, 10%, 5%, 4%, 3%, 2%, or 1%.
  • reoccurrence may involve, for example, reoccurrence of blasts in the blood, bone marrow (> 5%), or any extramedullary area after a complete response.
  • the overall response may involve ⁇ 5% of BM blasts.
  • a response e.g., complete response or partial response
  • MRD minimal residual disease
  • the initial response period is at least 1, 2, 3, 4, 5, or 6 days; at least 1, 2, 3 or 4 weeks; at least 1, 2, 3, 4, 6, 8, 10, or 12 months; or at least 1, 2, 3, 4, or 5 years.
  • BTK tyrosine kinase
  • ROR1 is an onco-embryonic tyrosine kinase-like receptor that is re-expressed at high levels on many solid and hematologic cancers such as MCL, CLL, and MZL but not on normal adult tissues. Without being limited to any particular theory, ROR1 binds Wnt5a, resulting in increased tumor growth, survival, metastasis, cancer cell sternness and epithelial mesenchymal transition.
  • the present disclosure provides a method for treating a cancer or tumor with a TP53 mutation in an individual by targeting both ROR1 and BTK.
  • the method halts progression of the cancer. In certain embodiments, the method halts progression of the cancer for at least 12 months. In certain embodiments, the method halts progression of the cancer at least 24 months. In certain embodiments, the method halts progression of the cancer at least 36 months. In certain embodiments, the method halts progression of the cancer at least 48 months.
  • the ROR1 antagonist disclosed herein can be an antibody or an antigen binding fragment thereof that specifically binds to a R0R1 polypeptide.
  • the antibody can be an anti-RORl antibody.
  • the anti-RORl antibody can be a humanized antibody.
  • the anti-RORl antibody or the antigen binding fragment thereof comprises complementarity-determining regions (CDRs), allowing it to bind portions of a R0R1 polypeptide or a fragment thereof.
  • CDRs complementarity-determining regions
  • the antibody or the antigen binding fragment thereof comprises a heavy chain CDR1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 1, a heavy chain CDR2 (HCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 2, a heavy chain CDR3 (HCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 3, a light chain CDR1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 4, a light chain CDR2 (LCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 5, and/or a light chain CDR3 (LCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1
  • HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2
  • HCDR3 HCDR3
  • the antibody comprises a heavy chain CDR1 (HCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 1.
  • the antibody comprises a heavy chain CDR2 (HCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 2.
  • the antibody comprises a heavy chain CDR3 (HCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 3.
  • the antibody comprises a light chain CDR1 (LCDR1) comprising the amino acid sequence set forth in SEQ ID NO: 4.
  • the antibody comprises a light chain CDR2 (LCDR2) comprising the amino acid sequence set forth in SEQ ID NO: 5.
  • the antibody comprises a light chain CDR3 (LCDR3) comprising the amino acid sequence set forth in SEQ ID NO: 6.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 7; and/or a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region consisting of an amino acid sequence set forth in SEQ ID NO: 7; and/or a light chain variable region consisting of an amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence set forth in SEQ ID NO: 9; and/or a light chain (LC) comprising an amino acid sequence set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) consisting of an amino acid sequence set forth in SEQ ID NO: 9; and/or a light chain (LC) consisting of an amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 7.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 7.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 7. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain variable region consisting of an amino acid sequence set forth in SEQ ID NO: 7.
  • the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 8. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain variable region consisting of an amino acid sequence set forth in SEQ ID NO: 8.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 9.
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO:
  • the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) comprising an amino acid sequence set forth in SEQ ID NO: 9. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (HC) consisting of an amino acid sequence set forth in SEQ ID NO: 9.
  • the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 75% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 80% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 85% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 90% identical to that set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 95% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 96% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a heavy chain (LC) comprising an amino acid sequence at least about 97% identical to that set forth in SEQ ID NO:
  • the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 98% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 99% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence at least about 99.5% identical to that set forth in SEQ ID NO: 10. In some instances, the antibody or the antigen binding fragment thereof comprises a light chain (LC) comprising an amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or the antigen binding fragment thereof comprises a light chain (LC) consisting of an amino acid sequence set forth in SEQ ID NO: 10.
  • the antibody or antigen biding fragment thereof is zilovertamab (formerly called cirmtuzumab or UC-961 or 99961.1) or an ROR1 binding fragment thereof.
  • zilovertamab previously called cirmtuzumab or UC-961 or 99961.1
  • ROR1 binding fragment thereof is disclosed in U.S. Patent No. US 9,758,591, which is incorporated by reference herein in its entirety and for all purposes.
  • the antibody or antigen biding fragment thereof comprises a humanized heavy chain variable region and a humanized light chain variable region, wherein the humanized heavy chain variable region includes the sequences set forth in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17; and wherein the humanized light chain variable region includes the sequences set forth in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO:20.
  • An antibody including the amino acid sequences (i.e., CDRs) set forth by SEQ ID NOs: 15, 16, 17, 18, 19, 20 may be referred to herein as antibody D10.
  • the development and use of antibody D10 is disclosed in U.S. Patent No. US 9,217,040 which is incorporated by reference herein in its entirety and for all purposes.
  • the antibody or antigen biding fragment thereof binds to amino acids 130-160 of ROR1 or a fragment thereof. In some instances, the antibody or antigen biding fragment thereof binds a peptide including a glutamic acid at a position corresponding to position 138 of ROR1. In some instances, the antibody or antigen biding fragment thereof specifically binds either the 3 ’ or middle Ig-like region of the extracellular domain of the ROR1 protein. In some instances, the antibody or antigen biding fragment thereof binds the 3' end of the Ig-like region of the extracellular domain of ROR1 protein from position 1-147.
  • the antibody or antigen biding fragment thereof inhibits metastasis.
  • the antibody or antigen biding fragment thereof can be an antibody fragment.
  • the antibody can be a human antibody.
  • the antibody can be humanized.
  • the antibody can be a chimeric antibody.
  • the antibody can be a single chain antibody.
  • the antibody can be a single chain fragment variable (scFv).
  • the antibody can be a fragment antigen-binding (Fab).
  • the antibody can be a diabody.
  • the antibody can be a nanobody.
  • the antibody can be a minibody.
  • the antibody can be a heavy chain-only antibody (HCAb).
  • the antibody or antigen biding fragment thereof can also be any equivalent of the antibodies or fragments thereof disclosed herein.
  • the antibody has a binding affinity of about 500 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 550 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 600 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 650 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 700 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 750 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 800 pM to about 6 nM.
  • the antibody has a binding affinity of about 850 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 900 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 950 pM to about 6 nM. In some instances, the antibody has a binding affinity of about 1 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 1 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 1.5 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 2 nM to about 6 nM.
  • the antibody has a binding affinity of about 2.5 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 3 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 3.5 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 4 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 4.5 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 5 nM to about 6 nM. In some instances, the antibody has a binding affinity of about 5.5 nM to about 6 nM.
  • the antibody has a binding affinity of 500 pM to 6 nM. In some instances, the antibody has a binding affinity of 550 pM to 6 nM. In some instances, the antibody has a binding affinity of 600 pM to 6 nM. In some instances, the antibody has a binding affinity of 650 pM to 6 nM. In some instances, the antibody has a binding affinity of 700 pM to 6 nM. In some instances, the antibody has a binding affinity of 750 pM to 6 nM. In some instances, the antibody has a binding affinity of 800 pM to 6 nM. In some instances, the antibody has a binding affinity of 850 pM to 6 nM.
  • the antibody has a binding affinity of 900 pM to 6 nM. In some instances, the antibody has a binding affinity of 950 pM to 6 nM. In some instances, the antibody has a binding affinity of 1 nM to 6 nM. In some instances, the antibody has a binding affinity of 1 nM to 6 nM. In some instances, the antibody has a binding affinity of 1.5 nM to 6 nM. In some instances, the antibody has a binding affinity of 2 nM to 6 nM. In some instances, the antibody has a binding affinity of 2.5 nM to 6 nM. In some instances, the antibody has a binding affinity of 3 nM to 6 nM. In some instances, the antibody has a binding affinity of
  • the antibody has a binding affinity of 4 nM to 6 nM. In some instances, the antibody has a binding affinity of 4.5 nM to 6 nM. In some instances, the antibody has a binding affinity of 5 nM to 6 nM. In some instances, the antibody has a binding affinity of
  • the antibody has a binding affinity of about 500 pM to about 5.5 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 5 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 4.5 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 4 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 3.5 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 3 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 3.5 nM.
  • the antibody has a binding affinity of about 500 pM to about 3 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 2.5 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 2 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 1.5 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 1 nM. In some instances, the antibody has a binding affinity of about 500 pM to about 950 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 900 pM.
  • the antibody has a binding affinity of about 500 pM to about 850 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 800 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 750 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 700 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 650 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 600 pM. In some instances, the antibody has a binding affinity of about 500 pM to about 550 pM.
  • the antibody has a binding affinity of 500 pM to 5.5 nM. In some instances, the antibody has a binding affinity of 500 pM to 5 nM. In some instances, the antibody has a binding affinity of 500 pM to 4.5 nM. In some instances, the antibody has a binding affinity of 500 pM to 4 nM. In some instances, the antibody has a binding affinity of 500 pM to 3.5 nM. In some instances, the antibody has a binding affinity of 500 pM to 3 nM. In some instances, the antibody has a binding affinity of 500 pM to 3.5 nM. In some instances, the antibody has a binding affinity of 500 pM to 3 nM. In some instances, the antibody has a binding affinity of 500 pM to 3 nM. In some instances, the antibody has a binding affinity of 500 pM to 3 nM.
  • the antibody has a binding affinity of 500 pM to 2.5 nM. In some instances, the antibody has a binding affinity of 500 pM to 2 nM. In some instances, the antibody has a binding affinity of 500 pM to 1.5 nM. In some instances, the antibody has a binding affinity of 500 pM to 1 nM. In some instances, the antibody has a binding affinity of 500 pM to 950 pM. In some instances, the antibody has a binding affinity of 500 pM to 900 pM. In some instances, the antibody has a binding affinity of 500 pM to 850 pM. In some instances, the antibody has a binding affinity of 500 pM to 800 pM.
  • the antibody has a binding affinity of 500 pM to 750 pM. In some instances, the antibody has a binding affinity of 500 pM to 700 pM. In some instances, the antibody has a binding affinity of 500 pM to 650 pM. In some instances, the antibody has a binding affinity of 500 pM to 600 pM. In some instances, the antibody has a binding affinity of 500 pM to 550 pM.
  • the antibody has a binding affinity of about 500 pM. In some instances, the antibody has a binding affinity of 500 pM. In some instances, the antibody has a binding affinity of about 550 pM. In some instances, the antibody has a binding affinity of 550 pM. In some instances, the antibody has a binding affinity of about 600 pM. In some instances, the antibody has a binding affinity of 600 pM. In some instances, the antibody has a binding affinity of about 650 pM. In some instances, the antibody has a binding affinity of 650 pM. In some instances, the antibody has a binding affinity of about 700 pM. In some instances, the antibody has a binding affinity of 700 pM.
  • the antibody has a binding affinity of about 750 pM. In some instances, the antibody has a binding affinity of 750 pM. In some instances, the antibody has a binding affinity of about 800 pM. In some instances, the antibody has a binding affinity of 800 pM. In some instances, the antibody has a binding affinity of about 850 pM. In some instances, the antibody has a binding affinity of 850 pM. In some instances, the antibody has a binding affinity of about 900 pM. In some instances, the antibody has a binding affinity of 900 pM. In some instances, the antibody has a binding affinity of about 950 pM. In some instances, the antibody has a binding affinity of 950 pM.
  • the antibody has a binding affinity of about 1 nM. In some instances, the antibody has a binding affinity of about 1 nM. In some instances, the antibody has a binding affinity of 1 nM. In some instances, the antibody has a binding affinity of about 1.5 nM. In some instances, the antibody has a binding affinity of 1.5 nM. In some instances, the antibody has a binding affinity of about 2 nM. In some instances, the antibody has a binding affinity of 2 nM. In some instances, the antibody has a binding affinity of about 2.5 nM. In some instances, the antibody has a binding affinity of 2.5 nM. In some instances, the antibody has a binding affinity of about 3 nM.
  • the antibody has a binding affinity of 3 nM. In some instances, the antibody has a binding affinity of about 3.5 nM. In some instances, the antibody has a binding affinity of 3.5 nM. In some instances, the antibody has a binding affinity of about 4 nM. In some instances, the antibody has a binding affinity of 4 nM. In some instances, the antibody has a binding affinity of about 4.5 nM. In some instances, the antibody has a binding affinity of 4.5 nM. In some instances, the antibody has a binding affinity of about 5 nM. In some instances, the antibody has a binding affinity of 5 nM. In some instances, the antibody has a binding affinity of about 5.5 nM.
  • the antibody has a binding affinity of 5.5 nM. In some instances, the antibody has a binding affinity of about 6 nM. In some instances, the antibody has a binding affinity of 6 nM. [0075] In some instances, the antibody binds to an ROR1 protein with a KD of less than about 40 nM (e.g., 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.25, 0.1 nM). In some instances, the antibody binds to an ROR1 protein with a KD of less than 40 nM (e.g., 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.25, 0.1 nM).
  • the antibody binds to an ROR1 protein with a KD of less than about 35 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 35 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 30 nM. In some instances, the antibody binds to an R0R1 protein with a KD of less than 30 nM. In some instances, the antibody binds to an R0R1 protein with a KD of less than about 25 nM. In some instances, the antibody binds to an R0R1 protein with a KD of less than 25 nM.
  • the antibody binds to an R0R1 protein with a KD of less than about 20 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 20 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 15 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 15 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 10 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 10 nM.
  • the antibody binds to an ROR1 protein with a KD of less than about 9 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 9 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 8 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 8 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 7 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 7 nM.
  • the antibody binds to an ROR1 protein with a KD of less than about 6 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 6 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 5 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 5 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 4 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 4 nM.
  • the antibody binds to an ROR1 protein with a KD of less than about 3 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 3 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 2 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 2 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 1 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 1 nM.
  • the antibody binds to an ROR1 protein with a KD of less than about 0.5 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 0.5 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 0.25 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 0.25 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than about 0.1 nM. In some instances, the antibody binds to an ROR1 protein with a KD of less than 0.1 nM.
  • the antibody is zilovertamab, also referred to herein as 99961.1 or UC- 961. In some instances, the antibody is D10.
  • the ROR1 antagonist as disclosed herein can be administered to a subject intravenously.
  • the R0R1 antagonist as disclosed herein can be administered to a subject every 1, 2, 4, or 6 weeks.
  • the R0R1 antagonist can be administered to a subject every 2 weeks.
  • the R0R1 antagonist can be administered to a subject every 4 weeks.
  • the R0R1 antagonist can be an antibody disclosed herein.
  • the antibody can be zilovertamab.
  • the antibody is administered to a subject intravenously.
  • the antibody can be administered to a subject every 2 weeks.
  • the antibody can be administered to a subject every 4 weeks.
  • the antibody is administered to a subject every 2 weeks for at least 2 administrations.
  • the antibody is administered to a subject every 2 weeks for at least 3 administrations. In some instances, the antibody is administered to a subject every 2 weeks for at least 4 administrations. In some instances, the antibody is administered to a subject every 2 weeks for at least 5 administrations. In some instances, the antibody is administered to a subject every 2 weeks for at least 6 administrations. In some instances, the antibody is administered to a subject every 2 weeks for 3 administrations and then every 4 weeks thereafter.
  • the R0R1 antagonist is administered at a dose of between about 200 milligrams and about 800 milligrams. In some instances, the R0R1 antagonist is administered at a dose of between about 220 milligrams and about 780 milligrams. In some instances, the R0R1 antagonist is administered at a dose of between about 240 milligrams and about 760 milligrams. In some instances, the R0R1 antagonist is administered at a dose of between about 260 milligrams and about 740 milligrams. In some instances, the R0R1 antagonist is administered at a dose of between about 280 milligrams and about 720 milligrams.
  • the R0R1 antagonist is administered at a dose of between about 300 milligrams and about 700 milligrams. In some instances, the R0R1 antagonist is administered at a dose of between about 320 milligrams and about 680 milligrams. In some instances, the ROR1 antagonist is administered at a dose of between about 340 milligrams and about 660 milligrams. In some instances, the ROR1 antagonist is administered at a dose of between about 360 milligrams and about 640 milligrams. In some instances, the ROR1 antagonist is administered at a dose of between about 380 milligrams and about 620 milligrams.
  • the ROR1 antagonist is administered at a dose of between about 400 milligrams and about 600 milligrams. In some instances, the ROR1 antagonist is administered at a dose of between about 420 milligrams and about 580 milligrams. In some instances, the ROR1 antagonist is administered at a dose of between about 440 milligrams and about 560 milligrams. In some instances, the ROR1 antagonist is administered at a dose of between about 550 milligrams and about 650 milligrams. In some instances, the ROR1 antagonist is administered at a dose of about 200 milligrams. In some instances, the ROR1 antagonist is administered at a dose of about 300 milligrams.
  • the ROR1 antagonist is administered at a dose of about 400 milligrams. In some instances, the R0R1 antagonist is administered at a dose of about 500 milligrams. In some instances, the ROR1 antagonist is administered at a dose of about 600 milligrams. In some instances, the ROR1 antagonist is administered at a dose of about 650 milligrams.
  • the ROR1 antagonist is administered at a dose of about 600 milligrams intravenously every 2 weeks for 3 administrations and then every 4 weeks thereafter.
  • the anti-RORl antibody is administered at a dose of about 600 milligrams intravenously every 2 weeks for 3 administrations and then every 4 weeks thereafter.
  • the anti-RORl antibody zilovertamab is administered at a dose of about 600 milligrams intravenously every 2 weeks for 3 administrations and then every 4 weeks thereafter.
  • BTK inhibitor (BTKi) BTK inhibitor
  • the BTK inhibitor (BTKi) disclosed herein can be a small molecule.
  • the BTKi is ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, orelabrutinib, rilzabrutinib, tolebrutinib, branebrutinib, nemtabrutinib, elsubrutinib, remibrutinib, vecabrutinib, remibrutinib, spebrutinib tirabrutinib, AC0058TA, pirtobrutinib (LOXO-305), zanubrutinib, Spebrutinib, DTRMWXHS-12, M7583, SN-1011, or TG-1701
  • the BTKi is ibrutinib.
  • the BTKi is acalabrutinib. In some instances, the BTKi is tirabrutinib (ONO/GS-4059). In some instances, the BTKi is zanubrutinib (BGB-3111). In some instances, the BTKi is CC-292. In some instances, the BTKi is Spebrutinib (AVL-292).
  • the BTKi comprises ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, orelabrutinib, rilzabrutinib, tolebrutinib, branebrutinib, nemtabrutinib, elsubrutinib, remibrutinib, vecabrutinib, remibrutinib, spebrutinib tirabrutinib, AC0058TA, pirtobrutinib (LOXO-305), zanubrutinib, Spebrutinib, DTRMWXHS-12, M7583, SN-1011, or TG-1701.
  • the BTKi comprises ibrutinib. In some instances, the BTKi comprises acalabrutinib. In some instances, the BTKi comprises evobrutinib. In some instances, the BTKi comprises fenebrutinib. In some instances, the BTKi comprises orelabrutinib. In some instances, the BTKi comprises rilzabrutinib. In some instances, the BTKi comprises tolebrutinib.
  • the BTKi comprises at least two molecules selected from the group consisting of ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, orelabrutinib, rilzabrutinib, tolebrutinib, branebrutinib, nemtabrutinib, elsubrutinib, remibrutinib, vecabrutinib, remibrutinib, spebrutinib tirabrutinib, AC0058TA, pirtobrutinib (LOXO-305), zanubrutinib, Spebrutinib, DTRMWXHS-12, M7583, SN-1011, or TG-1701.
  • the BTKi is ibrutinib. In some instances, the BTKi is acalabrutinib. In some instances, the BTKi is evobrutinib. In some instances, the BTKi is fenebrutinib. In some instances, the BTKi is orelabrutinib. In some instances, the BTKi is rilzabrutinib. In some instances, the BTKi is tolebrutinib.
  • the BTKi comprises ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, orelabrutinib, rilzabrutinib, tolebrutinib, branebrutinib, nemtabrutinib, elsubrutinib, remibrutinib, vecabrutinib, remibrutinib, spebrutinib tirabrutinib, AC0058TA, pirtobrutinib (LOXO-305), zanubrutinib, Spebrutinib, DTRMWXHS-12, M7583, SN-1011, or TG-1701.
  • the BTKi comprises branebrutinib. In some instances, the BTKi comprises elsubrutinib. In some instances, the BTKi comprises remibrutinib. In some instances, the BTKi comprises vecabrutinib. In some instances, the BTKi comprises nemtabrutinib. In some instances, the BTKi comprises spebrutinib. In some instances, the BTKi comprises tirabrutinib. In some instances, the BTKi comprises AC0058TA. In some instances, the BTKi comprises LOXO-305. In some instances, the BTKi comprises DTRMWXHS-12. In some instances, the BTKi comprises M7583.
  • the BTKi comprises SN-1011. In some instances, the BTKi comprises TG-1701. In some instances, the BTKi comprises at least two molecules selected from the group consisting of ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, orelabrutinib, rilzabrutinib, tolebrutinib, branebrutinib, nemtabrutinib, elsubrutinib, remibrutinib, vecabrutinib, remibrutinib, spebrutinib tirabrutinib, AC0058TA, pirtobrutinib (LOXO-305), zanubrutinib, Spebrutinib, DTRMWXHS-12, M7583, SN-1011, or TG-1701.
  • the BTKi is branebrutinib. In some instances, the BTKi is elsubrutinib. In some instances, the BTKi is remibrutinib. In some instances, the BTKi is vecabrutinib. In some instances, the BTKi is spebrutinib. In some instances, the BTKi is tirabrutinib. In some instances, the BTKi is AC0058TA. In some instances, the BTKi is LOXO- 305. In some instances, the BTKi is DTRMWXHS-12. In some instances, the BTKi is M7583. In some instances, the BTKi is SN-1011. In some instances, the BTKi is TG-1701. In some instances, the BTKi is nemtabrutinib.
  • the BTKi as disclosed herein can be administered to a subject orally.
  • the BTKi as disclosed herein can be administered to a subject intravenously.
  • the BTKi as disclosed herein can be administered to a subject daily.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 4 weeks.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 8 weeks.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 12 weeks.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 16 weeks.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 18 weeks.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 24 weeks.
  • the BTKi as disclosed herein can be administered to a subject daily for at least 30 weeks.
  • the BTKi is administered at a dose of between about 280 and about 700 milligrams. In some instances, the BTKi is administered at a dose of between about 300 and about 680 milligrams. In some instances, the BTKi is administered at a dose of between about 320 and about 660 milligrams. In some instances, the BTKi is administered at a dose of between about 340 and about 640 milligrams. In some instances, the BTKi is administered at a dose of between about 360 and about 620 milligrams. In some instances, the BTKi is administered at a dose of between about 380 and about 600 milligrams.
  • the BTKi is administered at a dose of between about 400 and about 580 milligrams. In some instances, the BTKi is administered at a dose of between about 420 and about 560 milligrams. In some instances, the BTKi is administered at a dose of about 420 milligrams. In some instances, the BTKi is administered at a dose of about 560 milligrams.
  • the BTKi is administered at a dose of about 20 mg to about 160 mg. In some instances, the BTKi is administered at a dose of about 20 mg to about 25 mg, about 20 mg to about 40 mg, about 20 mg to about 45 mg, about 20 mg to about 50 mg, about 20 mg to about 65 mg, about 20 mg to about 80 mg, about 20 mg to about 90 mg, about 20 mg to about 100 mg, about 20 mg to about 125 mg, about 20 mg to about 150 mg, about 20 mg to about 160 mg, about 25 mg to about 40 mg, about 25 mg to about 45 mg, about 25 mg to about 50 mg, about 25 mg to about 65 mg, about 25 mg to about 80 mg, about 25 mg to about 90 mg, about 25 mg to about 100 mg, about 25 mg to about 125 mg, about 25 mg to about 150 mg, about 25 mg to about 160 mg, about 40 mg to about 45 mg, about 40 mg to about 50 mg, about 40 mg to about 65 mg, about 40 mg to about 80 mg, about 40 mg to about 90 mg, about 40 mg to about 50 mg, about 40
  • the BTKi is administered at a dose of about 20 mg, about 25 mg, about 40 mg, about 45 mg, about 50 mg, about 65 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 160 mg. In some instances, the BTKi is administered at a dose of at least about 20 mg, about 25 mg, about 40 mg, about 45 mg, about 50 mg, about 65 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, or about 150 mg. In some instances, the BTKi is administered at a dose of at most about 25 mg, about 40 mg, about 45 mg, about 50 mg, about 65 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 160 mg.
  • the BTKi is administered at a dose of about 25 mg to about 480 mg. In some instances, the BTKi is administered at a dose of about 25 mg to about 50 mg, about 25 mg to about 75 mg, about 25 mg to about 100 mg, about 25 mg to about 125 mg, about 25 mg to about 150 mg, about 25 mg to about 160 mg, about 25 mg to about 175 mg, about 25 mg to about 200 mg, about 25 mg to about 320 mg, about 25 mg to about 375 mg, about 25 mg to about 480 mg, about 50 mg to about 75 mg, about 50 mg to about 100 mg, about 50 mg to about 125 mg, about 50 mg to about 150 mg, about 50 mg to about 160 mg, about 50 mg to about 175 mg, about 50 mg to about 200 mg, about 50 mg to about 320 mg, about 50 mg to about 375 mg, about 50 mg to about 480 mg, about 75 mg to about 100 mg, about 75 mg to about 125 mg, about 75 mg to about 150 mg, about 75 mg to about 160 mg, about 75 mg to about 160 mg,
  • the BTKi is administered at a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 320 mg, about 375 mg, or about 480 mg. In some instances, the BTKi is administered at a dose of at least about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 320 mg, or about 375 mg.
  • the BTKi is administered at a dose of at most about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 160 mg, about 175 mg, about 200 mg, about 320 mg, about 375 mg, or about 480 mg. In some instances, the BTKi is administered at a dose of about 280 mg to about 800 mg.
  • the BTKi is administered at a dose of about 280 mg to about 300 mg, about 280 mg to about 340 mg, about 280 mg to about 360 mg, about 280 mg to about 400 mg, about 280 mg to about 420 mg, about 280 mg to about 500 mg, about 280 mg to about 560 mg, about 280 mg to about 580 mg, about 280 mg to about 600 mg, about 280 mg to about 700 mg, about 280 mg to about 800 mg, about 300 mg to about 340 mg, about 300 mg to about 360 mg, about 300 mg to about 400 mg, about 300 mg to about 420 mg, about 300 mg to about 500 mg, about 300 mg to about 560 mg, about 300 mg to about 580 mg, about 300 mg to about 600 mg, about 300 mg to about 700 mg, about 300 mg to about 800 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 420 mg, about 340 mg to about 500 mg, about 340 mg to about 560 mg, about 300 mg to about 800 mg, about
  • the BTKi is administered at a dose of about 280 mg, about 300 mg, about 340 mg, about 360 mg, about 400 mg, about 420 mg, about 500 mg, about 560 mg, about 580 mg, about 600 mg, about 700 mg, or about 800 mg. In some instances, the BTKi is administered at a dose of at least about 280 mg, about 300 mg, about 340 mg, about 360 mg, about 400 mg, about 420 mg, about 500 mg, about 560 mg, about 580 mg, about 600 mg, or about 700 mg.
  • the BTKi is administered at a dose of at most about 300 mg, about 340 mg, about 360 mg, about 400 mg, about 420 mg, about 500 mg, about 560 mg, about 580 mg, about 600 mg, about 700 mg, or about 800 mg. In some instances, the BTKi is administered once daily. In some instances, the BTKi is administered twice daily.
  • the BTKi is administered to a subject orally at a dose of between about 280 and about 700 milligrams. In some instances, the BTKi is administered to a subject orally at a dose of between about 280 and about 700 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 280 and about 700 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 280 and about 700 milligrams, wherein the subject has MZL.
  • the BTKi is administered to a subject orally at a dose of between about 300 and about 680 milligrams. In some instances, the BTKi is administered to a subject orally at a dose of between about 300 and about 680 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 300 and about 680 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 300 and about 680 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of between about 320 and about 660 milligrams.
  • the BTKi is administered to a subject orally at a dose of between about 320 and about 660 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 320 and about 660 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 320 and about 660 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of between about 340 and about 640 milligrams.
  • the BTKi is administered to a subject orally at a dose of between about 340 and about 640 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 340 and about 640 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 340 and about 640 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of between about 360 and about 620 milligrams.
  • the BTKi is administered to a subject orally at a dose of between about 360 and about 620 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 360 and about 620 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 360 and about 620 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of between about 380 and about 600 milligrams.
  • the BTKi is administered to a subject orally at a dose of between about 380 and about 600 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 380 and about 600 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 380 and about 600 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of between about 400 and about 580 milligrams.
  • the BTKi is administered to a subject orally at a dose of between about 400 and about 580 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 400 and about 580 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 400 and about 580 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of between about 420 and about 560 milligrams.
  • the BTKi is administered to a subject orally at a dose of between about 420 and about 560 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of between about 420 and about 560 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of between about 420 and about 560 milligrams, wherein the subject has MZL.
  • the BTKi is administered to a subject orally at a dose of about 420 milligrams. In some instances, the BTKi is administered to a subject orally at a dose of about 420 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of about 420 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of about 420 milligrams, wherein the subject has MZL. In some instances, the BTKi is administered to a subject orally at a dose of about 560 milligrams.
  • the BTKi is administered to a subject orally at a dose of about 560 milligrams, wherein the subject has CLL. In some instances, the BTKi is administered to a subject orally at a dose of about 560 milligrams, wherein the subject has MCL. In some instances, the BTKi is administered to a subject orally at a dose of about 560 milligrams, wherein the subject has MZL.
  • TP53 encodes the tumor-suppressor protein p53. Protein p53 play an important role in various cellular activities including regulation of the cell cycle and apoptosis and promotion of DNA repair in response to cellular stress signals such as DNA damage (E. Campo et al., Haematologica, 2018; 103(12)).
  • the cancer or tumor as disclosed herein comprises a mutation in a gene TP53. TP53 mutations are associated with poor outcome in cancers. In some instances, the mutation is in an exon of the TP53 gene. In some instances, the mutation is in an intron of the TP53 gene. In some instances, the mutation is a nonsense mutation in the TP53 gene.
  • the mutation is a missense mutation in the TP53 gene. In some instances, the mutation results in an amino acid insertion, deletion, or substitution in a protein encoded by the TP53 gene. In some instances, the mutation is associated with del( 17p). In some instances, the mutation is a splice-site mutation. In some instances, the mutation is in at least one exon from exons 4-8 of TP53. For example, the mutation can be in exon 4, exon 5, exon 6, exon 7, or exon 8 of TP53. In some instances, the mutation results in an aberration in the DNA-binding domain of p53. In some instances, the mutation results in an aberration in the oligomerization domain of p53.
  • the mutation results in an aberration in the C-terminal domain of p53.
  • the mutation comprises a single mutation as described herein or a combination of the single mutations as described herein.
  • the mutation can comprise a missense mutation and a del(17p) mutation.
  • the mutation in TP53 can comprise a missense mutation.
  • the mutation in TP 53 can comprise a conformational mutations which charges the p53 protein conformation.
  • the mutation can comprise an insertion mutation and a del(17p) mutation.
  • the mutation can comprise a gene deletion mutation and a del(17p) mutation.
  • the mutation can comprise a splice-site mutation and a del(17p) mutation.
  • the mutation can comprise an insertion mutation and a missense mutation.
  • the mutation can comprise a gene deletion mutation and a missense mutation.
  • the mutation can comprise a splice-site mutation and a missense mutation.
  • the mutation can comprise an insertion mutation and a gene deletion mutation.
  • the mutation can comprise an insertion mutation and a splice-site mutation.
  • the mutation can comprise a gene deletion mutation and a splice-site mutation.
  • the mutation in TP53 can comprise any mutation that results in a loss of wildtype p53 function in a cell.
  • the mutation in TP53 can comprise a mutation at a position of R175H, R248Q, R273H, R248W, R273C, R282W, G245S, R249S, or Y220C.
  • the TP53 mutation may be a contact mutant and may result in the loss of DNA binding.
  • the TP53 R248Q mutation may be a hotspot mutation that lies within the DNA-binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 R273H mutation may a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 R248W mutation may be a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 R175 mutation may be a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 R175 mutation may be a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 G245mutation may be a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 R249mutation may be a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the p53 R282mutation may be a hotspot mutation that lies within the DNA binding domain of the Tp53 protein which results in a loss of DNA binding.
  • the TP53 mutation may be a conformational mutations which charges the p53 protein conformation.
  • the TP53 mutation may be a conformational mutations which charges the p53 protein conformation.
  • the p53 R175H mutation and p53 R249S mutation may be conformational mutations, which dramatically change the TP53 conformation
  • the methods disclosed herein can comprise determining if the tumor or cancer comprises a mutation in the TP53 gene.
  • a test can be performed on the tumor or cancer to determine if the tumor or cancer comprises a mutation in the TP53 gene.
  • the test can be based either on genomic DNA or mRNA as template.
  • the test can also be based on p53 protein.
  • the test can be immunohistochemistry, immunofluorescence, PCR, RT-PCR, real-time PCR, fluorescence in situ hybridization (FISH), sequencing including next generation sequencing, or genomic arrays, or any combination thereof.
  • the methods provided herein are useful for the treatment of cancer or tumor, particular cancer or tumor having a mutation in TP53.
  • the methods and compositions as described herein provide effective treatment for cancers expressing ROR1.
  • a method of treating a cancer or tumor in an individual comprising administering to the individual a ROR1 antagonist and a BTKi, wherein the tumor or cancer comprises a mutation in a TP53 gene.
  • the mutation in the TP53 gene can be any mutation or a combination of mutations as disclosed herein.
  • the method comprises administering to the subject in need thereof a therapeutically effective amount of a BTKi and a ROR1 antagonist.
  • the BTKi can be a small molecule.
  • the BTKi can be any of the BTKi small molecules as disclosed herein.
  • the ROR1 antagonist can be an anti-RORl antibody or antigen binding fragment thereof.
  • the antibody or antigen binding fragment thereof can be any antibody or fragment disclosed herein.
  • the BTKi is ibrutinib.
  • the ROR1 antagonist is zilovertamab.
  • the BTKi and the ROR1 antagonist are administered in a combined synergistic amount.
  • the BTKi and anti-RORl antibody are administered in a combined synergistic amount.
  • a “combined synergistic amount” as used herein refers to the sum of a first amount (e.g., an amount of a BTKi) and a second amount (e.g., an amount of a ROR1 antagonist) that results in a synergistic effect (i.e., an effect greater than an additive effect).
  • the terms “synergy”, “synergism”, “synergistic”, “combined synergistic amount”, and “synergistic therapeutic effect” which are used herein interchangeably, refer to a measured effect of compounds administered in combination where the measured effect is greater than the sum of the individual effects of each of the compounds administered alone as a single agent.
  • a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 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,
  • a synergistic amount may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2,
  • the synergistic effect may be a BTK activity decreasing effect and/or a ROR1 activity decreasing effect.
  • synergy between the BTKi and the ROR1 antagonist may result in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,
  • synergy between the BTKi and the ROR1 antagonist may result in 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,
  • the synergistic effect may be a cancer-treating effect such as a lymphoma (i.e. a lymphoma-treating synergistic effect), leukemia (i.e. a leukemia-treating synergistic effect), myeloma (i.e. a myeloma-treating synergistic effect), AML (i.e. a AML-treating synergistic effect), B-ALL (i.e. a B-ALL-treating synergistic effect), T-ALL (i.e. a T-ALL-treating synergistic effect), renal cell carcinoma (i.e. a renal cell carcinoma-treating synergistic effect), colon cancer (i.e.
  • a colon cancer-treating synergistic effect colorectal cancer (i.e. a colorectal cancer-treating synergistic effect), breast cancer (i.e. a breast cancer-treating synergistic effect), epithelial squamous cell cancer (i.e., epithelial squamous cell cancer-treating synergistic effect), melanoma (i.e., melanoma-treating synergistic effect), stomach cancer (i.e. a stomach cancertreating synergistic effect), brain cancer (i.e. a brain cancer -treating synergistic effect), lung cancer (i.e. a lung cancer-treating synergistic effect), pancreatic cancer (i.e.
  • a pancreatic cancertreating synergistic effect cervical cancer (i.e. a cervical cancer-treating synergistic effect), ovarian cancer (i.e. an ovarian cancer-treating synergistic effect), liver cancer (i.e. a liver cancertreating synergistic effect), bladder cancer (i.e. a bladder cancer-treating synergistic effect), prostate cancer (i.e. a prostate cancer-treating synergistic effect), testicular cancer (i.e. a testicular cancer-treating synergistic effect), thyroid cancer (i.e. a thyroid cancer -treating synergistic effect), head and neck cancer (i.e.
  • a head and neck cancer-treating synergistic effect uterine cancer (i.e. an uterine cancer-treating synergistic effect), adenocarcinoma (i.e. an adenocarcinoma-treating synergistic effect), adrenal cancer (i.e. an adrenal cancer-treating synergistic effect), chronic lymphocytic leukemia (i.e. a chronic lymphocytic leukemia-treating synergistic effect), small lymphocytic lymphoma (i.e. a small lymphocytic lymphoma-treating synergistic effect), marginal cell B-Cell lymphoma (i.e.
  • the cancer or tumor disclosed herein may comprise any of the TP53 mutations as disclosed herein.
  • the methods as disclosed herein can achieve a high overall response rate (ORR) in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve a higher ORR in patients with cancer or tumor comprising a TP53 mutation as compared to single treatment with BTKi (such as a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib)) alone.
  • BTKi such as a Bruton’s Kinase Inhibitor BTKI (e.g., ibrutinib)
  • the methods of combination treatment disclosed herein can achieve at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% ORR in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve at least about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% ORR in patients with cancer or tumor comprising a TP53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 80% ORR in patients with cancer or tumor comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a high complete response rate (CR) in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve a higher CR in patients with cancer or tumor comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% CR in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve at least about 5%, about 10%, about 15%, or about 20% CR in patients with cancer or tumor comprising a TP 53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 15% CR in patients with cancer or tumor comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a high partial response rate (PR) in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve a higher PR in patients with cancer or tumor comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% PR in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve at least about 60%, about 65%, or about 70% PR in patients with cancer or tumor comprising a TP53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 65% PR in patients with cancer or tumor comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a low stable disease rate (SD) in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve a lower SD in patients with cancer or tumor comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve an SD no more than about 15%, about 12%, about 10%, about 8% or about 6% in patients with cancer or tumor comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a low progressive disease rate (PD) in patients with cancer or tumor comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve a lower PD in patients with cancer or tumor comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve an PD no more than about 25%, about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% in patients with cancer or tumor comprising a TP53 mutation.
  • the methods as disclosed herein can achieve an ORR of at least about 60%, about 70%, about 75%, about 80%, about 85%, or about 90% for at least 3, 6, 9, 12, 15, or 26 months. In some instances, the methods as disclosed herein can achieve a CR of at least about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% for at least 3, 6, 9, 12, 15, or 26 months. In some instances, the methods as disclosed herein can achieve a PR of at least about 40%, about 45%, about 50%, about 55%, or about 60% for at least about 3, about 6, about 9, about 12, about 15, or about 26 months.
  • the methods as disclosed herein can achieve a prolonged progression free survival (PFS).
  • PFS progression free survival
  • the methods as disclosed herein can achieve a median PFS of at least about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 months.
  • the methods as disclosed herein can achieve a median PFS of at least about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 months.
  • the methods as disclosed herein can achieve a median PFS from about 10 to about 20 months.
  • the methods as disclosed herein can achieve a median PFS from about 12 to about 18 months.
  • the methods as disclosed herein can achieve a median PFS from about 17 months.
  • the cancer or tumor to be treated can be MCL.
  • the cancer or tumor to be treated can be CLL.
  • the cancer or tumor to be treated can be small cell lymphocytic leukemia (SLL).
  • the cancer or tumor to be treated can be marginal zone lymphoma (MZL).
  • the cancer or tumor to be treated can be diffuse large B cell lymphoma (DLBCL).
  • the cancer or tumor can be an MCL that is a high-risk subtype according to the simplified mantle cell lymphoma international prognostic index.
  • the cancer or tumor to be treated can be relapsed or refractory.
  • the cancer or tumor to be treated can have failed 1, 2, 3, 4 or more previous treatment courses or interventions intended to treat the cancer or tumor.
  • the cancer or tumor comprising a TP53 mutation can be MCL.
  • the cancer or tumor comprising a TP53 mutation can be CLL.
  • the cancer or tumor comprising a TP53 mutation can be small cell lymphocytic leukemia (SLL).
  • the cancer or tumor comprising a TP53 mutation can be marginal zone lymphoma (MZL).
  • the cancer or tumor comprising a TP53 mutation can be diffuse large B cell lymphoma (DLBCL).
  • the cancer or tumor comprising a TP53 mutation can be an MCL that is a high-risk subtype according to the simplified mantle cell lymphoma international prognostic index.
  • the cancer or tumor with the P53 mutation can be relapsed or refractory.
  • the cancer or tumor with the P53 mutation can have failed 1, 2, 3, 4 or more previous treatments intended to treat the cancer or tumor.
  • the methods as disclosed herein can achieve a high overall response rate (ORR) in patients with MCL comprising a TP53 mutation.
  • ORR overall response rate
  • the methods of combination treatment disclosed herein can achieve a higher ORR in patients with MCL comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% ORR in patients with MCL comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve at least about 60%, about 65%, about 70%, about 75%, about 80%, or about 85% ORR in patients with MCL comprising a TP53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 80% ORR in patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a high complete response rate (CR) in patients with MCL comprising a TP 53 mutation.
  • the methods of combination treatment disclosed herein can achieve a higher CR in patients with MCL comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve at least about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% CR in patients with MCL comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve at least about 5%, about 10%, about 15%, or about 20% CR in patients with MCL comprising a TP53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 15% CR in patients with MCL comprising a TP53 mutation. [0110]
  • the methods as disclosed herein can achieve a high partial response rate (PR) in patients with MCL comprising a TP53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve a higher PR in MCL or tumor comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • BTKi such as ibrutinib
  • the methods of combination treatment disclosed herein can achieve at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70% PR in patients with MCL comprising a TP 53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 60%, about 65%, or about 70% PR in patients with MCL comprising a TP 53 mutation. In some instances, the methods of combination treatment disclosed herein can achieve at least about 65% PR in patients with MCL comprising a TP 53 mutation.
  • the methods as disclosed herein can achieve a low stable disease rate (SD) in patients with MCL comprising a TP53 mutation.
  • the methods of combination treatment disclosed herein can achieve a lower SD in patients with MCL comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve an SD no more than about 15%, about 12%, about 10%, about 8% or about 6% in patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a low progressive disease rate (PD) in patients with MCL comprising a TP 53 mutation.
  • the methods of combination treatment disclosed herein can achieve a lower PD in patients with MCL comprising a TP53 mutation as compared to single treatment with BTKi (such as ibrutinib) alone.
  • the methods of combination treatment disclosed herein can achieve an PD no more than about 25%, about 20%, about 15%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% in patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve an ORR of at least about 60%, about 70%, about 75%, about 80%, about 85%, or about 90% for at least about 3, about 6, about 9, about 12, about 15, or about 26 months for patients with MCL comprising a TP53 mutation. In some instances, the methods as disclosed herein can achieve a CR of at least about 20%, about 25%, about 30%, about 35%, about 40%, or about 45% for at least about 3, about 6, about 9, about 12, about 15, or about 26 months for patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a PR of at least about 40%, about 45%, about 50%, about 55%, or about 60% for at least about 3, about 6, about 9, about 12, about 15, or about 26 months for patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a prolonged progression free survival (PFS) for patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a median PFS of at least about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 months for patients with MCL comprising a TP53 mutation.
  • the methods as disclosed herein can achieve a median PFS of at least about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 months for patients with MCL comprising a TP53 mutation. In some instances, the methods as disclosed herein can achieve a median PFS from about 10 to about 20 months for patients with MCL comprising a TP53 mutation. In some instances, the methods as disclosed herein can achieve a median PFS from about 12 to about 18 months for patients with MCL comprising a TP53 mutation. In some instances, the methods as disclosed herein can achieve a median PFS from about 17 months for patients with MCL comprising a TP53 mutation.
  • the BTKi and the ROR1 antagonist may be administered in combination either simultaneously (e.g., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent).
  • combination is used to refer to concomitant, simultaneous or sequential administration of the BTKi and the ROR1 antagonist.
  • the BTKi and the ROR1 antagonist are administered simultaneously or sequentially. In some instances, the BTKi and the ROR1 antagonist are administered simultaneously. In some instances, the BTKi and the ROR1 antagonist are administered sequentially. During the course of treatment, the BTKi and ROR1 antagonist may at times be administered sequentially and at other times be administered simultaneously.
  • the ROR1 antagonist is administered at a first time point and the BTKi is administered at a second time point, wherein the first time point precedes the second time point.
  • the BTKi and the ROR1 antagonist are administered sequentially, the BTKi is administered at a first time point and the ROR1 antagonist is administered at a second time point, wherein the first time point precedes the second time point.
  • the course of treatment is best determined on an individual basis depending on the particular characteristics of the subject and the type of treatment selected.
  • the treatment can be administered to the subject on a daily, twice daily, bi-weekly, monthly or any applicable basis that is therapeutically effective.
  • the treatment can be administered alone or in combination with any other treatment disclosed herein or known in the art.
  • the additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule (e.g., the first treatment can be daily, while the additional treatment is weekly).
  • the BTKi and ROR1 antagonist may be administered as a mixture.
  • the BTKi and the ROR1 antagonist are admixed prior to administration.
  • the BTKi is administered at an amount of about 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg or 15 mg/kg. In some instances, the BTKi is administered at an amount of about 1 mg/kg. In some instances, the BTKi is administered at an amount of 1 mg/kg. In some instances, the BTKi is administered at an amount of about 2 mg/kg. In some instances, the BTKi is administered at an amount of 2 mg/kg. In some instances, the BTKi is administered at an amount of about 5 mg/kg. In some instances, the BTKi is administered at an amount of 5 mg/kg. In some instances, the BTKi is administered at an amount of about 10 mg/kg.
  • the BTKi is administered at an amount of 10 mg/kg. In some instances, the BTKi is administered at an amount of about 15 mg/kg. In some instances, the BTKi is administered at an amount of 15 mg/kg. In some instances, the BTKi is administered at an amount of about 420 mg. In some instances, the BTKi is administered at an amount of 420 mg. In some instances, the BTKi is administered at an amount of about 560 mg. In some instances, the BTKi is administered at an amount of 560 mg.
  • the ROR1 antagonist is administered at an amount of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg or 10 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of about 1 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of 1 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of about 2 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of 2 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of about 3 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of 3 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of about 5 mg/kg.
  • the ROR1 antagonist is administered at an amount of 5 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of about 10 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of 10 mg/kg. In some instances, the ROR1 antagonist is administered at an amount of about 600 mg. In some instances, the ROR1 antagonist is administered at an amount of 600 mg.
  • the BTKi is administered at an amount of about 5 mg/kg and the ROR1 antagonist is administered at about 2 mg/kg. In some instances, the BTKi is administered at an amount of 5 mg/kg and the ROR1 antagonist is administered at 2 mg/kg. In some instances, the BTKi is administered at an amount of about 5 mg/kg and the R0R1 antagonist is administered at about 1 mg/kg. In some instances, the BTKi is administered at an amount of 5 mg/kg and the R0R1 antagonist is administered at 1 mg/kg. In some instances, the BTKi is administered at an amount of about 420 mg and the ROR1 antagonist is administered at an amount of about 600 mg. In some instances, the BTKi is administered at an amount of about 560 mg and the ROR1 antagonist is administered at an amount of about 600 mg.
  • the BTKi is administered daily over the course of at least 14 days (e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, or 50 days). In some instances, the BTKi is administered daily over the course of at least 15 days. In some instances, the BTKi is administered daily over the course of at least 16 days. In some instances, the BTKi is administered daily over the course of at least 17 days. In some instances, the BTKi is administered daily over the course of at least 18 days. In some instances, the BTKi is administered daily over the course of at least 19 days. In some instances, the BTKi is administered daily over the course of at least 20 days.
  • 14 days e.g., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, or 50 days. In some instances, the BTKi is administered daily over the course of at least 15 days. In some instances, the BTKi is administered daily over the course of at least
  • the BTKi is administered daily over the course of at least 21 days. In some instances, the BTKi is administered daily over the course of at least 22 days. In some instances, the BTKi is administered daily over the course of at least 23 days. In some instances, the BTKi is administered daily over the course of at least 24 days. In some instances, the BTKi is administered daily over the course of at least 25 days. In some instances, the BTKi is administered daily over the course of at least 26 days. In some instances, the BTKi is administered daily over the course of at least 27 days. In some instances, the BTKi is administered daily over the course of at least 28 days. In some instances, the BTKi is administered daily over the course of at least 29 days.
  • the BTKi is administered daily over the course of at least 30 days. In some instances, the BTKi is administered daily over the course of at least 31 days. In some instances, the BTKi is administered daily over the course of at least 32 days. In some instances, the BTKi is administered daily over the course of at least 33 days. In some instances, the BTKi is administered daily over the course of at least 34 days. In some instances, the BTKi is administered daily over the course of at least 35 days. In some instances, the BTKi is administered daily over the course of at least 40 days. In some instances, the BTKi is administered daily over the course of at least 45 days. In some instances, the BTKi is administered daily over the course of at least 50 days.
  • the BTKi is administered daily over the course of about 28 days. In some instances, the BTKi is administered daily over the course of 28 days. [0125] In some instances, the ROR1 antagonist is administered once over the course of about 28 days. In some instances, the ROR1 antagonist is administered once over the course of 28 days. [0126] In some instances, the BTKi is administered orally. In some instances, the BTKi is administered intravenously. In some instances, the ROR1 antagonist is administered intravenously.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 1 mg/kg and zilovertamab is administered intravenously at an amount of 1 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 1 mg/kg and zilovertamab is administered intravenously at an amount of 2 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 1 mg/kg and zilovertamab is administered intravenously at an amount of 3 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 1 mg/kg and zilovertamab is administered intravenously at an amount of 5 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 1 mg/kg and zilovertamab is administered intravenously at an amount of 10 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 2 mg/kg and zilovertamab is administered intravenously at an amount of 1 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days. [0133] In some instances, the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 2 mg/kg and zilovertamab is administered intravenously at an amount of 2 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 2 mg/kg and zilovertamab is administered intravenously at an amount of 3 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 2 mg/kg and zilovertamab is administered intravenously at an amount of 5 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 2 mg/kg and zilovertamab is administered intravenously at an amount of 10 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 5 mg/kg and zilovertamab is administered intravenously at an amount of 1 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 5 mg/kg and zilovertamab is administered intravenously at an amount of 2 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 5 mg/kg and zilovertamab is administered intravenously at an amount of 3 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days. [0140] In some instances, the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 5 mg/kg and zilovertamab is administered intravenously at an amount of 5 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 5 mg/kg and zilovertamab is administered intravenously at an amount of 10 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 10 mg/kg and zilovertamab is administered intravenously at an amount of 1 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 10 mg/kg and zilovertamab is administered intravenously at an amount of 2 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 10 mg/kg and zilovertamab is administered intravenously at an amount of 3 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 10 mg/kg and zilovertamab is administered intravenously at an amount of 5 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 10 mg/kg and zilovertamab is administered intravenously at an amount of 10 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days. [0147] In some instances, the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 15 mg/kg and zilovertamab is administered intravenously at an amount of 1 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 15 mg/kg and zilovertamab is administered intravenously at an amount of 2 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 15 mg/kg and zilovertamab is administered intravenously at an amount of 3 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 15 mg/kg and zilovertamab is administered intravenously at an amount of 5 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 15 mg/kg and zilovertamab is administered intravenously at an amount of 10 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 420 mg and zilovertamab is administered intravenously at an amount of 1 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 420 mg and zilovertamab is administered intravenously at an amount of 2 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days. [0154] In some instances, the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 420 mg and zilovertamab is administered intravenously at an amount of 3 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 420 mg and zilovertamab is administered intravenously at an amount of 5 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously at an amount of 420 mg and zilovertamab is administered intravenously at an amount of 10 mg/kg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously or orally at an amount of about 420 mg and zilovertamab is administered intravenously at an amount of about 600 mg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously or orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg. In some instances, ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered to a subject in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously or orally at an amount of about 420 mg and zilovertamab is administered intravenously at an amount of about 600 mg, wherein the subject has CLL.
  • ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered to a subject in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously or orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg, wherein the subject has MCL.
  • ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the BTKi ibrutinib is administered to a subject in combination with the ROR1 antagonist zilovertamab, and ibrutinib is administered intravenously or orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg, wherein the subject has MZL.
  • ibrutinib is administered daily over the course of 28 days and zilovertamab is administered once over the course of 28 days.
  • the ROR1 antagonist and the BTKi can be administered separately.
  • the BTKi ibrutinib and the ROR1 antagonist zilovertamab can be administered separately.
  • the BTKi ibrutinib is administered prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 2 weeks prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 4 weeks prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 6 weeks prior to the administration of the ROR1 antagonist zilovertamab.
  • the BTKi ibrutinib is administered daily for at least 8 weeks prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 10 weeks prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 12 weeks prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 14 weeks prior to the administration of the ROR1 antagonist zilovertamab.
  • the BTKi ibrutinib is administered daily for at least 16 weeks prior to the administration of the ROR1 antagonist zilovertamab. In some instances, the BTKi ibrutinib is administered daily for at least 18 weeks prior to the administration of the ROR1 antagonist zilovertamab.
  • the ROR1 antagonist zilovertamab is administered prior to the administration of the BTKi ibrutinib. In some instances, the ROR1 antagonist zilovertamab is administered once a week for at least 2 weeks prior to the administration of the BTKi ibrutinib. In some instances, the ROR1 antagonist zilovertamab is administered once a week for at least 4 weeks prior to the administration of the BTKi ibrutinib. In some instances, the ROR1 antagonist zilovertamab is administered once a week for at least 8 weeks prior to the administration of the BTKi ibrutinib.
  • the ROR1 antagonist zilovertamab is administered twice a week for at least 4 weeks prior to the administration of the BTKi ibrutinib. In some instances, the ROR1 antagonist zilovertamab is administered twice a week for at least 8 weeks prior to the administration of the BTKi ibrutinib. In some instances, the ROR1 antagonist zilovertamab is administered twice a week for at least 12 weeks prior to the administration of the BTKi ibrutinib. In some instances, the ROR1 antagonist zilovertamab is administered twice a week for at least 16 weeks prior to the administration of the BTKi ibrutinib.
  • the R0R1 antagonist zilovertamab is administered once four weeks for at least 4 weeks prior to the administration of the BTKi ibrutinib. In some instances, the R0R1 antagonist zilovertamab is administered once four weeks for at least 8 weeks prior to the administration of the BTKi ibrutinib. In some instances, the R0R1 antagonist zilovertamab is administered once four weeks for at least 12 weeks prior to the administration of the BTKi ibrutinib. In some instances, the R0R1 antagonist zilovertamab is administered once four weeks for at least 16 weeks prior to the administration of the BTKi ibrutinib. In some instances, the R0R1 antagonist zilovertamab is administered once four weeks for at least 20 weeks prior to the administration of the BTKi ibrutinib.
  • ibrutinib is daily administered orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 2 weeks. In some instances, ibrutinib is daily administered orally at an amount of about 420 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 2 weeks. In some instances, ibrutinib is daily administered orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 4 weeks. In some instances, ibrutinib is daily administered orally at an amount of about 420 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 4 weeks.
  • ibrutinib is daily administered to a subject at an amount of about 560 mg and zilovertamab is administered at an amount of about 600 mg once every 2 weeks, wherein the subject has MCL or MZL. In some instances, ibrutinib is daily administered to a subject at an amount of about 420 mg and zilovertamab is administered at an amount of about 600 mg once every 2 weeks, wherein the subject has CLL. In some instances, ibrutinib is daily administered to a subject at an amount of about 560 mg and zilovertamab is administered at an amount of about 600 mg once every 4 weeks, wherein the subject has MCL or MZL. In some instances, ibrutinib is daily administered to a subject at an amount of about 420 mg and zilovertamab is administered at an amount of about 600 mg once every 4 weeks, wherein the subject has CLL.
  • ibrutinib is daily administered to a subject at an amount of about 560 mg for at least 4, 8, or 16 weeks and followed by administering zilovertamab at an amount of about 600 mg once every 2 weeks for 3 administration and once every 4 weeks thereafter, wherein the subject has MCL or MZL. In some instances, ibrutinib is daily administered to a subject at an amount of about 420 mg for at least 4, 8, or 16 weeks and followed by administering zilovertamab at an amount of about 600 mg once every 2 weeks for 3 administration and once every 4 weeks thereafter, wherein the subject has CLL.
  • ibrutinib is daily administered to a subject orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 2 weeks, wherein the subject has MCL or MZL. In some instances, ibrutinib is daily administered to a subject orally at an amount of about 420 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 2 weeks, wherein the subject has CLL. In some instances, ibrutinib is daily administered to a subject orally at an amount of about 560 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 4 weeks, wherein the subject has MCL or MZL. In some instances, ibrutinib is daily administered to a subject orally at an amount of about 420 mg and zilovertamab is administered intravenously at an amount of about 600 mg once every 4 weeks, wherein the subject has CLL.
  • ibrutinib is daily administered to a subject orally at an amount of about 560 mg for at least 4, 8, or 16 weeks and followed by administering zilovertamab intravenously at an amount of about 600 mg once every 2 weeks for 3 administration and once every 4 weeks thereafter, wherein the subject has MCL or MZL. In some instances, ibrutinib is daily administered to a subject orally at an amount of about 420 mg for at least 4, 8, or 16 weeks and followed by administering zilovertamab intravenously at an amount of about 600 mg once every 2 weeks for 3 administration and once every 4 weeks thereafter, wherein the subject has CLL.
  • the methods disclosed herein can be used for treating patients with cancer or tumor having a TP53 mutation as disclosed herein.
  • the cancer or tumor may further express ROR1.
  • the cancer is lymphoma, leukemia, myeloma, AML, B-ALL, T-ALL, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, head and neck cancer, uterine cancer, adenocarcinoma, or adrenal cancer.
  • the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, marginal cell B-Cell lymphoma, Burkitt's Lymphoma, or B cell leukemia.
  • the tumor or the cancer comprises a blood cancer.
  • the tumor or the cancer comprises a leukemia or a lymphoma.
  • the tumor or the cancer comprises a B cell leukemia or B cell lymphoma.
  • the tumor or the cancer comprises CLL.
  • the tumor or the cancer comprises small cell lymphocytic leukemia (SLL).
  • the tumor or the cancer comprises MZL.
  • the tumor or the cancer comprises diffuse large B cell lymphoma (DLBCL).
  • the tumor or the cancer comprises MCL.
  • the MCL is a high-risk subtype according to the simplified mantle cell lymphoma international prognostic index (sMIPI, E Hoster, et al, Blood, 111 (2) (2008), pp. 558- 565, incorporated by reference herein in its entirety).
  • the MCL is a high-risk subtype according to sMIPI and comprises a TP53 mutation.
  • the cancer or tumor comprises at least one mutation in TP53.
  • the mutation is in an exon of the TP53 gene.
  • the mutation is in an intron of the TP53 gene.
  • the mutation is a nonsense mutation in the TP53 gene.
  • the mutation is a missense mutation in the TP53 gene.
  • the mutation results in an amino acid insertion, deletion, or substitution in a protein encoded by the TP53 gene.
  • the mutation is associated with del(17p).
  • the mutation is a splice-site mutation.
  • the mutation is in at least one exon from exons 4-8 of TP53.
  • the mutation can be in exon 4, exon 5, exon 6, exon 7, or exon 8 of TP53.
  • the mutation results in an aberration in the DNA-binding domain of p53.
  • the mutation results in an aberration in the oligomerization domain of p53.
  • the mutation results in an aberration in the C-terminal domain of p53.
  • the mutation comprises a single mutation as described herein or a combination of the single mutations as described herein.
  • the mutation can comprise a missense mutation and a del(17p) mutation.
  • the mutation can comprise an insertion mutation and a del(17p) mutation.
  • the mutation can comprise a gene deletion mutation and a del(17p) mutation.
  • the mutation can comprise a splice-site mutation and a del(17p) mutation.
  • the mutation can comprise an insertion mutation and a missense mutation.
  • the mutation can comprise a gene deletion mutation and a missense mutation.
  • the mutation can comprise a splice-site mutation and a missense mutation.
  • the mutation can comprise an insertion mutation and a gene deletion mutation.
  • the mutation can comprise an insertion mutation and a splice-site mutation.
  • the mutation can comprise a gene deletion mutation and a splice-site mutation.
  • the mutation in TP53 can comprise any mutation that results in a loss of wildtype p53 function in a cell.
  • the subject may be screened for ROR1 expression before, at the time of, or after administration of the BTKi and ROR1 antagonist.
  • the subject may be further subject to a TP 53 mutation screening before, at the time of, or after administration of the BTKi and ROR1 antagonist.
  • the methods disclosed herein comprises determining if the tumor or cancer comprises a mutation in the TP53 gene.
  • a test can be performed on the tumor or the cancer to determine if the tumor or cancer comprises a mutation in the TP53 gene.
  • the test can be performed on a biopsy sample of the tumor or the cancer of the subject.
  • the test can be based either on genomic DNA or mRNA as template.
  • the test can also be based on p53 protein.
  • the test can be immunohistochemistry, immunofluorescence, PCR, RT-PCR, real-time PCR, fluorescence in situ hybridization (FISH), sequencing including next generation sequencing, or genomic arrays.
  • the subject is a mammal. In some instances, the subject is a human. In some instances, the subject having a tumor or cancer with a TP 53 mutation. In some instances, the subject having a tumor or cancer with a TP 53 mutation and ROR1 expression. In some instances, the subject is a relapsed patient from prior treatment of the cancer or tumor. In some instances, the subject is a patient who developed resistance to prior treatment of the cancer or tumor.
  • compositions comprising a BTKi, a ROR1 antagonist and a pharmaceutically acceptable excipient for use in treating patients having a cancer or tumor, wherein the tumor or cancer comprises a mutation in a TP53 gene.
  • the pharmaceutical composition comprises a BTKi, an anti-RORl antibody, and a pharmaceutically acceptable excipient.
  • the BTKi and the anti-RORl antibody are present in a combined synergistic amount, wherein the combined synergistic amount is effective to treat cancer in a subj ect in need thereof.
  • the BTKi and ROR1 antagonist included in the pharmaceutical compositions provided herein may be any one of the BTKi and/or ROR1 antagonists described herein.
  • the BTKi may be ibrutinib and the ROR1 antagonist may be zilovertamab.
  • pharmaceutical compositions provided herein may be formulated such that the administered amount of BTKi and ROR1 antagonist is any one of the amounts as described herein.
  • the ibrutinib may be present in an amount such that administration of the composition results in a dosage of about 420 mg or about 560 mg and zilovertamab may be present in an amount that results in a dosage of about 600mg.
  • R/R mantle cell lymphoma
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • the recommended dosing regime was 600 mg of zilovertamab (i.v.) once every 2 weeks by three times and then once every 4 weeks in combination with ibrutinib at approved doses per indication (i.e., 420 mg for CLL, 560 mg for MCL).
  • the patients were treated with the recommended dosing regimen from Phase 1 study, that is, zilovertamab (600 mg) and ibrutinib at approved dose (420 mg CLL, 560 mg MCL and MZL).
  • the demography, disease characteristics and disposition of the patient population is provided in Table 1. As shown in Table 1, the patient population included patients with high- risk disease and who were heavily pre-treated. The most common reason for discontinuation was the completion of 2 years of treatment.
  • Progression-free Survival was compared between the combination treatment (zilovertamab + ibrutinib) and historical ibrutinib treatment alone. The results show that the combination treatment provided favorable PFS benefit compared to historical ibrutinib treatment alone (FIGs. 5A-5B). Further analysis was performed based on prior systemic treatment and the results show that favorable PFS was sustained in heavily pre-treated MCL subjects (FIGs. 6A- 6B). Additionally, PFS was assessed based on MIPI subgroups and the results show that favorable PFS was sustained in higher risk MIPI subgroups (FIGs. 7A-7B).
  • PFS was measured in CLL patients and the results suggest that PFS was not reached at 23+ months in both treatment naive and relapsed/refractory CLL patients (Table 10 and FIGs. 9A-9C). As is shown in FIG. 9C, a 100% PFS rate was observed in both TN and R/R subjects with p53 mutation. Next, PFS was assessed based on p53 mutation status (FIGs. 10A-10C). As is shown in FIG. 10C, a 100% PFS rate was observed in subjects with p53 mutation across parts 1, 2, and 3; and outperformed either ibrutinib or zanubrutinib alone.
  • the ORR was 89.3%, CRR 43% and median DOR 34.1 months for patients with R/R MCL on zilovertamab + ibrutinib.
  • the PFS rate for Zilovertamab + Ibrutinib was -95% at 24 months in patients with R/R CLL (median 2 prior LOT) and the PFS rate was 100% at -42 months for patients with TP53 mutations/del(17p) on zilovertamab + ibrutinib.

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Abstract

Une méthode de traitement d'un cancer ou d'une tumeur chez un individu est divulgué, comprenant l'administration à l'individu d'un antagoniste de ROR1 et d'un inhibiteur de tyrosine kinase de Bruton (BTKi), la tumeur ou le cancer comprenant une mutation dans un gène TP53. La méthode peut arrêter la progression du cancer pendant au moins 12 mois par rapport à un individu qui ne comprend pas de mutation dans un gène TP53.
PCT/US2023/068368 2022-08-19 2023-06-13 Méthodes de traitement associées pour cancer à mutation tp53 WO2024039925A1 (fr)

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Citations (1)

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US20170368173A1 (en) * 2016-06-27 2017-12-28 The Regents Of The University Of California Cancer treatment combinations

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US20170368173A1 (en) * 2016-06-27 2017-12-28 The Regents Of The University Of California Cancer treatment combinations

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