Combination of a B-RAF inhibitor with an anti-EGFR antibody for the treatment of cancer

Abstract

(i) The name 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or the formula (I): Provided herein are combinations comprising Compound A having the structure: JPEG2025532826000026.jpg51165, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, and an anti-EGFR antibody, e.g., panitumumab; compositions comprising the combinations; and methods of using such combinations and compositions in the treatment of cancer, e.g., colorectal cancer, pancreatic cancer, and non-small cell lung cancer.

Description

[Technical Field]

[0001] Provided herein are novel combinations comprising a B-Raf inhibitor, particularly 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a pharmaceutically acceptable salt thereof, and an anti-EGFR antibody, pharmaceutical compositions comprising the same, and methods of using such combinations and compositions in the treatment of conditions in which inhibition of B-Raf, KRAS, NRAS, and / or EGFR is beneficial, e.g., cancer. [Background technology]

[0002] Effective treatment of hyperproliferative disorders, including cancer, is a continuing goal in the field of oncology. Generally, cancer arises from the unregulated normal processes that control cell division, differentiation, and apoptotic cell death and is characterized by the proliferation of malignant cells, with the potential for uncontrolled growth, local spread, and systemic metastasis. Dysregulation of normal processes includes abnormalities in signal transduction pathways and abnormal responses to factors that differ from those seen in normal cells.

[0003] An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. Protein kinases convert ATP-Mg 2+Protein kinases catalyze the phosphorylation of amino acid side chains in various proteins by transferring the γ-phosphate of a complex to the amino acid side chain. These enzymes control a large number of intracellular signaling processes, thereby governing cell function, proliferation, differentiation, and destruction (apoptosis) through the reversible phosphorylation of hydroxyl groups on serine, threonine, and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cellular functions, including signal transduction, transcriptional control, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in tumorigenesis. These processes are often highly regulated by complex interlocking pathways, in which each kinase is regulated by one or more other kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the development of pathologies associated with such aberrant kinase activity, including benign and malignant proliferative disorders, as well as diseases resulting from inappropriate activation of the immune and nervous systems. Due to their physiological relevance, diversity, and ubiquity, protein kinases have become one of the most important and extensively studied families of enzymes in biochemical and medical research.

[0004] The protein kinase family of enzymes is typically classified into two major subfamilies: protein tyrosine kinases and protein serine / threonine kinases, based on the amino acid residues they phosphorylate. Protein serine / threonine kinases (PSTKs) include cyclic AMP-dependent and cyclic GMP-dependent protein kinases, calcium- and phospholipid-dependent protein kinases, calcium- and calmodulin-dependent protein kinases, casein kinases, and cell division cycle protein kinases. These kinases are typically cytoplasmic or associated with the particulate fraction of cells, sometimes by anchoring proteins. Ectopic serine / threonine kinase activity has been implicated or suspected in numerous pathologies, including rheumatoid arthritis, psoriasis, septic shock, bone mineral loss, many cancers, and other proliferative disorders. Therefore, serine / threonine kinases and the signal transduction pathways they are part of are important targets for drug design. Tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play equally important roles in cellular regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet-derived growth factor receptor, etc. Research has shown that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much research is also underway to identify modulators of tyrosine kinases.

[0005] Receptor tyrosine kinases (RTKs) regulate cell growth, proliferation, and differentiation by catalyzing the phosphorylation of specific tyrosyl amino acid residues in various proteins, including RTKs themselves.

[0006] Several signaling pathways exist downstream of some RTKs, including the Ras-Raf-MEK-ERK kinase pathway. It is now understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates the phosphorylation and activation of Raf kinase. These kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and ERK2. This signaling pathway, also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. Its ultimate function is to link receptor activity at the cell membrane with the modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival.

[0007] Constitutive activation of this pathway is sufficient to induce cellular transformation. Dysregulated activation of the MAP kinase pathway, due to ectopic receptor tyrosine kinase activation, Ras mutations, or Raf mutations, is frequently found in human cancers and represents a major factor determining aberrant growth control. Ras mutations are common in human malignancies, having been identified in approximately 30% of cancers. The Ras family of GTPase proteins (proteins that convert guanosine triphosphate to guanosine diphosphate) relays signals from activated growth factor receptors to downstream intracellular partners. Among the targets recruited by active membrane-bound Ras, the Raf family of serine / threonine protein kinases stands out. The Raf family consists of three related kinases (A-, B-, and C-Raf) that act as downstream effectors of Ras. Ras-mediated Raf activation then leads to activation of MEK1 and MEK2 (MAP / ERK kinases 1 and 2), which in turn phosphorylate ERK1 and ERK2 (extracellular signal-regulated kinases 1 and 2) on tyrosine-185 and threonine-183. Activated ERK1 and ERK2 translocate and accumulate in the nucleus, where they can phosphorylate a variety of substrates, including transcription factors that control cell growth and survival.

[0008] Mutations in various Ras GTPases and B-Raf kinases have been identified that can result in sustained and constitutive activation of the MAPK pathway, ultimately leading to increased cell division and survival. As a result, these mutations are strongly associated with the establishment, development, and progression of a wide range of human cancers. The biological role of Raf kinases, and in particular B-Raf, in signal transduction has been reviewed in Davies, H., et al., Nature (2002) 9:1-6; Garnett, MJ & Marais, R., Cancer Cell (2004) 6:313-319; Zebisch, A. & Troppmair, J., Cell. Mol. Life Sci. (2006) 63:1314-1330; Midgley, RS & Kerr, DJ, Crit. Rev. Onc / Hematol. (2002) 44:109-120; Smith, RA, et al., Curr. Top. Med. Chem. (2006) 6:1071-1089; and Downward, J., Nat. Rev. Cancer (2003) 3:11-22.

[0009] Naturally occurring mutations in B-Raf kinase, which activates MAPK pathway signaling, have been found in a high percentage of human melanomas (Davies (2002) supra) and thyroid carcinomas (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003) 63(7) 1454-1457), as well as in lower, but still significant, percentages of:

[0010] Central nervous system tumors, including primary CNS tumors such as Barrett's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6 313-319 and Sommerer et al Oncogene (2004) 23(2) 554-558), cholangiocarcinoma (Zebisch et al., Cell. Mol. Life Sci. (2006) 63 1314-1330), breast cancer (Davies (2002) supra), cervical cancer (Moreno-Bueno et al Clin. Cancer Res. (2006) 12(12) 3865-3866), cholangiocarcinoma (Tannapfel et al Gut (2003) 52(5) 706-712), glioblastoma, astrocytoma, and ependymoma (Knobbe et al Acta Neuropathol. (Berl.) (2004) 108(6) 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra), as well as secondary CNS tumors (i.e., metastasis to the central nervous system of tumors originating outside the central nervous system), colorectal cancer, including colorectal cancer (Yuen et al. Cancer Res. (2002) 62(22) 6451-6455, Davies (2002) supra, and Zebisch et al., Cell. Mol. Life Sci. (2006)), gastric cancer (Lee et al. Oncogene (2003) 22(44) 6942-6945), head and neck cancer, including squamous cell carcinoma of the head and neck (Cohen et al. J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Weber et al Oncogene (2003) 22(30) 4757-4759), blood cancers including leukemia (Garnett et al., Cancer Cell (2004) supra), especially acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra, and Gustafsson et al Leukemia (2005) 19(2) 310-312), acute myeloid leukemia (AML) (Lee et al Leukemia (2004) 18(1) 170-172, and Christiansen et al Leukemia (2005) 19(12) 2232-2240), myelodysplastic syndrome (Christiansen et al Leukemia (2005) supra), and chronic myeloid leukemia (Mizuchi et al Biochem. Biophys. Res. Commun. (2005) 326(3) 645-651); Hodgkin's lymphoma (Figl et al Arch. Dermatol. (2007) 143(4) 495-499), non-Hodgkin's lymphoma (Lee et al Br.J.Cancer(2003) 89(10) 1958-1960), megakaryoblastic leukemia (Eychene et al Oncogene(1995) 10(6) 1159-1165) and multiple myeloma (Ng et al Br.J.Haematol.(2003) 123(4) Brose et al Cancer Res. (2002) 62(23) 6997-7000,Cohen et al J.Nat.Cancer Inst. (2003) supra, and Davies (2002) supra), ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203(2) 617-619 and Davies (2002) supra), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno-Bueno et al Clin. Cancer Res. (2006) supra), pancreatic cancer (Ishimura et al Cancer Lett. (2003) 199(2) 169-173), pituitary adenoma (De Martino et al J. Endocrinol. Invest.(2007) 30(1) RC1-3), prostate cancer (Cho et al Int.J. Cancer(2006) 119(8) 1858-1862), renal cancer (Nagy et al Int. (2002) supra), and skin cancer (Rodriguez-Viciana et al Science (2006) 311(5765) 1287-1290 and Davies (2002) supra). Overexpression of c-Raf has been associated with AML (Zebisch et al., Cancer Res. (2006) 66(7) 3401-3408, and Zebisch (Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et al., Cell. Mol. Life Sci. (2006)).

[0011] The epidermal growth factor receptor (EGFR) is a cell surface receptor for members of the epidermal growth factor family and is activated by binding to specific ligands, including epidermal growth factor. EGFR undergoes a transition from an inactive monomeric form to an active homodimer (Yarden et al., Biochemistry, 26(5) 1443-1451). The homodimer stimulates intracellular protein kinase activity, resulting in the phosphorylation of several tyrosine residues within the C-terminal domain of EGFR (Downward et al., Nature 311(5985) 483-485). This phosphorylation triggers downstream activation, initiating several signal transduction cascades, primarily the MAPK, Akt, and JNK pathways, ultimately leading to DNA synthesis and cell proliferation (Oda et al., Mol. Syst. Biol. 1(1)).

[0012] Overexpression of the epidermal growth factor receptor (EGFR) is associated with a number of cancers, including lung cancer, anal cancer, and glioblastoma (Walker et al, Hum. Pathol. 40(11) 1517-1527). Inhibition of EGFR is an effective treatment for certain cancers; however, many patients develop resistance (Jackman et al Clin. Cancer. Res. 15(16) 5267-5273).

[0013] Panitumumab (Vectibix) is a fully human monoclonal antibody that specifically binds to and antagonizes EGFR. Panitumumab has been approved by the U.S. Food and Drug Administration for the treatment of wild-type RAS metastatic colorectal cancer (mCRC) in combination with FOLFOX for first-line treatment, and as monotherapy after disease progression following prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. Panitumumab is commercially available from Amgen Inc. under the trade name Vectibix. Other anti-EGFR antibodies include, but are not limited to, cetuximab, zalutumumab, nimotuzumab, and matuzumab.

[0014] Although many advances have been made in recent years in the treatment of cancer, there remains a need for more effective and / or alternative treatments for individuals suffering from the effects of cancer (e.g., individuals with B-Raf, KRAS, or NRAS mutations). Citation or identification of any reference in this section shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Davies, H., et al., Nature(2002) 9:1-6; Garnett, MJ & Marais, R., Cancer Cell(2004) 6:313-319

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Summary of the Invention

Means for Solving the Problems

[0016] 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or formula (I) [ka] Provided herein is a combination of Compound A having the structure: or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab, cetuximab, zalutumumab, nimotuzumab, or matuzumab, or an antigen-binding fragment thereof. In one embodiment, the anti-EGFR antibody is panitumumab or an antigen-binding fragment thereof. In one embodiment, the combination comprises an anti-EGFR antibody. In one embodiment, the anti-EGFR antibody is panitumumab.

[0017] The combinations provided herein are useful in the treatment of cancer. In one embodiment, provided herein is a method for treating cancer in a mammal in need thereof, comprising administering a therapeutically effective amount of a combination provided herein. In one embodiment, Compound A is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, or about 40 mg. In one embodiment, Compound A is administered once a day. In one embodiment, panitumumab is administered in an amount of about 6 mg / kg as an intravenous infusion over about 60 minutes every two weeks.

[0018] In one embodiment, the cancer is colorectal cancer, pancreatic cancer, or non-small cell lung cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is metastatic colorectal cancer. In one embodiment, the cancer is BRAF mutant metastatic colorectal cancer. In one embodiment, the cancer is BRAF V600E mutant metastatic colorectal cancer. In one embodiment, the cancer is KRAS mutant colorectal cancer. In one embodiment, the cancer is KRAS G12C mutant colorectal cancer. In one embodiment, the cancer is KRAS G12D mutant colorectal cancer. In one embodiment, the cancer is KRAS G12V mutant colorectal cancer. In one embodiment, the cancer is Trp53 mutant colorectal cancer. In one embodiment, the cancer is NRAS mutant colorectal cancer. In one embodiment, the cancer is KRAS / NRAS mutant colorectal cancer.

[0019] In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is pancreatic ductal adenocarcinoma (PDAC). In one embodiment, the cancer is BRAF mutant pancreatic cancer. In one embodiment, the cancer is BRAF V600E mutant pancreatic cancer. In one embodiment, the cancer is KRAS mutant pancreatic cancer. In one embodiment, the cancer is KRAS G12C mutant pancreatic cancer. In one embodiment, the cancer is KRAS G12D mutant pancreatic cancer. In one embodiment, the cancer is KRAS G12V mutant pancreatic cancer. In one embodiment, the cancer is Trp53 mutant pancreatic cancer. In one embodiment, the cancer is NRAS mutant pancreatic cancer.

[0020] In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is BRAF mutant non-small cell lung cancer. In one embodiment, the cancer is BRAF V600E mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS G12C mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS G12D mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS G12V mutant non-small cell lung cancer. In one embodiment, the cancer is Trp53 mutant non-small cell lung cancer. In one embodiment, the cancer is NRAS mutant non-small cell lung cancer.

[0021] In one embodiment, the methods described herein provide for the administration of a plasma Compound A AUC of about 2,128 ng*h / mL to about 3,192 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 4,576 ng*h / mL to about 6,864 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 7,944 ng*h / mL to about 11,916 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 9,840 ng*h / mL to about 14,760 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 12,640 ng*h / mL to about 18,960 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide for the administration of a plasma Compound A AUC of about 30,000 ng*h / mL to about 45,000 ng*h / mL in a subject. 8h to provide.

[0022] In one embodiment, the subject achieves stable disease, a partial response, or a complete response. In one embodiment, the subject does not experience progressive disease.

[0023] In one embodiment, provided herein is the use of Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, in combination with panitumumab, in the manufacture of a medicament for treating cancer in a subject in need thereof. In one embodiment, provided herein is the use of Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is suitable for administration together with panitumumab. In one embodiment, provided herein is the use of panitumumab in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is suitable for administration together with Compound A. [Brief explanation of the drawings]

[0024] [Figure 1] Safety observations and dose escalation plans will be described. [Figure 2] Study Design: Part 1 (dose finding) and Part 2 (dose expansion) are described. [Figure 3] Describe the research period. DETAILED DESCRIPTION OF THE INVENTION

[0025] definition As used herein, "Compound A" refers to the compound having the name 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or the structure of formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof. Compound A is disclosed and claimed in WO2014206343 and WO2020151756, together with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of BRAF activity, inter alia, in the treatment of cancer, the entire disclosures of which are incorporated herein by reference. Compound A is compound 1.49 in WO2014206343 and compound 1 in WO2020151756. Compound A can be prepared as described in WO2014206343 and WO2020151756. In one embodiment, compound A is a hydrate. Unless otherwise specified, "Compound A" as used herein refers to Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

[0026] As used herein, the term "antibody" collectively refers to immunoglobulins or immunoglobulin-like molecules, including, by way of example and not limitation, IgA, IgD, IgE, IgG, and IgM, combinations thereof, and similar molecules produced during the immune response in any vertebrate, e.g., mammals such as humans, goats, rabbits, and mice, as well as non-mammalian species, e.g., shark immunoglobulins. The term "antibody" includes intact immunoglobulins, as well as "antibody fragments" or "antigen-binding fragments" (e.g., fragments with a binding constant at least 10 times greater than that for other molecules in a biological sample) that specifically bind to a molecule of interest (or a group of closely related molecules of interest) to the substantial exclusion of binding to other molecules. 3 M -1 Large, at least 10 4 M -1 Greater than or at least 10 5 M -1"Antibody" includes antibodies and antibody fragments that have a large binding constant for a molecule of interest. The term "antibody" also includes genetically engineered forms such as chimeric antibodies (e.g., humanized mouse antibodies), heteroconjugate antibodies (bispecific antibodies, etc.). Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J., Immunology 3 rd See also Neurology, Ed., W.H. Freeman & Co., New York, 1997.

[0027] More specifically, "antibody" refers to a polypeptide ligand comprising at least a light or heavy immunoglobulin chain variable region that specifically recognizes and binds to an epitope of an antigen. Antibodies are composed of heavy and light chains, each of which contains a variable heavy (V) domain. H ) area and variable light (V L ) region, which is variable in the V H Area and V L Together the regions are responsible for binding the antigen recognized by the antibody.

[0028] Immunoglobulins typically have heavy (H) chains and light (L) chains interconnected by disulfide bonds. There are two types of light chains: lambda (λ) and kappa (κ). There are five major heavy chain classes (or isotypes) that determine the functional activity of antibody molecules: IgM, IgD, IgG, IgA, and IgE. Each heavy and light chain contains a constant region and a variable region (the regions are also known as "domains"). In combination, the heavy and light chain variable regions specifically bind antigens. The light and heavy chain variable regions contain a "framework" region interrupted by three hypervariable regions, also called "complementarity-determining regions" or "CDRs." The sizes of the framework regions and CDRs have been defined (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, USDapartment of Health and Human Services, 1991, incorporated herein by reference). The Kabat database is currently maintained online. The sequences of framework regions of different light or heavy chains are relatively conserved within a species. The framework regions of antibodies, i.e., the combined framework regions of the constituent light and heavy chains, largely adopt a β-sheet conformation, with the CDRs forming loops that connect, and in some cases form part of, the β-sheet structure. Thus, the framework regions act to form a scaffold that orients the CDRs by non-covalent interactions between the chains.

[0029] CDRs are primarily responsible for binding to an epitope of an antigen. The CDRs of each chain are usually referred to as CDR1, CDR2, and CDR3, numbered consecutively starting from the N-terminus, and are also usually identified by the chain in which the particular CDR is located. Thus, V H CDR3 is located in the variable region of the heavy chain of the antibody in which it is found, while V LCDR1 is derived from the variable region of the light chain of the antibody in which it is found. Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. Although it is the CDRs that differ from antibody to antibody, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDRs are called specificity-determining residues (SDRs).

[0030] The term "antibody" is further intended to encompass digest fragments, specified portions, derivatives, and variants thereof, including antibody mimetics, or portions of antibodies that mimic the structure and / or function of an antibody or specified fragment or portion thereof, including single chain antibodies and fragments thereof. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include Fab fragments, i.e., V L , V H , C L , and C H a monovalent fragment consisting of the Fab domain; a F(ab')2 fragment, i.e., a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; a V H and C H F consisting of domains d Fragment, V of a single arm of an antibody L and V H F consisting of domains v Fragment, V H dAb fragments consisting of domains (Ward et al., Nature 341:544-546 (1989)), as well as isolated complementarity determining regions (CDRs). v The two domains of the fragment V L and V H Although the V are encoded by separate genes, they can be joined by a synthetic linker that allows them to be produced as a single protein chain using recombinant methods. L and V H The domains pair to form a monovalent molecule (single-chain F v (scF v(1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883. Single-chain antibodies are also intended to be encompassed by the term "antibody fragment." Any of the above antibody fragments can be obtained using conventional techniques known to those skilled in the art, and the fragments are screened for binding specificity and neutralizing activity in the same manner as intact antibodies.

[0031] "Antibody fragments" or "antigen-binding fragments" include proteolytic antibody fragments (such as F(ab')2 fragments, Fab fragments, Fab'-SH fragments, and Fab fragments known in the art), recombinant antibody fragments (sF v Fragment, dsF v fragment, bispecific sF v fragment, bispecific dsF v fragments, F(ab)'2 fragments, etc.), single chain Fv proteins ("scF v "), disulfide-stabilized F v Protein ("dsF v "), diabodies, and triabodies (known in the art), and camelid antibodies (see, e.g., U.S. Patent Nos. 6,015,695, 6,005,079, 5,874,541, 5,840,526, 5,800,988, and 5,759,808). v The protein is a fusion protein in which the light chain variable region of an immunoglobulin and the heavy chain variable region of an immunoglobulin are linked by a linker, while dsF v In , the chains are mutated to introduce disulfide bonds to stabilize the association of the chains.

[0032] As used herein, the term "anti-EGFR antibody" generally refers to an antibody or antigen-binding fragment thereof that specifically or preferentially binds to EGFR. In some cases, the anti-EGFR antibody can bind to a mutant form of EGFR (e.g., EGFR variant III (also known as EGFRvIII), the most common extracellular domain mutation of EGFR; this mutation results in the deletion of exons 2-7 of the EGFR gene, resulting in a mutant receptor that is unable to bind any known ligands). For example, the anti-EGFR antibody can be panitumumab, cetuximab, zalutumumab, nimotuzumab, or matuzumab.

[0033] Panitumumab (Vectibix®) is a recombinant human IgG2 monoclonal antibody that specifically binds to human EGFR, which can be made according to the procedures described in U.S. Patent Publication No. 2015 / 0152184, which is incorporated by reference herein in its entirety. The heavy and light chain sequences for panitumumab are known in the art and can also be found in public databases, such as Inxight Drugs, developed by The National Center for Advancing Translational Sciences (NCATS). In one embodiment, panitumumab is the generic, compendial, non-proprietary, or official FDA name for the product marketed as Vectibix by Amgen, and is an interchangeable or equivalent product to the product marketed as Vectibix.

[0034] In one embodiment, panitumumab is a recombinant human IgG2 monoclonal antibody that specifically binds to human EGFR. Panitumumab is composed of one heavy chain variable region and one light chain variable region and can be produced according to the procedures described in U.S. Patent No. 6,235,883. The sequences of the heavy chain and its corresponding light chain for panitumumab, as disclosed in U.S. Patent No. 6,235,883, are listed below:

[0035] Heavy Chain 1 VSGGSVSSGD YYWTWIRQSP GKGLEWIGHI YYSGNTNYNP SLKSRLTISI DTSKTQFSLK LSSVTAADTA IYYCVRDRVT GAFDIWGQGT MVTSS (SEQ ID NO: 1)

[0036] Light chain 1 TITCQASQDI SNYLNWYQQK PGKAPKLLIY DASNLETGVP SRFSGSGSGT DFTFTISSLQ PEDIATYFCQ HFDHLPLAFG GGTKVEIKRT VAAPSVFIFP PSDEQ (SEQ ID NO: 2)

[0037] Heavy Chain 1 and Light Chain 1 correspond to sequences 37 and 38 of US Pat. No. 6,235,883, which is incorporated by reference herein in its entirety.

[0038] Heavy Chain 2 VSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS (SEQ ID NO: 3)

[0039] Light chain 2 TITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQ (SEQ ID NO: 4)

[0040] Heavy chain 2 and light chain 2 correspond to sequences 76 and 54 of US Pat. No. 7,807,798, which is incorporated by reference herein in its entirety.

[0041] In one embodiment, panitumumab is an isolated human antibody disclosed in U.S. Patent No. 7,807,798 that binds to the human epidermal growth factor receptor (EGF-r). a) CDR1 comprising amino acids 8 to 15 of SEQ ID NO: 3; b) CDR2 comprising amino acids 29 to 45 of SEQ ID NO: 3; and c) CDR3 comprising amino acids 77 to 85 of SEQ ID NO: 3; and a heavy chain immunoglobulin molecule comprising d) CDR1 comprising amino acids 5 to 15 of SEQ ID NO: 4; e) CDR2 comprising amino acids 31 to 37 of SEQ ID NO: 4; and f) CDR3 comprising amino acids 70 to 78 of SEQ ID NO: 4 and a light chain immunoglobulin molecule comprising:

[0042] The sequences of cetuximab, zalutumumab, nimotuzumab, and matuzumab are known in the art and can also be found in public databases, such as Inxight Drugs, developed by the National Center for Advancing Translational Sciences (NCATS). Cetuximab, zalutumumab, nimotuzumab, and matuzumab can be easily prepared using general knowledge in the art. In one embodiment, cetuximab is the anti-epidermal growth factor receptor monoclonal antibody Mab C225, as defined in US 7960516 B2, the entire contents of which are incorporated herein by reference. In one embodiment, cetuximab is an anti-EGFR antibody disclosed in US 4,943,533 and WO 96 / 40210. In one embodiment, zaltuzumab (Humax-EGFR) is an anti-EGFR antibody described in WO 02 / 100348 and WO 2004 / 056847. In one embodiment, nimotuzumab (TheraCIM hR3) is an anti-EGFR antibody described in US 5,891,996 and US 6,506,883. In one embodiment, matuzumab (EMD72000) is an anti-EGFR antibody described in WO 02 / 66058. The disclosures of these references are incorporated herein by reference in their entireties.

[0043] In one embodiment, a solid form of Compound A is used for the treatments provided herein. In one embodiment, a crystalline form of Compound A is used for the treatments provided herein. In one embodiment, an amorphous form of Compound A is used for the treatments provided herein. In one embodiment, the free base of Compound A is used for the treatments provided herein. In one embodiment, the hydrochloride salt of Compound A is used for the treatments provided herein. In one embodiment, a solid form of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, a solid form of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, Form A, A*, A**, B, C, D, E, F, G, H, I, J, or K of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, Form F of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, Form F of Compound A, described in Example 7 of WO2020151756, is used for the treatments provided herein. The entire disclosure of WO2020151756 is incorporated herein by reference.

[0044] As used herein, the term "neoplasm" refers to an abnormal growth of cells or tissues and is understood to include benign, i.e., non-cancerous, and malignant, i.e., cancerous, growths. The term "neoplastic" means of or relating to a neoplasm.

[0045] As used herein, the term "drug" is understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. Thus, the term "anti-tumor agent" is understood to mean a substance that produces an anti-tumor effect in a tissue, system, animal, mammal, human, or other subject. It should also be understood that an "drug" can be a single compound, or a combination or composition of two or more compounds.

[0046] As used herein, the term "treating" and variations thereof refer to therapeutic therapy. With reference to a particular condition, treating means (1) alleviating the condition or one or more of the biological symptoms of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or is responsible for the condition, or (b) one or more of the biological symptoms of the condition, (3) alleviating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more of the biological symptoms of the condition.

[0047] As used herein, "prevention" is understood to mean administering an agent prophylactically to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations. Preventive therapy is appropriate, for example, when a subject is considered to be at high risk of developing cancer, for example, when the subject has a strong family history of cancer, or when the subject has been exposed to a carcinogen.

[0048] As used herein, the term "effective amount" refers to an amount of a drug or agent that elicits the biological or medical response in a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Furthermore, a "therapeutically effective amount" refers to a dose that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the incidence of a disease or disorder, compared to matched controls that have not received such a dose. This term also includes within its scope amounts effective to enhance normal physiological function.

[0049] Compound A disclosed herein may contain one or more chiral atoms and may be capable of existing as enantiomers. Thus, the compounds of the present invention include mixtures of enantiomers, as well as purified enantiomers or enantiomer-enriched mixtures. It is also understood that all tautomers and mixtures of tautomers are included within the scope of Compound A.

[0050] As used herein, the term "solvate" refers to a stoichiometrically variable complex formed by a solute (in this invention, a compound of formula (I) or a salt thereof, and a solvent). It is also understood that Compound A may be presented as a solvate, either separately or both. For the purposes of this invention, such a solvent may be one that does not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethyl sulfide, ethanol, and acetic acid. In one embodiment, the solvent used is pharmaceutically acceptable. Examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, and acetic acid. In another embodiment, the solvent used is water (i.e., a hydrate).

[0051] Compound A may have the ability to crystallize in more than one form, a property known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of Compound A. Polymorphism generally occurs as a response to changes in temperature or pressure, or both, and may also result from variations in the crystallization process. Polymorphs can be distinguished by various physical properties known in the art, such as x-ray diffraction patterns, solubility, and melting point.

[0052] As used herein in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly indicates otherwise.

[0053] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0054] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or value provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., those describing melting, dehydration, desolvation, or glass transition temperature); mass change (e.g., mass change as a function of temperature or humidity); solvent or water content (e.g., in terms of mass or percentage); or peak position (e.g., such as in analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art and still describe the solid form. Techniques for characterizing crystalline forms and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In some embodiments, the terms "about" and "approximately" used in this context indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the stated value or range of values. For example, in some embodiments, the value of an XRPD peak position can vary by up to ±0.2 degrees 2θ (or ±0.2 degrees 2θ) and still describe a particular XRPD peak.

[0055] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases and organic acids and bases). Suitable pharmaceutically acceptable base addition salts of the compounds include, but are not limited to, those well known in the art, for example, those described in Remington's Pharmaceutical Sciences, 18 theds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0056] As used herein, and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of that compound. The compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0057] The use of stereomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0058] It should also be noted that the compounds can include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0059] "Tautomer" refers to isomers of a compound that are in equilibrium with each other. The concentration of the isomers depends on the environment in which the compound is found and may vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are called tautomers of each other: [ka]

[0060] As one of ordinary skill in the art would readily appreciate, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds are within the scope of the invention.

[0061] It should also be noted that the compounds may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as C) or deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15 The compound may be isotopically enriched, such as with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 132, 133, 144, 154, 165, 170, 171, 182, 191, 192, 193, 194, 195, 196, 197, 198,

[0062] The term "subject" includes, but is not limited to, animals, including animals such as primates, cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs. In some embodiments, the subject is a mammal, e.g., a human.

[0063] When used in therapy, Compound A may potentially be administered as a raw chemical, but the active ingredient can also be provided as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable carriers, diluents, or excipients. Compound A is as described above. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense that they are compatible with the other ingredients of the formulation, allowing for pharmaceutical formulation and not harmful to the recipient. According to another aspect of the present invention, a process for preparing a pharmaceutical composition is also provided, comprising mixing Compound A with one or more pharmaceutically acceptable carriers, diluents, or excipients. Such components of the pharmaceutical composition utilized may be provided in separate pharmaceutical combinations or may be formulated together in a single pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising Compound A and one or more pharmaceutically acceptable carriers, diluents, or excipients. Compound A, as described above, can be utilized in any of the aforementioned compositions.

[0064] Pharmaceutical compositions can be provided in unit dose forms, each containing a predetermined amount of active ingredient. As is well known to those skilled in the art, the amount of active ingredient per dose depends on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations contain the daily dose or daily sub-dose of active ingredient described herein, or an appropriate fraction thereof. Furthermore, such pharmaceutical compositions can be prepared by any method well known in the art of pharmacy.

[0065] The combination can be administered by any suitable route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), intravaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary depending on, for example, the condition of the person receiving the combination therapy and the cancer condition being treated. It will also be understood that each of the administered agents may be administered by the same or different routes, and the combinations provided herein may be combined together in a pharmaceutical composition or separated into two pharmaceutical compositions.

[0066] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foams; or oil-in-water or water-in-oil liquid emulsions.

[0067] Unless otherwise defined, in all dosing protocols described herein, the regimen of administered compounds does not necessarily begin with the initiation of treatment and end with the end of treatment, only the number of consecutive days on which both compounds are administered. The indicated dosing protocol, including the optional number of consecutive days on which only one of the component compounds is administered, or the amount of compound administered, occurs at some point during the course of treatment.

[0068] Compound A may be used in combination with an anti-EGFR antibody or antigen-binding fragment thereof in accordance with the present disclosure by administering them simultaneously in a single pharmaceutical composition containing both compounds.

[0069] Furthermore, it does not matter if the compounds are administered in the same dosage form, for example, Compound A may be administered orally and the anti-EGFR antibody or antigen-binding fragment thereof may be administered orally.

[0070] As used herein, the term "kit" or "kit of parts" refers to a pharmaceutical composition or combination used to administer a combination according to the present disclosure. In one embodiment, the kit may contain the combination in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. In one aspect, a kit is provided that includes the components of the combination in association with a pharmaceutically acceptable excipient, diluent, or carrier. The kit may also be provided with instructions, such as dosage and administration instructions. Such dosage and administration instructions may be of the type provided to a physician, for example, by a pharmaceutical label, or they may be of the type provided by a physician, such as in instructions to a patient.

[0071] The term "dose" as used herein is understood to mean a dose intended to either slowly raise the plasma or blood concentration level of a compound to a therapeutically effective level or to maintain such a therapeutically effective level.

[0072] In certain embodiments, cancer treatment can be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see The National Center for Advancing Translational Sciences (NCATS). J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer, Elizabeth A., et al., European journal of cancer 45.2 (2009): 228-247). New response evaluation criteria in solid tumors: revised RECIST guidelines (version 1.1). European J. Cancer; 2009; (45) 228-247). The overall response rate for all possible combinations of tumor response in target and non-target lesions, regardless of the appearance of new lesions, is as follows: [Table 8]

[0073] Regarding the evaluation of target lesions, a complete response (CR) was the disappearance of all target lesions, a partial response (PR) was a reduction of at least 30% in the sum of the longest diameters of the target lesions based on the baseline sum of the longest diameters, progressive disease (PD) was an increase of at least 20% in the sum of the longest diameters of the target lesions based on the minimum sum of the longest diameters recorded since the start of treatment, or the appearance of one or more new lesions, and stable disease (SD) was neither sufficient shrinkage to qualify as a partial response nor sufficient increase to qualify as progression based on the minimum sum of the longest diameters since the start of treatment.

[0074] Regarding the evaluation of non-target lesions, a complete response (CR) is the disappearance of all non-target lesions and normalization of tumor marker levels; an incomplete response / stable disease (SD) is the persistence of one or more non-target lesion(s) and / or tumor marker levels remaining above the upper limit of normal, and a progressive disease (PD) is the appearance of one or more new lesions and / or clear worsening of existing non-target lesions.

[0075] The procedures, practices, and definitions described below provide guidance for implementing the recommendations of the Neuro-Oncology Response Assessment (RANO) Working Group on response criteria for high-grade gliomas (see Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010;28:1963-1972). Key modifications to the RANO criteria for time-point response criteria (TPR) may include the addition of operational practices to define changes in glucocorticoid dose and the removal of the subject's clinical deterioration component to focus on objective radiological assessment. A baseline MRI is defined as an assessment performed at the end of the postoperative rest period before initiating or restarting compound treatment. The baseline MRI is used as the standard for assessing complete response (CR) and partial response (PR). Meanwhile, the smallest SPD (sum of products of perpendicular diameters) obtained at either baseline or subsequent assessments is designated the nadir assessment and serves as the criterion for determining progression. For the 5 days prior to any protocol-defined MRI examination, subjects must be glucocorticoid-free or on a stable dose of glucocorticoids. A stable dose is defined as the same daily dose for 5 consecutive days prior to the MRI examination. If the prescribed glucocorticoid dose is changed within the 5 days prior to the baseline scan, a new baseline scan is required with glucocorticoid use that meets the above criteria. The following definitions are used:

[0076] Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured two-dimensionally. Measurements are taken of the maximum enhancing diameter (also known as the longest diameter, LD). The maximum perpendicular diameter is measured on the same image. The crosshairs of the two-dimensional measurement must intersect, and the product of these diameters is calculated.

[0077] Minimum diameter: T1-weighted images with 5 mm sections and a 1 mm skip. The minimum LD for a measurable lesion is set at 5 mm x 5 mm. Larger diameters may be required for inclusion and / or designation as a target lesion. After baseline, target lesions that become smaller than the minimum measurement requirement or are no longer suitable for two-dimensional measurement are recorded with a default value of 5 mm for each diameter less than 5 mm. Lesions that disappear are recorded as 0 mm x 0 mm.

[0078] Multicentric Lesions: Lesions considered multicentric (as opposed to contiguous) are those with two (or more) lesions intervening with normal brain tissue. For multicentric lesions with separate enhancing foci, the approach is to measure each enhancing lesion that meets the inclusion criteria separately. If there is no normal brain tissue between two (or more) lesions, they are considered the same lesion.

[0079] Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable disease defined above are considered nonmeasurable, as well as all nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include enhancing lesions smaller than a specified minimum diameter (i.e., less than 5 mm × 5 mm), nonenhancing lesions (e.g., on post-contrast T1-weighted, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or primarily cystic or necrotic lesions, and leptomeninges. Hemorrhagic lesions often have inherent T1-weighted hyperintensity that can be misinterpreted as enhancing tumor; therefore, pre-contrast T1-weighted images may be examined to rule out baseline or intermittent subacute hemorrhage.

[0080] At baseline, lesions are classified as follows: Target Lesions: Up to five measurable lesions may be selected as target lesions, each measuring at least 10 mm x 5 mm to represent the disease of interest; Non-Target Lesions: All other lesions, including all non-measurable lesions (including mass effect and T2 / FLAIR findings), and any measurable lesions not selected as target lesions. At baseline, target lesions are measured as described in the definition of a measurable lesion, and the SPD of all target lesions is determined. The presence of all other lesions is documented. At all post-treatment (follow-up) assessments, the baseline classification of lesions (target and non-target lesions) is maintained, and lesions are recorded and described consistently over time (e.g., recorded in the same order on source documents and eCRFs). To reduce the difficulty of interpreting changes, all measurable and non-measurable lesions must be assessed using the same methodology as at baseline throughout the study (e.g., subjects should be imaged on the same MRI scanner, or at least with the same magnetic strength). At each assessment, target lesions are measured and the SPD calculated. Non-target lesions are assessed qualitatively, and new lesions, if any, are recorded separately. At each assessment, progression status is determined based on the time-point status for target lesions, non-target lesions, and new lesions. Tumor progression can be established even when only a subset of lesions is assessed. However, unless progression is observed, objective status (stable, PR, or CR) can only be determined when all lesions are assessed.

[0081] Confirmatory assessment of overall time point response for CR and PR will be performed at the next scheduled assessment, but may not be performed if there are fewer than 28 days between tests. Best response incorporating confirmatory criteria will be derived from a series of time points.

[0082] As used herein, "in some embodiments," "in one embodiment," and "in certain embodiments" are all used interchangeably. In some embodiments, the recitation of Compound A can be replaced with "Compound A, or a pharmaceutically acceptable salt or solvate thereof," or "Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof," or vice versa.

[0083] As used herein, all amounts specified for Compound A or panitumumab are given as the amount of the free or non-salt compound.

[0084] combination 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or formula (I) [ka] Provided herein is a combination of Compound A having the structure: or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, with an anti-EGFR antibody or antigen-binding fragment thereof. The combination is useful in the treatment of cancer. In some embodiments, the anti-EGFR antibody is panitumumab, cetuximab, zalutumumab, nimotuzumab, or matuzumab, or an antigen-binding fragment thereof. In one embodiment, the anti-EGFR antibody is panitumumab or an antigen-binding fragment thereof. In one embodiment, the combination includes an anti-EGFR antibody. In one embodiment, the combination includes panitumumab.

[0085] In one embodiment, a solid form of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, Form A, A*, A**, B, C, D, E, F, G, H, I, J, or K of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, Form F of Compound A described in WO2020151756 is used for the treatments provided herein. In one embodiment, Compound A is Form F.

[0086] In one embodiment, a combination kit is provided herein, comprising the combination provided herein together with one or more pharmaceutically acceptable carriers. In one embodiment, a treatment method is provided herein using a combination kit comprising the combination provided herein. In one embodiment, a use is provided herein for a combination kit comprising the combination provided herein.

[0087] In one embodiment, the anti-EGFR antibody, eg, panitumumab, is provided in a form suitable for IV administration.

[0088] In one embodiment, the anti-EGFR antibody, eg, panitumumab, is provided in a form suitable for subcutaneous administration.

[0089] Treatment method Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a combination disclosed herein. Provided herein is a combination disclosed herein for use in treating or preventing cancer. Provided herein is the use of a combination disclosed herein in the manufacture of a medicament for treating or preventing cancer.

[0090] Also provided herein is Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, for use in treating or preventing (e.g., treating) cancer in a subject, and Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, can be administered in combination with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab.

[0091] Also provided herein is a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, for use in the treatment or prevention (e.g., treatment) of cancer in a subject, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, can be administered in combination with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab.

[0092] Also provided herein are anti-EGFR antibodies for use in the treatment or prevention (e.g., treatment) of cancer, which can be administered in combination with Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof. In some embodiments, the anti-EGFR antibody is panitumumab.

[0093] Also provided herein are pharmaceutical compositions comprising an anti-EGFR antibody for use in the treatment or prevention (e.g., treatment) of cancer, wherein the anti-EGFR antibody can be administered in combination with Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof. In some embodiments, the anti-EGFR antibody is panitumumab.

[0094] Also provided herein is the use of Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, for the manufacture of a medicament for treating or preventing (e.g., treating) cancer, wherein the medicament can be administered together with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab.

[0095] Also provided herein is the use of an anti-EGFR antibody for the manufacture of a medicament for treating or preventing (e.g., treating) cancer, wherein the medicament can be administered together with Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof. In some embodiments, the anti-EGFR antibody is panitumumab.

[0096] Further provided herein is a method for treating cancer in a human in need thereof, comprising administering a therapeutically effective amount of Compound A and an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab, cetuximab, zalutumumab, nimotuzumab, or matuzumab, or an antigen-binding fragment thereof. In one embodiment, the anti-EGFR antibody is panitumumab or an antigen-binding fragment thereof. In one embodiment, the administered anti-EGFR antibody is panitumumab.

[0097] In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered orally at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at about 10±5 mg, about 15±5 mg, about 20±5 mg, about 25±5 mg, about 30±5 mg, about 35±5 mg, about 40±5 mg, about 45±5 mg, about 50±5 mg, about 55±5 mg, or about 60±5 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at about 5±3 mg, about 10±3 mg, about 15±3 mg, about 20±3 mg, about 25±3 mg, about 30±3 mg, about 35±3 mg, about 40±3 mg, about 45±3 mg, about 50±3 mg, about 55±3 mg, or about 60±3 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at about 5±1 mg, about 10±1 mg, about 15±1 mg, about 20±1 mg, about 25±1 mg, about 30±1 mg, about 35±1 mg, about 40±1 mg, about 45±1 mg, about 50±1 mg, about 55±1 mg, or about 60±1 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 5 mg to about 60 mg per day.In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 5 mg to about 40 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 5 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 10 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 15 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 20 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 25 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 30 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at a dose of about 35 mg per day. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotope, solvate, or prodrug thereof, is administered at a dose of about 40 mg per day. In some embodiments, the administration is oral.

[0098] In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered once daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered twice daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered three times daily.

[0099] In some embodiments, panitumumab is administered in an amount of about 6 mg / kg. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg. In one embodiment, panitumumab is administered in an amount of about 6 mg / kg administered as an intravenous infusion over about 60 minutes. In one embodiment, panitumumab is administered in an amount of about 6 mg / kg administered as an intravenous infusion over about 60 minutes approximately every two weeks.

[0100] In one embodiment, panitumumab is administered in an amount of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, or about 8 mg / kg about every two weeks. In one embodiment, panitumumab is administered in an amount of about 1 mg / kg ± 0.5 mg / kg, about 2 mg / kg ± 0.5 mg / kg, about 3 mg / kg ± 0.5 mg / kg, about 4 mg / kg ± 0.5 mg / kg, about 5 mg / kg ± 0.5 mg / kg, about 6 mg / kg ± 0.5 mg / kg, about 7 mg / kg ± 0.5 mg / kg, or about 8 mg / kg ± 0.5 mg / kg about every two weeks. In one embodiment, panitumumab is administered in an amount of about 1 mg / kg±0.3 mg / kg, about 2 mg / kg±0.3 mg / kg, about 3 mg / kg±0.3 mg / kg, about 4 mg / kg±0.3 mg / kg, about 5 mg / kg±0.3 mg / kg, about 6 mg / kg±0.3 mg / kg, about 7 mg / kg±0.3 mg / kg, or about 8 mg / kg±0.3 mg / kg about every two weeks. In one embodiment, panitumumab is administered in an amount of about 1 mg / kg±0.1 mg / kg, about 2 mg / kg±0.1 mg / kg, about 3 mg / kg±0.1 mg / kg, about 4 mg / kg±0.1 mg / kg, about 5 mg / kg±0.1 mg / kg, about 6 mg / kg±0.1 mg / kg, about 7 mg / kg±0.1 mg / kg, or about 8 mg / kg±0.1 mg / kg about every two weeks.

[0101] In one embodiment, panitumumab is administered in an amount of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, or about 8 mg / kg administered as an intravenous infusion over about 60 minutes approximately every two weeks. In one embodiment, panitumumab is administered in an amount of about 1 mg / kg ± 0.5 mg / kg, about 2 mg / kg ± 0.5 mg / kg, about 3 mg / kg ± 0.5 mg / kg, about 4 mg / kg ± 0.5 mg / kg, about 5 mg / kg ± 0.5 mg / kg, about 6 mg / kg ± 0.5 mg / kg, about 7 mg / kg ± 0.5 mg / kg, or about 8 mg / kg ± 0.5 mg / kg administered as an intravenous infusion over about 60 minutes approximately every two weeks. In one embodiment, panitumumab is administered in an amount of about 1 mg / kg±0.3 mg / kg, about 2 mg / kg±0.3 mg / kg, about 3 mg / kg±0.3 mg / kg, about 4 mg / kg±0.3 mg / kg, about 5 mg / kg±0.3 mg / kg, about 6 mg / kg±0.3 mg / kg, about 7 mg / kg±0.3 mg / kg, or about 8 mg / kg±0.3 mg / kg administered as an intravenous infusion over about 60 minutes approximately every two weeks. In one embodiment, panitumumab is administered in an amount of about 1 mg / kg±0.1 mg / kg, about 2 mg / kg±0.1 mg / kg, about 3 mg / kg±0.1 mg / kg, about 4 mg / kg±0.1 mg / kg, about 5 mg / kg±0.1 mg / kg, about 6 mg / kg±0.1 mg / kg, about 7 mg / kg±0.1 mg / kg, or about 8 mg / kg±0.1 mg / kg administered as an intravenous infusion over about 60 minutes approximately every two weeks.

[0102] In some embodiments, panitumumab is administered in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered is about 1000 mg or less in 14 days, or over about 90 minutes when the amount of panitumumab administered is more than about 1000 mg in 14 days. In some embodiments, panitumumab is administered in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered is about 1000 mg or less in 14 days, or over 90 minutes when the amount of panitumumab administered is more than about 1000 mg in 14 days.

[0103] In one embodiment, panitumumab is co-administered with Compound A, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, panitumumab and Compound A, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously, sequentially, or separately. In some embodiments, panitumumab and Compound A, or a pharmaceutically acceptable salt or solvate thereof, are administered within about 30 minutes of each other. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is less than or equal to about 1000 mg, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally once daily at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 5 mg once daily. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 10 mg once daily. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 15 mg once daily.In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 20 mg once daily. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 25 mg once daily. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 30 mg once daily. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 35 mg once daily. In some embodiments, panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally at about 40 mg once daily.

[0104] In some embodiments, the cancer is colorectal cancer, pancreatic cancer, or non-small cell lung cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is metastatic colorectal cancer. In one embodiment, the cancer is BRAF mutant metastatic colorectal cancer. In one embodiment, the cancer is BRAF V600E mutant metastatic colorectal cancer. In one embodiment, the cancer is KRAS mutant colorectal cancer. In one embodiment, the cancer is KRAS G12C mutant colorectal cancer. In one embodiment, the cancer is KRAS G12D mutant colorectal cancer. In one embodiment, the cancer is KRAS G12V mutant colorectal cancer. In one embodiment, the cancer is Trp53 mutant colorectal cancer. In one embodiment, the cancer is NRAS mutant colorectal cancer.

[0105] In some embodiments, provided herein are methods for treating colorectal cancer in a subject by administering to the subject an anti-EGFR antibody and Compound A. In some embodiments, the colorectal cancer has an oncogenic K-RAS, N-RAS, or B-RAF mutation. In some embodiments, the colorectal cancer is metastatic or unresectable colorectal cancer. In some embodiments, prior to administration, the subject has been treated with another therapy and has experienced cancer progression after the other therapy.

[0106] In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is pancreatic ductal adenocarcinoma (PDAC). In one embodiment, the cancer is BRAF mutant pancreatic cancer. In one embodiment, the cancer is BRAF V600E mutant pancreatic cancer. In one embodiment, the cancer is KRAS mutant pancreatic cancer. In one embodiment, the cancer is KRAS G12C mutant pancreatic cancer. In one embodiment, the cancer is KRAS G12D mutant pancreatic cancer. In one embodiment, the cancer is KRAS G12V mutant pancreatic cancer. In one embodiment, the cancer is Trp53 mutant pancreatic cancer. In one embodiment, the cancer is NRAS mutant pancreatic cancer.

[0107] In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is BRAF mutant non-small cell lung cancer. In one embodiment, the cancer is BRAF V600E mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS G12C mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS G12D mutant non-small cell lung cancer. In one embodiment, the cancer is KRAS G12V mutant non-small cell lung cancer. In one embodiment, the cancer is Trp53 mutant non-small cell lung cancer. In one embodiment, the cancer is NRAS mutant non-small cell lung cancer.

[0108] In some embodiments, the cancer is colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, or thyroid cancer. In some embodiments, the patient has progressed through one or more prior therapies.

[0109] In some embodiments, the cancer is characterized by a mutation in a gene selected from RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and any combination thereof; preferably RAS, NRAS, KRAS, RAF, BRAF, and any combination thereof; more preferably NRAS, KRAS, BRAF, and any combination thereof. In some embodiments, the cancer is characterized by a mutation in a gene selected from RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and any combination thereof; preferably RAS, NRAS, KRAS, RAF, BRAF, and any combination thereof; more preferably NRAS, KRAS, BRAF, and any combination thereof, and the patient has progressed on one or more prior therapies.

[0110] In some embodiments, the cancer is characterized by a mutation selected from NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusions, and any combination thereof; preferably, NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusions, and any combination thereof; more preferably, RAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and any combination thereof.

[0111] In one embodiment, the cancer is characterized by a genomic abnormality in another MAPK pathway. In one embodiment, the other MAPK pathway genomic abnormality is a RAS A1 splice isoform.

[0112] In some embodiments, the cancer is characterized by a mutation in a gene selected from ARAF, BRAF, RAF1, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and any combination thereof.

[0113] In some embodiments, the cancer is BRAF N20T, BRAF A33T, BRAF S36A, BRAF V47_G393del, BRAF V47_G327del, BRAF V47_D380del, BRAF V47_M438del, BRAF N49I, BRAF M53I, BRAF L64I, BRAF G69S, BRAF A81_D380del, BRAF A81_M438del, BRAF G104E, BRAF T119S, BRAF P141L, BRAF S151A, BRAF P162S, BRAF V169_G327del, BRAF V169_D380del, BRAF R188T, BRAF Q201H, BRAF G203_G393del, BRAF K205Q, BRAF V226L, BRAF E228V, BRAF R239Q, BRAF T241P, BRAF T241M, BRAF L245F, BRAF A246P, BRAF F247L, BRAF Q257R, BRAF Q257H, BRAF G258V, BRAF F259L, BRAF Q262R, BRAF H269Y, BRAF R271H, BRAF E275K, BRAF D287H, BRAF F294L, BRAF T310I, BRAF A320T, BRAF I326V, BRAF P341S, BRAF R347*, BRAF P348T, BRAF S363F, BRAF S364L, BRAF P367S, BRAF P367R, BRAF P367L, BRAF D380H, BRAF R389C, BRAF T401I, BRAF A404Cfs*9, BRAF P407L, BRAF S419Y, BRAF G421V, BRAF R444W, BRAF D448Y, BRAF D449Y, BRAF W450*, BRAF W450L, BRAF E451K, BRAF E451Q, BRAF P453T, BRAF V459L, BRAF R462E, BRAF R462K, BRAF R462I, BRAF I463T, BRAF I463S, BRAF G464I, BRAF G464R, BRAF G464E, BRAF G464A, BRAF G464V, BRAF S465D, BRAF S465E, BRAF S465A, BRAF G466R, BRAF G466E, BRAFG466A、BRAF G466V、BRAF S467A、BRAF S467L、BRAF F468C、BRAF G469L、BRAF G469del、BRAF G469S、BRAF G469R、BRAF G469E、BRAF G469A、BRAF G469V、BRAF T470K、BRAF V471I、BRAF V471F、BRAF Y472dup、BRAF Y472S、BRAF Y472C、BRAF G478C、BRAF K483E、BRAF K483M、BRAF L485_P490del、BRAF L485Y、BRAF L485_P490delinsY、BRAF L485S、BRAF L485W、BRAF L485F、BRAF L485_P490delinsF、BRAF N486_Q494del、BRAF N486del、BRAF N486_T488del、BRAF N486_T491del、BRAF N486_L495del、BRAF N486D、BRAF N486_V487del、BRAF N486_P490del、BRAF N486_A489delinsK、BRAF N486_T491delinsK、BRAF V487_P490del、BRAF V487_P492delinsA、BRAF T488_P492del、BRAF T488_Q493delinsK、BRAF A489_P490del、BRAF P490del、BRAF P490_Q494del、BRAF K499E、BRAF K499N、BRAF E501K、BRAF E501G、BRAF V504_R506dup、BRAF V504I、BRAF L505F、BRAF L505H、BRAF R509G、BRAF R509H、BRAF L514V、BRAF M517I、BRAF Q524L、BRAF L525R、BRAF T529M、BRAF T529N、BRAF T529I、BRAF W531C、BRAF G534D、BRAF Y538H、BRAF R558Q、BRAF G563D、BRAF H568D、BRAF H574N、BRAF H574Y、BRAF H574Q、BRAF N581D、BRAF N581Y、BRAF N581T、BRAF N581S、BRAF N581I、BRAFN581K、BRAF I582M、BRAF F583C、BRAF L584F、BRAF H585Y、BRAF E586K、BRAF D587A、BRAF D587G、BRAF D587E、BRAF V590I、BRAF V590G、BRAF I592V、BRAF I592M、BRAF G593D、BRAF D594N、BRAF D594H、BRAF D594Y、BRAF D594_T599dup、BRAF D594A、BRAF D594G、BRAF D594V、BRAF D594E、BRAF F595L、BRAF F595S、BRAF G596S、BRAF G596R、BRAF G596C、BRAF G596D、BRAF G596V、BRAF L597S、BRAF L597V、BRAF L597Q、BRAF L597P、BRAF L597R、BRAF A598T、BRAF A598S、BRAF A598V、BRAF A598_T599insARC、BRAF A598_T599insV、BRAF T599dup、BRAF T599A、BRAF T599K、BRAF T599R、BRAF T599I、BRAF T599_V600insTT、BRAF T599_V600insS、BRAF T599_V600insETT、BRAF T599_V600insEAT、BRAF V600_K601delinsEN、BRAF V600_S605delinsEISRWR、BRAF V600K、BRAF V600R、BRAF V600Q、BRAF V600dup、BRAF V600delinsYM、BRAF V600M、BRAF V600L、BRAF V600D、BRAF V600_K601delinsE、BRAF V600E、BRAF V600A、BRAF V600G、BRAF K601del、BRAF K601Q、BRAF K601E、BRAF K601_W604del、BRAF K601T、BRAF K601I、BRAF K601_S602delinsNT、BRAF K601N、BRAF S602T、BRAF S602Y、BRAF S602F、BRAF R603*、BRAF W604del、BRAF W604R、BRAF W604G、NICE S605A、NICES605F, BRAF S605E, BRAF S605G, BRAF S605N, BRAF S605I, BRAF G606W, BRAF G606E, BRAF G606A, BRAF G606V, BRAF S607P, BRAF S607F, BRAF H608R, BRAF Q609E, BRAF Q609L, BRAF Q609H, BRAF E611D, BRAF L613F, BRAF G615R, BRAF L618F, BRAF W619R, BRAF S637*, BRAF V639I, BRAF E648Q, BRAF Y656D, BRAF R671Q, BRAF P676S, BRAF L678I, BRAF V681I, BRAF E695K, BRAF K698R, BRAF The present invention is characterized by a mutation selected from BRAF L711F, BRAF A712T, BRAF R719S, BRAF H725Y, BRAF A728V, BRAF P731T, BRAF P731S, BRAF P731L, BRAF A762E, BRAF A762V, and any combination thereof.

[0114] In some embodiments, the cancer is characterized by a mutation selected from a KIAA1549-BRAF fusion, a BCAS1-BRAF fusion, a CCDC6-BRAF fusion, a CDC42BPB-BRAF fusion, a FAM131B-BRAF fusion, a FXR1-BRAF fusion, a GIT2-BRAF fusion, a KLHL7-BRAF fusion, a RNF130-BRAF fusion, a TMEM106B-BRAF fusion, a MKRN1-BRAF fusion, an AGAP3-BRAF fusion, an AGK-BRAF fusion, an AKAP9-BRAF fusion, an ARMC10-BRAF fusion, a CUL1-BRAF fusion, a GTF2I-BRAF fusion, a PAPSS1-BRAF fusion, a PCBP2-BRAF fusion, a PPFIBP2-BRAF fusion, a SND1-BRAF fusion, a TRIM24-BRAF fusion, a ZKSCAN1-BRAF fusion, a SEPT3-BRAF fusion, and any combination thereof.

[0115] In some embodiments, the cancer is NRAS G12A, NRAS G12C, NRAS G12D, NRAS G12N, NRAS G12P, NRAS G12R, NRAS G12S, NRAS G12V, NRAS G12Y, NRAS G13A, NRAS G13C, NRAS G13D, NRAS G13E, NRAS G13N, NRAS G13R, NRAS G13S, NRAS G13V, NRAS A18T, NRAS I24N, NRAS P34L, NRAS Y40*, NRAS Q43*, NRAS T50I, NRAS T58I, NRAS A59G, NRAS A59D, NRAS A59T, NRAS G60E, NRAS G60R, NRAS Q61E, NRAS Q61H, NRAS Q61H, NRAS Q61K, NRAS Q61L, NRAS and NRAS Q61L, NRAS Q61P, NRAS Q61R, NRAS Q61R, NRAS Q61R, NRAS Q61*, NRAS E63K, NRAS Y64D, NRAS S65C, NRAS R68S, NRAS S89A, NRAS G115Efs*46, NRAS E132K, NRAS K135N, NRAS A146P, NRAS A146T, NRAS A146V, NRAS E162*, and any combination thereof.

[0116] In some embodiments, the cancer has one or more of the mutations described herein. In some embodiments, the subject with cancer has one or more of the mutations described herein.

[0117] In some embodiments, Compound A is administered 1 to 3 times daily. In one embodiment, Compound A is administered 3 times daily. In one embodiment, Compound A is administered 2 times daily. In one embodiment, Compound A is administered once daily.

[0118] In some embodiments, the methods described herein provide for the administration of a plasma Compound A AUC of about 2,000 ng*h / mL to about 3,200 ng*h / mL in a subject. 8hIn one embodiment, the methods described herein provide a plasma Compound A AUC of about 2,128 ng*h / mL to about 3,192 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 2,400 ng*h / mL to about 2,900 ng*h / mL in a subject. 8h to provide.

[0119] In some embodiments, the methods described herein provide for the administration of a plasma Compound A AUC of about 4,600 ng*h / mL to about 6,900 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 4,576 ng*h / mL to about 6,864 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 5,100 ng*h / mL to about 6,300 ng*h / mL in a subject. 8h to provide.

[0120] In some embodiments, the methods described herein provide for the administration of a plasma Compound A AUC of about 8,000 ng*h / mL to about 12,000 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 7,944 ng*h / mL to about 11,916 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 8,900 ng*h / mL to about 10,900 ng*h / mL in a subject. 8h to provide.

[0121] In some embodiments, the methods described herein provide for the administration of a plasma Compound A AUC of about 10,000 ng*h / mL to about 14,800 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 9,840 ng*h / mL to about 14,760 ng*h / mL in a subject. 8hIn one embodiment, the methods described herein provide for a plasma Compound A AUC of about 11,100 ng*h / mL to about 13,500 ng*h / mL in a subject. 8h to provide.

[0122] In some embodiments, the methods described herein provide for the administration of a plasma Compound A AUC of about 12,700 ng*h / mL to about 19,000 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 12,640 ng*h / mL to about 18,960 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 14,200 ng*h / mL to about 17,400 ng*h / mL in a subject. 8h to provide.

[0123] In some embodiments, the methods described herein provide for the administration of a plasma Compound A AUC of about 30,000 ng*h / mL to about 45,000 ng*h / mL in a subject. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 33,800 ng*h / mL to about 41,300 ng*h / mL in a subject. 8h to provide.

[0124] In some embodiments, the methods described herein provide for a plasma Compound A AUC of about 2,000 ng*h / mL to about 3,200 ng*h / mL in a subject receiving Compound A treatment at about 5 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 2,128 ng*h / mL to about 3,192 ng*h / mL in a subject receiving Compound A treatment at about 5 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 2,400 ng*h / mL to about 2,900 ng*h / mL in a subject receiving Compound A treatment at about 5 mg / day. 8h to provide.

[0125] In some embodiments, the methods described herein provide for a plasma Compound A AUC of about 4,600 ng*h / mL to about 6,900 ng*h / mL in a subject receiving Compound A treatment at about 10 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 4,576 ng*h / mL to about 6,864 ng*h / mL in a subject receiving Compound A treatment at about 10 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 5,100 ng*h / mL to about 6,300 ng*h / mL in a subject receiving Compound A treatment at about 10 mg / day. 8h to provide.

[0126] In some embodiments, the methods described herein provide for a plasma Compound A AUC of about 8,000 ng*h / mL to about 12,000 ng*h / mL in a subject receiving Compound A treatment at about 15 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 7,944 ng*h / mL to about 11,916 ng*h / mL in a subject receiving Compound A treatment at about 15 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 8,900 ng*h / mL to about 10,900 ng*h / mL in a subject receiving Compound A treatment at about 15 mg / day. 8h to provide.

[0127] In some embodiments, the methods described herein provide for a plasma Compound A AUC of about 10,000 ng*h / mL to about 14,800 ng*h / mL in a subject receiving Compound A treatment at about 25 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 9,840 ng*h / mL to about 14,760 ng*h / mL in a subject receiving Compound A treatment at about 25 mg / day. 8hIn one embodiment, the methods described herein provide a plasma Compound A AUC of about 11,100 ng*h / mL to about 13,500 ng*h / mL in a subject receiving Compound A treatment at about 25 mg / day. 8h to provide.

[0128] In some embodiments, the methods described herein provide for a plasma Compound A AUC of about 12,700 ng*h / mL to about 19,000 ng*h / mL in a subject receiving Compound A treatment at about 40 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 12,640 ng*h / mL to about 18,960 ng*h / mL in a subject receiving Compound A treatment at about 40 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 14,200 ng*h / mL to about 17,400 ng*h / mL in a subject receiving Compound A treatment at about 40 mg / day. 8h to provide.

[0129] In some embodiments, the methods described herein provide for a plasma Compound A AUC of about 30,000 ng*h / mL to about 45,000 ng*h / mL in a subject receiving Compound A treatment at about 60 mg / day. 8h In one embodiment, the methods described herein provide a plasma Compound A AUC of about 33,800 ng*h / mL to about 41,300 ng*h / mL in a subject receiving Compound A treatment at about 60 mg / day. 8h to provide.

[0130] In some embodiments, the AUC 8h is measured in the plasma of the subject. In some embodiments, AUC 8h is measured in the subject's blood. In some embodiments, AUC 8h is measured in the subject's plasma or blood on Day 1 of Cycle 2. In some embodiments, AUC 8h is measured in the plasma or blood of the subject at about day 29 of treatment with Compound A.

[0131] In one embodiment, the subject receives one to twelve cycles of the treatment provided herein, each cycle consisting of about 28 days. In one embodiment, the subject receives one to twelve cycles of the treatment provided herein, each cycle consisting of about 21 days. In one embodiment, the subject receives one to twelve cycles of the treatment provided herein, each cycle consisting of about 14 days. In one embodiment, the subject receives one to twelve cycles of the treatment provided herein, each cycle consisting of about 7 days.

[0132] In one embodiment, the subject receives a treatment provided herein for 1 to 12 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 1 to 10 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 1 to 8 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 1 to 6 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 1 to 4 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 4 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 3 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 2 cycles, each cycle consisting of about 28 days. In one embodiment, the subject receives a treatment provided herein for 1 cycle, each cycle consisting of about 28 days.

[0133] In one embodiment, the subject achieves stable disease, a partial response, or a complete response. In one embodiment, the subject achieves a partial response or a complete response. In one embodiment, the subject achieves a complete response. In one embodiment, the subject does not experience progressive disease. In one embodiment, the subject achieves stable disease. In one embodiment, the subject achieves a partial response. In one embodiment, the subject achieves stable disease, a partial response, or a complete response for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the subject achieves stable disease, a partial response, or a complete response for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In one embodiment, the subject achieves stable disease, a partial response, or a complete response for 1 year, 2 years, 3 years, or 4 years.

[0134] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a combination provided herein, wherein the cancer is characterized by a mutation selected from BRAF, RAS, NRAS, KRAS, and a combination thereof; preferably NRAS and KRAS, and a combination thereof; more preferably KRAS. Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a BRAF inhibitor, wherein the cancer is characterized by a KRAS mutation. In one embodiment, the cancer is colorectal cancer (CRC). In one embodiment, the cancer is PDAC.

[0135] In some embodiments, the cancer is colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, or thyroid cancer.

[0136] In some embodiments, the cancer is characterized by a mutation selected from NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusions, and any combination thereof; preferably, NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusions, and any combination thereof; more preferably, RAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and any combination thereof. In one embodiment, the cancer is characterized by a mutation provided herein.

[0137] In certain embodiments, the patient has colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal gland cancer, cervical cancer, lymphoma, or thyroid cancer. In certain embodiments, the patient response measured is inhibition of disease progression, inhibition of tumor growth, reduction in primary and / or secondary tumor(s), alleviation of tumor-related symptoms, improvement in quality of life, delay in the appearance of primary and / or secondary tumors, slowing of the development of primary and / or secondary tumors, reduction in the occurrence of primary and / or secondary tumors, delay in or reduction in the severity of secondary effects of the disease, cessation of tumor growth, or tumor regression.

[0138] Provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a combination provided herein, wherein the cancer is metastatic, resistant, recurrent, and / or unresectable. In some embodiments, the subject is an adult patient, e.g., a patient aged 18 years or older.

[0139] In one embodiment, Form F is in powder form having a particle size with a D90 of less than about 200 μm. In one embodiment, Form F is in powder form having a particle size with a D90 of less than about 400 μm. In one embodiment, Form F is in powder form having a particle size with a D90 of less than about 600 μm. In one embodiment, Form F is in powder form having a particle size with a D90 of less than about 100 μm. In one embodiment, Form F is in powder form having a particle size with a D90 of less than about 50 μm. In one embodiment, the purity of Form F is greater than about 99.0%. In one embodiment, the purity of Form F is greater than about 98.0%. In one embodiment, the purity of Form F is greater than about 97.0%. In one embodiment, the purity of Form F is greater than about 96.0%. In one embodiment, the purity of Form F is greater than about 95.0%.

[0140] kit Provided herein are kits comprising Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, together with instructions for effective administration. For example, in some embodiments, the kit comprises Compound A and panitumumab, together with instructions for effective administration. In some embodiments, the kit is for use in a method described herein (e.g., in a method for treating cancer).

[0141] Provided herein are kits comprising a combination provided herein and a means for monitoring a patient's response to administration of the compounds provided herein.

[0142] In other embodiments, provided herein are kits comprising a combination provided herein and a means for measuring the amount of inhibition of B-RAF, KRAS, NRAS, or MEK in a patient. In certain embodiments, the kit comprises a means for measuring the inhibition of B-RAF or MEK in the patient's circulating plasma, blood, or tumor cells, and / or skin biopsy, or tumor biopsy / aspirate. In certain embodiments, provided herein are kits comprising a compound provided herein and a means for measuring the amount of inhibition of B-RAF, KRAS, or MEK before, during, and / or after administration of a compound provided herein. In certain embodiments, the patient has colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, or ovarian cancer.

[0143] In certain embodiments, the kits provided herein comprise a combination provided herein in an amount effective to treat or prevent colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, and thyroid cancer; preferably, melanoma, ovarian cancer, and non-small cell lung cancer. In certain embodiments, the kits provided herein comprise a compound provided herein in an amount effective to treat or prevent colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, or ovarian cancer.

[0144] In certain embodiments, the kits provided herein further comprise one or more pharmaceutically acceptable carriers.

[0145] In certain embodiments, the kits provided herein comprise instructions for administering a compound provided herein and / or for monitoring a patient's response to administration of the compound. [Example]

[0146] Example The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Unless otherwise indicated, the experimental methods in the examples described below are conventional methods. [Table 1-1] [Table 1-2]

[0147] Example 1 The investigational products are Compound A and panitumumab. The study title is "First in Human, Phase 1a / 1b, Open-Label, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, and Antitumor Activity of the RAF Dimer Inhibitor Compound A in Patients with Advanced and Refractory Tumors."

[0148] The study is a multicenter, open-label, two-part (safety observation and dose-expansion) phase 1a / 1b study of Compound A in combination with panitumumab in patients with tumors harboring B-RAF or K-RAS / N-RAS mutations that may respond to RAF dimer inhibitors.

[0149] The total number of patients will be approximately 64. Part 1 (safety observation) will have approximately 24 patients. Part 2 (dose expansion) will have approximately 40 patients.

[0150] Objectives and evaluation items The safety observational study objectives include primary, secondary, and exploratory objectives. The primary objective is to investigate the safety and tolerability of the combination of Compound A and panitumumab and to determine the recommended Phase 1b / 2 dose for the combination. The secondary objectives are to characterize the pharmacokinetics (PK) of Compound A and panitumumab in combination and to investigate the preliminary antitumor activity of the combination of Compound A and panitumumab. The exploratory objectives are to determine potential predictive biomarkers of efficacy, investigate potential pharmacodynamic (PD) biomarkers of target binding, biological activity, and mechanism of action, and explore mechanisms of treatment resistance in patients who did not respond or developed resistance.

[0151] The objectives of the dose-expansion study include primary, secondary, and exploratory objectives. The primary objective is to investigate the preliminary antitumor activity of the combination of Compound A and panitumumab. The secondary objectives are to further investigate the safety and tolerability of the combination of Compound A and panitumumab, and to further characterize the PK of Compound A and panitumumab. The exploratory objectives are to explore potential predictive biomarkers of efficacy, investigate potential PD biomarkers of target binding, biological activity, and mechanism of action, and explore mechanisms of resistance in patients who did not respond or did not develop resistance.

[0152] Study endpoints for safety monitoring The primary endpoint is the safety and tolerability of the combination of Compound A and panitumumab, as monitored throughout the study by the occurrence and severity of AEs and SAEs (coded into System Organ Classes (SOCs) and Preferred Terms (PTs) using the Medical Dictionary for Regulatory Activities (MedDRA)) and graded according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), physical examination, ophthalmologic examination, vital signs, electrocardiogram (ECG), echocardiogram (ECHO), and laboratory tests. The recommended Phase 1b / 2 dose will be determined based on safety, tolerability, PK, preliminary efficacy, and other available data.

[0153] Secondary endpoints include measuring the pharmacokinetic profile of Compound A and panitumumab in combination, including single dose: area under the plasma concentration curve (AUC), maximum observed plasma concentration (C max ), time to maximum observed plasma concentration (T max ); Steady state: AUC last,ss , C max,ss , and T max,ss PK parameters may include, but are not limited to, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), clinical benefit rate (CBR), and progression-free survival (PFS). Exploratory objectives are predictive biomarkers of efficacy, including, but not limited to, phosphorylated extracellular signal-regulated kinase (phospho-ERK) levels, mitogen-mediated protein kinase (MAPK) signaling, including v-RAF murine sarcoma viral oncogene homolog B (B-RAF), Kirsten rat sarcoma viral oncogene (K-RAS), neuroblastoma RAS viral oncogene (N-RAS), A-RAF proto-oncogene (A-RAF), neurofibromin-1 (NF-1) mutations, B-RAF or C-RAF amplification, and other abnormalities in or affecting the MAPK pathway.

[0154] Study endpoints for dose expansion The primary endpoints were efficacy parameters, including objective response rate (ORR), disease control rate (DCR), duration of response (DOR), clinical benefit rate (CBR), and progression-free survival (PFS). Secondary endpoints were safety and tolerability surveys of AEs, physical examination, ophthalmological examination, vital signs, ECG, ECHO, and laboratory measurements described in safety observations; AUC, Cmax, and T max PK parameters for Compound A, including but not limited to: AUC, Cmax, and T max PK parameters for panitumumab, including but not limited to:

[0155] Exploratory endpoints are predictive biomarkers of efficacy, including, but not limited to, mitogen-mediated protein kinase (MAPK) signaling, including phosphorylated extracellular signal-regulated kinase (phospho-ERK) levels, v-RAF murine sarcoma viral oncogene homolog B (B-RAF), Kirsten rat sarcoma viral oncogene (K-RAS), neuroblastoma RAS viral oncogene (N-RAS), A-RAF proto-oncogene (A-RAF), neurofibromin-1 (NF-1) mutations, B-RAF or C-RAF amplification, and other abnormalities in or affecting the MAPK pathway.

[0156] research design This is a two-part Phase 1b study of Compound A and panitumumab in combination in patients with tumors harboring oncogenic K-RAS / N-RAS or B-RAF mutations in colorectal cancer (CRC) and KRAS mutations in pancreatic cancer. Compound A in combination with panitumumab in patients with CRC K-RAS / N-RAS or B-RAF and pancreatic K-RAS mutations may enhance antitumor activity and address significant unmet medical needs in these patient populations.

[0157] The safety observation is a multicenter, open-label, multiple-dose, dose-escalation study in patients with colorectal or pancreatic cancer whose tumors harbor oncogenic B-RAF or K-RAS / N-RAS mutations. Three combination dose levels will be used. A Safety Monitoring Committee (SMC) will evaluate safety data and determine subsequent dose levels after patients have completed at least one cycle of treatment. The number of pancreatic patients cannot exceed one-third of the safety observation cohort.

[0158] The dose expansion is a multicentric, open-label, multi-arm, non-comparative index extension study for approximately 20 patients with colorectal cancer and approximately 20 patients with confirmed K-RAS / N-RAS mutations, and for approximately 20 patients with pancreatic cancer and confirmed K-RAS mutations. Based on the advice of the SMC, additional arms will be added to the study as needed, with Institutional Review Board (IRB) / Independent Ethics Committee (IEC) consent, to explore emerging signals.

[0159] Patients will be monitored for safety, tolerability, and efficacy throughout the study, from the date of the first administration of the investigational medicinal product (IMP) to a maximum of 30 days after the last dose of study medication. Radiographic surveillance of tumor response will occur approximately every 6 (± 1) weeks for the first 6 months, then every 8 (± 1) weeks, with surveillance potentially adjusted to every 12 (± 1) weeks after 1 year. Tumor response will be monitored by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

[0160] Patients receive the study agent(s) until progressive disease (PD), unacceptable toxicity, death, or other discontinuation criteria are met.

[0161] The study population is adult patients with advanced or metastatic, unresectable colorectal or pancreatic cancer who have experienced disease progression during or after at least one systemic therapy, or for whom treatment is unavailable, intolerable, or rejected. For safety observation, patients must have known mutation status and a histologically or cytologically confirmed diagnosis of colorectal or pancreatic cancer with an oncogenic B-RAF or K-RAS / N-RAS mutation for which effective standard therapy is unavailable or unacceptable. The number of pancreatic patients cannot exceed one-third of the safety observation cohort. For dose expansion, patients must have known mutation status and a histologically or cytologically confirmed advanced or refractory solid colorectal cancer with an oncogenic K-RAS / N-RAS mutation, or pancreatic cancer with a K-RAS mutation for which effective standard therapy is unavailable or unacceptable.

[0162] To be eligible for inclusion in this study, patients must be able to provide written informed consent and be able to understand and comply with the requirements of the study; must be 18 years of age or older (or of legal age of consent in the jurisdiction in which the study is conducted) as of the date of signing the Informed Consent Form (ICF); and must have advanced, metastatic, unresectable colorectal cancer that has experienced disease progression by RECIST v1.1 during or after at least one systemic therapy, or for which treatment is unavailable, intolerable, or rejected.

[0163] In addition, patients must meet the following eligibility criteria for the corresponding study part: In the safety observation cohort, patients must have known mutation status and must have histologically or cytologically confirmed colorectal or pancreatic cancer with oncogenic B-RAF or K-RAS / N-RAS mutations for which effective standard therapies are unavailable or not tolerated. The number of pancreatic patients cannot exceed one-third of the safety observation cohort. In the dose expansion cohort, patients must have known mutation status and must have histologically or cytologically confirmed advanced or refractory colorectal cancer with oncogenic K-RAS / N-RAS mutations, or pancreatic cancer with K-RAS mutations for which effective standard therapies are unavailable or not tolerated. Eligible patients must also have archived tumor tissue or consent to a baseline tumor biopsy for mutation and biomarker analysis, have measurable disease as defined by RECIST 1.1, have an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less at screening, have a life expectancy of 12 weeks or greater at the time of signing the ICF, and have adequate organ function without transfusions within 14 days of the first dose of IMP as demonstrated by the following laboratory values: Absolute neutrophil count (ANC) of 1500 cells / μL or greater Platelets greater than 100,000 / μL Hemoglobin greater than 9g / dL or greater than 5.6mmol / L Serum creatinine below 1.5 × upper limit of normal (ULN) or calculated creatinine clearance of 50 mL / min Serum total bilirubin of 1.5 x ULN or less (total bilirubin should be less than 3 x ULN for patients with Gilbert's syndrome), and Aspartate aminotransferase and alanine aminotransferase levels below 3 x ULN, or below 5 x ULN for patients with liver metastases.

[0164] Additionally, female patients are eligible to enroll and participate in the study if they are not of childbearing potential (i.e., physiologically unable to become pregnant), including any women who have undergone a hysterectomy, bilateral oophorectomy (oophorectomy), bilateral tubal ligation, or are postmenopausal (menstrual periods have ceased for more than one year). Female patients are also eligible to enroll and participate in the study if they are of childbearing potential, have a negative serum pregnancy test within seven days of the first dose of IMP, are not breastfeeding, and use protocol-approved contraception throughout the study prior to study enrollment and until 90 days after the last dose of IMP. Male patients are eligible to enroll and participate in the study if they have been vasectomized or agree to use protocol-approved contraception during study treatment and for at least 90 days after the last dose of IMP.

[0165] Any use of RAF or MEK inhibitors; current or history of central nervous system (CNS) metastases; history or evidence of retinal pathology or ophthalmologic examination that may be a risk factor for central serous retinopathy, RVO, or neovascular macular degeneration; patients may be excluded for pre-treatment if they have any of the following risk factors for RVO: Intraocular pressure of 21mmHg or higher Serum cholesterol grade 2 or higher Hypertriglyceridemia grade 2 or higher Grade 2 or higher or symptomatic hyperglycemia (fasting) · Hypertension grade 2 or higher.

[0166] Patients were required to have a history of glaucoma; pulmonary fibrosis / interstitial lung disease (ILD); active parathyroid disorder or a history of malignancy-associated hypercalcemia; experience any of the following within 6 months (24 weeks) after signing the informed consent form: clinically significant cardiac disease (New York Heart Association class III or IV), myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism; have a LVEF of 50% or less as determined by multi-gated acquisition (MUGA) scan or echocardiogram; and have electrolyte replacement therapy at screening. Patients may also be excluded if they have an abnormal QT interval (>450 msec for male patients, >470 msec for female patients, or >480 msec for patients with bundle branch block) corrected by the Fridericia formula after correction; current serious, uncontrolled systemic illness, including but not limited to clinically significant cardiovascular, pulmonary, or renal disease, or serious infection; or any unstable, preexisting, major medical condition that, in the investigator's opinion, contraindicates the use of IMP, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients who are hepatitis B surface antigen (HBsAg)-positive or HCV antibody-positive at screening will be enrolled only if their HBV DNA titer is <500 IU / mL or their HCV RNA polymerase chain reaction test is negative, respectively.

[0167] Patients were excluded if they had any bleeding or exsanguination event of CTCAE v5.0 grade 3 or higher within Day 1 of Cycle 1 of the 28-day period; increased serum calcium (>1×ULN) or serum phosphorus (>1×ULN) levels; inability to swallow oral medications (capsules and tablets) without chewing, destroying, crushing, opening, or otherwise altering the IMP formulation; gastrointestinal disease (e.g., absorption syndrome); use of concomitant systemic or intravenous glucocorticoid therapy; use of concomitant vitamin D; major surgery or significant traumatic injury within 4 weeks prior to the first dose of IMP treatment in Cycle 1, or anticipated need for major surgery during the course of study treatment; or receiving a concomitant medication that is a potent CYP3A inhibitor; a known history of significant toxicity from another RAF, MEK, ERK, or anti-EGFR antibody inhibitor requiring discontinuation of these agents from treatment; prior treatment with panitumumab at a reduced dose; underlying medical condition, laboratory abnormality, or alcohol or drug abuse or dependence that, in the investigator's opinion, is unfavorable to administration of study drug or affects the explanation for drug toxicity or adverse events; poor compliance during the study, in the investigator's judgment; or being pregnant or nursing an illness may also exclude participants.

[0168] Patients may also be excluded if they have received any of the following treatments: cyclic chemotherapy within a period shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosoureas, mitomycin-C) prior to starting study treatment; biologic therapy (e.g., antibodies), continuous or intermittent small molecule therapy, or any other investigational agent, other than bevacizumab or aflibercept within 5 half-lives (t) or 4 weeks (whichever is shorter) prior to starting study treatment; bevacizumab or aflibercept therapy within 3 weeks prior to starting study treatment; and radiation therapy to more than 30% of the bone marrow at any time prior to the first dose of study treatment or within 28 days.

[0169] The dose levels of panitumumab and Compound A in the safety observation period were as follows: Cohort 1: Panitumumab 6 mg / kg Q2W + Compound A 10 mg QD Cohort 2: Panitumumab 6 mg / kg Q2W + Compound A 20 mg QD Cohort 3: Panitumumab 6 mg / kg Q2W + Compound A 40 mg QD

[0170] Compound A can also be administered at 5 mg, 15 mg, 25 mg, 30 mg, or 35 mg. The recommended dose of panitumumab is 6 mg / kg, administered as an intravenous infusion over 60 minutes every 14 days. Doses greater than 1000 mg should be administered over 90 minutes. Compound A is administered orally (PO) once daily. The proposed dose levels are subject to change; additional dose levels (including higher doses) or dosing regimens may be considered. Any changes to dose levels or dosing regimens will be reviewed and approved by the SMC.

[0171] Dose levels for dose expansion are Compound A administered orally (PO) once daily in consecutive 28-day cycles at dose levels determined by dose escalation. In addition to the daily oral dose of Compound A, patients receive panitumumab IV every 2 weeks in 28-day cycles at dose levels determined by dose escalation.

[0172] The SMC will make recommendations on the selection of panitumumab dosing regimens based on safety, efficacy, PK, and exploratory data obtained from safety observations.

[0173] Example 2 The general properties of the solid form of Compound A used (Form F) are shown in Table 2. [Table 2]

[0174] After micronization, powder of Form F having a particle size with D90 less than 200 μm. The substance content (purity) was 98.0% or more.

[0175] Example 3 The investigational products are Compound A and panitumumab. The study title is "A Phase 1b, Open-Label, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, and Antitumor Activity of Compound A in Combination with Panitumumab in Patients with Advanced or Metastatic RAS-Mutant Colon and Pancreatic Ductal Carcinoma."

[0176] Objectives and evaluation items Dose titration (Part 1)

[0177] The primary objectives of the dose-finding (Part 1) study are to investigate the safety and tolerability of the combination of Compound A and panitumumab in patients with advanced or metastatic CRC, with known mutational status and tumors harboring oncogenic BRAF, KRAS, or NRAS mutations, who have documented disease progression during or after at least one prior line of therapy, and to determine the MTD of Compound A in combination with panitumumab and the RP2D of the combination.

[0178] Secondary objectives of the dose-finding (Part 1) study are to characterize the PK of Compound A and any associated metabolites following single and multiple doses of the combination of Compound A and panitumumab, and to investigate the preliminary antitumor activity of the combination of Compound A and panitumumab.

[0179] The primary endpoint of dose-finding (Part 1) included the safety and tolerability of the Compound A + panitumumab combination treatment, with the occurrence and severity of SAEs, as well as all TEAEs and adverse events of special interest (AESIs), with the severity of all AEs graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. Additional safety outcomes included: Laboratory values ​​(hematology, clinical chemistry, thyroid function tests, coagulation, and urinalysis) Vital signs Electrocardiogram (ECG) and echocardiogram (ECHO) / multiple gated acquisition (MUGA) findings (if applicable) Physical and ophthalmological examinations · Eastern Cooperative Oncology Group (ECOG) Activity Indicator Scale (PS) Discontinuation and / or reduction of Compound A administration.

[0180] The MTD was determined according to a modified toxicity probability interval-2 (mTPI-2) design (Guo W, Wang SJ, Yang S, Lynn H, Ji YA Bayesian interval dose-finding design addressing Ockham's razor: mTPI-2. Contemp Clin Trials. 2017 Jul;58:23-33) and was based on the occurrence of DLTs and the emerging safety and tolerability profile of the Compound A + panitumumab combination.

[0181] The RP2D is based on safety, preliminary efficacy, and other supporting data from all dose-finding cohorts.

[0182] The sponsor will recommend Compound A + panitumumab dose selection to be evaluated as the RP2D. Both the MTD and RP2D must be confirmed by the SMC.

[0183] Secondary endpoints for dose-finding (Part 1) are described here for Compound A and any associated metabolites, and PK will be investigated in plasma as depicted in the SOA (see Table 7). RECIST v1.1 will be used to measure tumor response based on the following efficacy endpoints: ORR, defined as the proportion of participants treated with Compound A and panitumumab with a confirmed CR or PR; duration of response (DOR), defined as the time from first measurement of response to first documentation of progression or death from any cause, whichever occurs first, in patients with a confirmed response; DCR, defined as the proportion of participants treated with Compound A and panitumumab with CR + PR + SD ≥ 24 weeks; and PFS, defined as the time from first administration of study drug to first documentation of disease progression or death from any cause, whichever occurs first.

[0184] Dose expansion (Part 2): The primary objective of dose expansion (Part 2) is to measure ORR, as investigated by initial investigator confirmation, using RECIST v1.1 with the combination treatment of Compound A and panitumumab at RP2D.

[0185] Secondary objectives of dose expansion (Part 2) are to further investigate the safety and tolerability of Compound A and panitumumab in patients with advanced or metastatic CRC harboring KRAS or NRAS mutations and patients with advanced or metastatic PDAC harboring KRAS mutations who have documented disease progression during or after at least one prior line of therapy; to measure ORR at RP2D as determined by central investigator confirmation using RECIST v1.1 with the combination treatment of Compound A and panitumumab; to measure preliminary activity of Compound A and panitumumab at RP2D as determined by initial investigator confirmation using RECIST v1.1, DOR, and PFS; and to further characterize the PK of Compound A and any associated metabolites.

[0186] The exploratory objectives of dose expansion (Part 2), the results of which may be reported separately in the Final Clinical Study Report (CSR), are to measure potential predictive biomarkers of molecular response to Compound A and panitumumab, as well as to investigate potential pharmacodynamic (PDx) biomarkers of target binding, biological activity, and mechanism of action.

[0187] Secondary endpoints Secondary endpoints for dose expansion (Part 2) are the safety and tolerability of the combination treatment with Compound A and panitumumab at RP2D based on the occurrence of SAEs, and the occurrence and severity of all TEAEs and AESIs, with the severity of all AEs graded according to NCI-CTCAE v5.0. Additional safety outcomes include laboratory values ​​(hematology, clinical chemistry, coagulation, and urinalysis); vital signs; ECG and ECHO / MUGA findings (if applicable); physical and ophthalmologic examinations; ECOG PS; interruptions and / or reductions in Compound A dosing; ORR, defined as the proportion of participants treated with Compound A and panitumumab at RP2D with confirmed CR or PR; DCR, DOR, and PFS—defined for the dose-finding portion of Part 1; and measurements of plasma concentrations of Compound A and any related metabolites.

[0188] Exploratory endpoints Exploratory endpoints for dose expansion (Part 2) will be predictive and PDx biomarkers, including but not limited to markers for mutational, amplification, transcriptional, and phosphorylation signatures of MAPK pathway signaling, investigated in baseline tumor tissue and peripheral blood samples, as well as in exploratory subgroup analyses of, for example, tumor deoxyribonucleic acid (ctDNA) / serum, which may be performed if data allow for investigation of mechanisms of resistance in participants treated with the combination of Compound A and panitumumab who do not respond or develop resistance.

[0189] Research Plan This is a multicentric, global, open-label, Phase 1b dose-finding and dose-expansion study in participants with advanced or metastatic CRC and PDAC, whose tumors harbor oncogenic mutations of BRAF and KRAS / NRAS, which may be responsive to treatment with Compound A, a RAF dimer inhibitor, when combined with the EGFR inhibitor, panitumumab.

[0190] Participants will be recruited into the study after initially being referred by a participating oncology center and receiving at least one standard of care anti-cancer treatment. Eligible, consented study participants will subsequently proceed to the dose-finding (Part 1) phase, followed by the dose-expansion (Part 2) phase. Part 1 of the study aims to establish the MTD and RP2D by investigating the safety, tolerability, preliminary anti-tumor activity, and PK of Compound A in combination with panitumumab. Part 2 of the study will further evaluate the safety, PK, and investigate the preliminary anti-tumor activity of the RP2D of the Compound A + panitumumab combination.

[0191] Exploratory investigations of predictive and PDx biomarkers will be conducted in both Part 1 and Part 2 of the study.

[0192] The study design is summarized in Figure 2 (by study part) and Figure 3 (by study period).

[0193] Part 1 - Dose finding Enrollment in the dose-finding portion of the study will occur in four planned sequential cohorts, consisting of a minimum of three and a maximum of six evaluable participants per dose level of Compound A in combination with panitumumab. The dose-finding cohorts will enroll patients with advanced or metastatic CRC with known mutational status and tumors harboring an oncogenic BRAF, KRAS, or NRAS mutation, and documented disease progression by RECIST criteria during or after at least one prior line of therapy. Approximately 30 participants will be enrolled, ensuring a total of approximately 24 evaluable participants.

[0194] All participants will receive repeated 28-day Compound A + panitumumab treatment cycles. The starting dose of Compound A will be 5 mg administered PO QD. Panitumumab will be administered by IV infusion at 6 mg / kg body weight Q2W, given within 60 minutes (+30 minutes) after oral administration of Compound A on these days.

[0195] To evaluate the combination, the following dose levels will be used in Part 1: Cohort 1 (dose level 1): Compound A 5 mg PO QD + panitumumab 6 mg / kg Q2W Cohort 2 (dose level 2): ​​Compound A 10 mg PO QD + panitumumab 6 mg / kg Q2W Cohort 3 (dose level 3): Compound A 20 mg PO QD + panitumumab 6 mg / kg Q2W Cohort 4 (dose level 4): Compound A 30 mg PO QD + panitumumab 6 mg / kg Q2W

[0196] Dose Escalation and Cohort Progression Periodic safety evaluations during the dose-finding portion of Part 1 of the study will be conducted by the SMC, which meets to actively monitor and review all accumulating data, including safety and efficacy data for ongoing studies and all available PK and PDx data, during the dose-finding portion. The SMC may make recommendations for early study termination or modifications to the conduct of the study. Dose cohort size management and dose escalation decisions for Part 1 will be made according to the mTPI-2 model-assisted design (Guo et al., 2017) and must be confirmed by the SMC. The sponsor may decide to stop or adapt the study based on the SMC's recommendations.

[0197] The target toxicity rate for the MTD is Φ = 0.30, and the allowed toxicity probability interval is (0.25, 0.33). The mTPI-2 design uses a Bayesian statistical framework and a hierarchical model of the beta-binomial distribution to calculate the posterior for dose intervals, reflecting the relative difference between toxicity rates at each dose level. Probability mass units (UPMs) are calculated for each of the following toxicity probability intervals: (0, 0.01), (0.01, 0.09), (0.09, 0.17), (0.17, 0.25), (0.25, 0.33), (0.33, 0.41), (0.41, 0.49), …, (0.89, 0.97), and (0.97, 1).

[0198] The width of each interval is 0.08 except for the first and last intervals. The UPM of an interval is the posterior probability of toxicity within the interval divided by the width of the interval (Ji et al., 2010).

[0199] The recommendations according to the mTPI-2 design are as follows: if the maximum UPM is below the interval (0.25,0.33), increase to the next dose (or maintain the same dose if the current dose is at the maximum dose level); if the maximum UPM is within the interval (0.25,0.33), maintain the same dose; if the maximum UPM is above the interval (0.25,0.33), decrease to the last safe dose. The following two additional safety measures (according to Ji et al., 2010) are observed for this study:

[0200] Safety Rule 1 (Early Termination): Dose 1 will be used to treat participants. If there is a 95% or greater posterior probability of toxicity greater than 0.30, the trial will be terminated due to excessive toxicity.

[0201] Safety Rule 2 (Dose Exclusion): The decision shall be to increase the current dose level I to the next level (i+1). If the posterior probability at dose level 1 greater than 0.3 is greater than 95%, treat the next cohort of participants at dose i and exclude doses (i+1) and above from the study, i.e., these doses will never be used again in the study.

[0202] A cohort of at least three participants per Compound A dose level in combination with panitumumab who have completed one cycle of treatment (up to and including day 28) must be evaluated before determining the dose level for the next titration cohort.

[0203] Table 3 shows a decision table based on mTPI-2 for each scenario of the number of DLTs observed among "n" participants at the dose level used to assist the SMC in its decision making. The SMC decision to maintain, increase, or decrease a particular Compound A dose level also considers the totality of the safety and efficacy data, as well as all available PK and PDx data.

[0204] If the planned maximum dose level (Dose Level 4 - Compound A 30 mg PO QD + panitumumab 6 mg / kg Q2W) is identified by the SMC based on mTPI-2 estimates of toxicity rates and review of all available data from the study, the sponsor, in consultation with the SMC, will recommend escalating Compound A to 40 mg (MTD based on Compound A monotherapy) and / or adding additional dosing schedules. The maximum dose of Compound A during the titration portion should not exceed 40 mg QD.

[0205] Cohorts may receive dose levels of Compound A already tested, but the dose associated with the "dose reduction, unacceptable toxicity" determination may not be revisited, and no more participants may be treated with this or any higher dose of Compound A for the remainder of the trial. [Table 3]

[0206] Dose-limiting toxicity For the purposes of tolerability determination in Part 1, a DLT is defined as any AE or abnormal laboratory value that occurs within the first 28-day cycle of treatment and is investigated as unrelated to underlying disease, disease progression, intercurrent illness, or concomitant medication / therapy. The severity of the DLT will be graded according to NCI-CTCAE v5.0. A DLT must meet at least one of the following criteria:

[0207] Hematological DLTs were any of Grade 4 or higher hematological toxicity; febrile neutropenia (an isolated body temperature of 38.3°C (101°F) or an absolute neutrophil count (ANC) of 1000 / mm3 with a sustained body temperature of 38.0°C (100.4°F) or higher for more than 1 hour); 3 Grade 3 neutropenia lasting more than 7 days; Grade 3 thrombocytopenia associated with clinically significant (CS) bleeding; or Grade 3 anemia requiring fluid transfusion according to local or international guidelines in the absence of bleeding.

[0208] Non-hematological DLTs were any death, whether due to the underlying disease or unrelated cause, or any toxicity requiring permanent discontinuation of the study drug(s); unless otherwise specified, any non-hematological event of Grade 4 or higher; total bilirubin (TBIL; excluding participants with Gilbert's syndrome) or transaminases (ALT or AST) of Grade 3 or higher; skin and subcutaneous tissue disease of Grade 3 or higher that does not begin to resolve within 28 days despite initiation of optimal medical and supportive care and protocol-directed Compound A and panitumumab dose management; or serious neurological disease of Grade 3 or higher. Toxicity (e.g., convulsions, hallucinations, confusion, or delirium); escalating symptoms, creatine phosphokinase (CPK) of Grade 3 or higher, or rhabdomyolysis of Grade 2 or higher; non-hematologic treatment-related toxicity of Grade 3 or higher not listed above that has not resolved to Grade 1 or lower within 3 days of initiating optimal medical and supportive therapy; other clinically significant or persistent toxicity that may also be considered a DLT, as confirmed by the sponsor in consultation with the investigator, or as confirmed by the SMC; confirmed development of Hy's law or potential drug-induced liver injury (DILI) according to the US FDA definition, without evidence of cholestasis and unexplained by any other cause(s) (e.g., viral hepatitis, exposure to other hepatotoxins), including the following laboratory abnormalities (this specific category of DLT uses the ULN, not the CTCAE grade, for NCI-definition): Patients with baseline AST or ALT and TBIL values ​​within the normal range who subsequently present with a TBIL value ≥ 2 × ULN, no evidence of hemolysis, an ALP value ≤ 2 × ULN, or an AST or ALT value ≥ 3 × normal (ULN) with other evidence of the absence of cholestasis; For participants with baseline ALT or AST values ​​greater than 2x the ULN, AST, or ALT value, the baseline value should be used as defined above.

[0209] Additionally, any CS toxicity occurring after the defined DLT observation period for a given dose level may be considered for subsequent dose escalation and / or RP2D determination. The following toxicities will not be considered DLTs: isolated and asymptomatic Grade 3 or higher laboratory abnormalities not listed above that have no clinical correlation and resolve to Grade 1 or lower within 3 days with or without initiation of medical and supportive therapy; Grade 3 or higher panitumumab infusion reactions; Grade 3 or higher laboratory abnormalities (e.g., hypoalbuminemia and lymphopenia) that are not clinically relevant or appear not to be adverse and are correctable; Grade 3 or higher nausea, vomiting, or diarrhea that resolve to Grade 1 or lower within 3 days; Grade 3 or higher fatigue that resolves to Grade 1 or lower within 5 days; and Grade 3 or higher asymptomatic increases in lipase or amylase without pancreatitis that resolve to Grade 1 or lower within 7 days.

[0210] Participants who experience a DLT due to a TATE in this procedure will be managed according to treatment modification guidelines.

[0211] To be considered evaluable for DLT, participants must receive 80% or more of their assigned doses of Compound A in combination with both doses of panitumumab and remain in the study for 28 days following the administration of Compound A + panitumumab on Day 1 of Cycle 1. If a participant discontinues study medication for any reason other than DLT and receives less than 80% of their assigned doses, they will be replaced.

[0212] Early stopping rules During the dose-finding portion, participants are closely monitored for AEs, SAEs, and DLTs. Recommendations follow a design aided by the mTPI-2 model. If the lowest dose is under investigation and the UPM is in the interval above (0.25, 0.33), the trial will be terminated due to excessive toxicity. Furthermore, if a posterior probability of toxicity above 0.30 is shown to be greater than 95% for the lowest dose, the study will be terminated due to excessive toxicity using Safety Rule 1. Otherwise, continue the study based on mTPI-2 recommendations.

[0213] Maximum tolerance (MTD) The MTD was determined according to a design aided by the mTPI-2 model and was based on the occurrence of DLTs and the emerging safety and tolerability profile of the Compound A + panitumumab combination. Using the mTPI-2 model, the target toxicity rate for the MTD is Φ = 0.30, and the allowed toxicity probability interval is (0.25, 0.33).

[0214] Recommended Phase 2 Dose (RP2D) The RP2D is the dose level and administration regimen for the Compound A + panitumumab combination selected for further investigation in the dose-expansion portion of the study. The sponsor will provide a recommendation on the selection of the Compound A + panitumumab dose. The RP2D must be confirmed by the SMC based on safety, preliminary efficacy, and other supporting data from all dose-finding cohorts.

[0215] Part 2 - Dose Expansion The dose expansion portion of Part 2 of the study will begin only after confirmation of the RP2D and dosing regimen in Part 1 of the dose-finding portion of the study. Participants enrolled in the dose-finding cohort will not be able to re-enroll in the dose expansion portion of the study. The dose expansion portion of the study will evaluate the RP2D in the following groups:

[0216] Group 1: Participants with advanced or metastatic CRC harboring a KRAS or NRAS mutation who have been treated by RECIST criteria and have documented disease progression during or after at least one prior line of therapy.

[0217] Group 2: Participants with KRAS-mutated, advanced or metastatic PDAC treated by RECIST criteria with documented disease progression during or after at least one prior line of therapy.

[0218] Each expansion cohort will enroll approximately 25 participants, achieving 20 efficacy-evaluable participants per group, all of whom will receive repeated 28-day Compound A plus panitumumab treatment cycles.

[0219] Research period Each study part consists of a screening, treatment, and safety follow-up period (Figure 3). The screening, treatment, and follow-up schedules are the same for both Part 1 and Part 2 of the study, as shown in Table 7.

[0220] Screening Period Screening for the study will occur prior to study enrollment and within 28 days prior to the first dose of study medication on Day 1 of Treatment Cycle 1. Informed consent (from the participant or the participant's legal representative) must be documented before any study-specific procedures, including screening, are performed.

[0221] At screening, consenting participants who meet all eligibility criteria will be enrolled upon confirmation of eligibility.

[0222] There will be a minimal washout / recovery period for previous anti-cancer treatment (e.g., systemic chemotherapy, radiation therapy, biotherapy, continuous or intermittent small molecule therapy, or any other investigational agent) and major surgery prior to the start of study treatment, as defined in the study eligibility criteria.

[0223] A baseline survey will be conducted for all participants before the first dose of study medication. Collection of tumor tissue at the screening visit, either from archived tumor tissue or fresh tumor biopsy, is mandatory to establish baseline retrospective mutation status.

[0224] In patients with readily accessible tumor lesions, it is highly recommended that a fresh baseline tumor biopsy be collected for analysis at the time of screening. Participants will be selected for screening and eligibility based on known mutation status from local molecular testing results obtained from tumor tissue samples collected any time before screening. Blood samples will be collected from all participants at baseline for biomarker analysis.

[0225] All screening and baseline assessments are outlined in Table 7.

[0226] Treatment period The treatment durations for both the Part 1 dose-finding and Part 2 dose-expansion portions of the study are as follows:

[0227] Participants will receive repeated 28-day treatment cycles with the combination of Compound A and panitumumab. Participants will receive study drug until, for example, clinical or radiological disease progression; patients found to have clinically or radiologically progressive disease (PD) by RECIST v1.1 discontinue the study; study treatment is terminated due to death, intolerance, or withdrawal of study consent; 2 years of treatment is completed (unless the investigator's benefit-risk assessment supports continued treatment); investigator decision; or the study is terminated by the sponsor for any reason.

[0228] All participants who discontinue participation in the study will complete all specified surveys, whenever possible, ahead of the end-of-treatment (EoT) visit, optimally within 7 days of the investigator's decision to no longer use the study medication.

[0229] Participants who discontinue study treatment early for reasons other than disease progression (e.g., toxicity) will continue to receive tumor assessments according to the procedural tumor response surveillance schedule until the participant begins subsequent anticancer treatment, experiences disease progression, withdraws consent, dies, or the study ends, whichever occurs first.

[0230] Safety follow-up period The safety follow-up period consisted of an on-site visit 30(+7) days after the last dose of study medication and another on-site visit 60(+7) days after the last dose of panitumumab.

[0231] After the defined safety follow-up period, investigators must continue to report any SAEs they become aware of that are thought to be related to the study drug(s) as well as death, regardless of cause. Study participants who discontinue study drug due to a Grade 3 or higher drug-related AE will be followed until the AE has resolved (to Grade 1 or lower, baseline, or stabilized) or until they start a new anti-cancer treatment, whichever occurs first.

[0232] That is, additional, unscheduled investigations and visits may occur at the investigator's discretion if deemed necessary for clinical safety reasons.

[0233] group definition Participants will formally participate in screening with informed consent.

[0234] A screen failure is defined as a patient who consents to participate in a clinical study but is subsequently not enrolled in the study intervention. To clearly report screen failure participants to meet requirements issued by the Consolidated Standards of Reporting of Trials (CONSORT) and to respond to inquiries from regulatory authorities, minimal screen failure information is required. This minimum information includes demographics, details of the screen failure, eligibility criteria, and any SAEs.

[0235] For administrative reasons, individuals who do not meet the study entry criteria (screen failure) or who have borderline test results may be rescreened once. Rescreened participants will be required to repeat all abnormal screening tests and procedures.

[0236] Eligible, consenting participants will be enrolled in the study. Before enrolling participants, the following must occur:

[0237] Acknowledgement that the participant (or LAR) has voluntarily signed the ICF.

[0238] Participants will be enrolled only if they meet all study eligibility criteria and have been investigated by the investigator as suitable candidates for study participation.

[0239] Proactive approval of procedural deviations from recruitment and enrollment standards, also known as procedural waivers or exemptions, is not permitted.

[0240] Investigators should refer to Compound A IB for detailed information regarding warnings, precautions, contraindications, AEs, and other significant data regarding the investigational drug used in this study.

[0241] Selection Criteria Participants who meet all of the following inclusion criteria at screening (and first dose date, if applicable) are eligible to participate in the study:

[0242] Participants must have voluntarily agreed to participate in the study by giving signed informed consent and be 18 years of age or older at the time of signing the ICF.

[0243] Patients with histologically confirmed advanced or metastatic solid tumors who have documented disease progression by RECIST criteria during or after at least one prior line of systemic anti-cancer therapy, or who are refractory to standard of care therapy(ies) as described by local guidelines, in a representative population.

[0244] Participants must meet the following eligibility criteria for the corresponding part of the study:

[0245] Dose finding: Participants with CRC whose tumors have known mutational status and harbor oncogenic mutations of BRAF, KRAS, or NRAS in archived tumor samples or fresh tumor biopsies as determined by local testing.

[0246] Dose expansion: Participants must have known mutation status according to local testing and meet one of the following criteria according to the enrolled cohort:

[0247] Group 1: Patients with CRC who have KRAS or NRAS mutations in archived tumor samples or fresh tumor biopsies.

[0248] Group 2: Patients with PDAC who have a KRAS mutation in an archived tumor sample or fresh tumor biopsy.

[0249] For prospective mutation status analysis by Clinical Laboratory Improvement Act (CLIA)-certified next-generation sequencing (NGS) assay and for biomarker analysis, participants must provide archived tumor tissue or a fresh tumor biopsy. A fresh tumor biopsy is highly recommended at the time of screening for patients with easily accessible tumor lesions.

[0250] Participants must have radiologically measurable disease at screening as defined according to RECIST v1.1; ECOG PS ≤ 1 at screening; life expectancy ≥ 12 weeks at screening according to the investigator's best judgment; baseline serum electrolytes in the normal range according to the local laboratory; if baseline serum electrolytes are out of range, electrolytes will be collected and potential patients may be rescreened; adequate renal function characterized by an estimated creatinine clearance; Chronic Kidney Disease Epidemiology Simultaneous Equation (CKD-EPI) ≥ 50 mL / min; TBIL ≤ 1.5 x ULN (≤ 3 x ULN for participants with Gilbert's syndrome); AST and ALT ≤ 3 x ULN or ≤ 5 x ULN for patients with liver metastases; and adequate cardiac function as measured by: systolic blood pressure less than 160mmHg and diastolic blood pressure less than 100mmHg, Despite optimal antihypertensive control (Grade 2 or less), · Left ventricular ejection fraction (LVEF) of 50% or more by ECHO or MUGA; · CS ECG waveform is normal, QTcF of 470 msec or less as measured by mean QTcF value from ECG evaluation at screening (1 in triplicate).

[0251] and, prior to Day 1 of Cycle 1, had adequate hematological and organ function as shown by laboratory values: 1500 / mm 3 or more, or 1.5 x 10 9 ANC of / L: 100,000 / mm 3 or more, or 1.0×10 9 Platelet count ≥ 1 / L; hemoglobin ≥ 8 g / dL. Due to hematological function, participants must not have received blood transfusions or growth factor support within 14 days prior to sample collection. Female participants are eligible to enroll and participate in the study if they are not of childbearing potential; have a negative serum pregnancy test at screening (within 7 days of the first dose of study medication) and agree to use contraception throughout the study before study enrollment and until 180 days after the last dose of study medication. Male participants are eligible to enroll and participate in the study if they have a vasectomy or agree to use contraception during the treatment period and for at least 180 days after the last dose of study medication.

[0252] Participants who meet any of the following exclusion criteria at screening and on the day of first dosing are ineligible for the study: pregnant or lactating female participants; undergoing any major surgery within 4 weeks prior to Cycle 1 Day 1; having an active infection requiring systemic treatment at the start of study treatment; or receiving cancer therapy (chemotherapy or other systemic anticancer therapy, immunotherapy, radiation therapy, or surgery) as of Cycle 1 Day 1. Examples of such cancer therapy are systemic chemotherapy within 4 weeks prior to Cycle 1 Day 1, or nitrosoureas and mitomycin C within 6 weeks; biologic therapy (i.e., antibodies), continuous or intermittent small molecule therapy, or any other investigational agent within 5 half-lives of the drug or within 4 weeks prior to Cycle 1 Day 1 (whichever is shorter); and curative radiation therapy within 2 weeks of Cycle 1 Day 1.

[0253] Participants who meet any of the following cardiovascular exclusion criteria at screening and on the day of first dosing are also ineligible for the study: current unstable angina or another form of symptomatic cardiac ischemia; symptomatic pulmonary embolism or other CS episode of thromboembolism within 6 months prior to Day 1 of Cycle 1; acute myocardial infarction within 6 months prior to Day 1 of Cycle 1; New York Heart Association class III or IV heart failure within 6 months prior to Day 1 of Cycle 1; grade 2 or higher ventricular arrhythmia within 6 months prior to Day 1 of Cycle 1; cerebrovascular accident (CVA) or grade 2 or higher transient ischemic attack (TIA) within 6 months prior to Day 1 of Cycle 1; grade 2 or higher hypertension that cannot be controlled with standard antihypertensive medication before Day 1 of Cycle 1.

[0254] Participants who meet any of the following exclusion criteria at screening and on the day of first dose are also ineligible for the study: syncope or seizure within 6 months prior to Day 1 of Cycle 1; any major surgery within 28 days prior to Day 1 of Cycle 1; toxicity that has not resolved or stabilized to Grade 1 or less and is listed as permitted in other eligibility criteria, with Grade 2 toxicity; Grade 2 neuropathy without clinical correlation or isolated asymptomatic Grade 2 laboratory abnormalities may be unacceptable at the investigator's discretion after consultation with medical oversight; participants with a history of pneumonia or interstitial lung disease. Patients with immune-related toxicities, including myositis, skin toxicity, colitis, and myocarditis, that have not resolved with appropriate management (i.e., thyroid replacement or diabetic management) after discontinuing checkpoint inhibitor use; history or presence of gastrointestinal disease or other conditions known to interfere with drug absorption; history of ulcerative colitis or Crohn's disease, or delayed or ongoing immune-mediated diarrhea following previous checkpoint inhibitor use; history of corneal lacerations, keratitis, or severe dry eye; current symptomatic CNS metastases, leptomeningeal carcinoma, or untreated spinal cord compression.Participants were judged by the investigator to be clinically stable; had any active malignancy within the 3 years prior to Day 1 of Cycle 1, except for the specific cancers being investigated in this study and any localized or non-invasive cancers that have been curatively treated (e.g., excised basal or squamous cell skin cancer, superficial bladder cancer, or in situ cervical or breast cancer); had any unstable, pre-existing, major medical condition that, in the opinion of the investigator, contraindicated the use of the study drug, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; patients who were hepatitis B surface antigen (HBsAg)-positive or HCV antibody-positive at screening could only be enrolled if their HBV deoxyribonucleic acid (DNA) titer was less than 500 IU / mL or if their HCV ribonucleic acid (RNA) polymerase chain reaction test was negative, respectively; and had CD4+ Participants with HIV infection at screening may be enrolled only if their T cell (CD4+) count is ≥ 350 cells / μL; known hypersensitivity to RAF inhibitors, anti-EGFR monoclonal antibodies, or their excipients; any known history of grade 3 or higher toxicity from another RAF, MEK, ERK, or anti-EGFR antibody inhibitor lasting more than 14 days, requiring discontinuation of these agents from treatment; a history of solid organ transplant requiring anti-rejection medication; psychological, familial, social, or geographic medical conditions likely to interfere with procedural compliance are deemed unsuitable for the study by the investigator after the medical interview, physical examination, and / or screening surveys; are receiving or are expected to require any of the prohibited medications listed in the procedures; are concurrently participating in another therapeutic clinical trial; or have received any treatment with a strong CYP3A4 inhibitor or inducer within 14 days (or within 5 half-lives, whichever is longer) prior to Day 1 of Cycle 1 and for at least 5 half-lives until completion of Compound A administration. Asymptomatic treated or asymptomatic untreated brain metastases are permitted.

[0255] Study limitations Contraception Requirements Any participant who becomes pregnant during the study will be required to immediately discontinue further treatment with the study drug.

[0256] Fasting and dietary restrictions In safety laboratory studies, participants are not required to fast prior to collection of blood samples.

[0257] For both Part 1 and Part 2, Compound A will be administered orally either 1 hour before or 2 hours after breakfast on each dosing day during the treatment period.

[0258] Consumption of grapefruit and grapefruit juice, oranges, pomelo, exotic citrus fruits, or grapefruit hybrids is not permitted within 14 days prior to the start of study treatment, during treatment, or until the EoT visit. No other dietary restrictions apply.

[0259] Other lifestyle restrictions Sun exposure may exacerbate skin toxicities associated with Compound A and panitumumab treatment. Participants will be advised to wear sunscreen and limit sun exposure while receiving treatment with study medication.

[0260] Previous and concomitant treatments Cancer therapies or procedures (chemotherapy or other systemic anti-cancer therapy, immunotherapy, radiation therapy, or surgery) are prohibited or restricted during the study from Cycle 1 Day 1 through the completion of the study treatment period, including: systemic chemotherapy within 4 weeks of the last dose prior to Cycle 1 Day 1, or within 6 weeks for nitrosoureas and mitomycin, through the completion of the treatment period; biologic therapy (i.e., antibodies), continuous or intermittent small molecule therapy, or any other investigational agent within 5 half-lives of the drug or within 4 weeks prior to Cycle 1 Day 1 (whichever is shorter) through the completion of the treatment period; any major surgery within 4 weeks prior to Cycle 1 Day 1 through the completion of the treatment period.

[0261] The following therapies are prohibited or restricted during the study: any major surgery within 4 weeks prior to Day 1 of Cycle 1 through the completion of the treatment period; chronic systemic or ocular glucocorticoid therapy within 14 days prior to the start of study treatment through the completion of the treatment period, with the following exceptions: physiological or stress administration of steroids as indicated in patients with endocrine insufficiency; corticosteroids given as premedication for blood product infusion; corticosteroids given as pulse treatment for acute allergic reactions or bronchospasm; inhaled corticosteroids for asthma and reactive airway disease; and oral or IV corticosteroids for up to 6 consecutive days as indicated for management of an AE (e.g., Grade 3 or greater thrombocytopenia) after consultation with a medical monitor and / or ophthalmologist (as appropriate).

[0262] The following therapies are prohibited or restricted during the study: platelets or transfusions for the treatment of thrombocytopenia within 14 days prior to the start of study treatment and during the DLT period (Cycle 1) (however, platelets or transfusions for the treatment of thrombocytopenia may be permitted at the investigator's discretion after that specific event of thrombocytopenia has been identified as a DLT); red blood cell (RBC) or transfusions or erythropoietin (EPO) for the treatment of anemia within 14 days prior to the start of study treatment and during the DLT evaluation period (Cycle 1) (however, RBC or transfusions for the treatment of anemia must be permitted within 28 days of the start of study treatment). may be allowed at the investigator's discretion if chronic anemia persists during the study; granulocyte colony-stimulating factor (GCSF) / granulocyte-macrophage colony-stimulating factor (GMCSF) for the treatment of leukopenia / neutropenia within 14 days prior to the start of study treatment and during the DLT evaluation period (Cycle 1); strong CYP3A4 inhibitors and inducers within 14 days prior to the start of the treatment period and throughout the treatment period until its completion (see Table 4); and CYP2C8 or CYP2C9 substrates with narrow therapeutic windows during the treatment period until its completion (see Table 5).

[0263] EPO to treat anemia may be allowed at the investigator's discretion if the EPO dose has been stable within 28 days prior to the start of study treatment.

[0264] The following therapies are also prohibited or restricted during the study: herbal remedies (i.e., hypericin) or those acting as strong CYP3A4 inhibitors known to potentially interfere with liver or other major organ function within 14 days of the start of study treatment through the completion of the treatment period; live and live-attenuated vaccines, including intranasal influenza vaccine and monkeypox vaccine, are prohibited (within 4 weeks before the start of study treatment); and coronavirus disease 2019 (COVID-19) vaccine procedures must be completed at least 2 weeks before the start of study treatment. COVID-19 vaccination is prohibited during the DLT period (Cycle 1) but is permitted from Day 1 of Cycle 2 through the end of the study, although short treatment interruptions (1–2 days before and / or after each dose of vaccine) may be indicated at the investigator's discretion. Note: Injectable influenza vaccine is permitted at any time before and during the trial.

[0265] As in vitro data indicate that Compound A is primarily metabolized by the CYP3A pathway, COVID-19 treatment with PAXLOVID (nimarelvir + ritonavir) is contraindicated with drugs that are highly dependent on CYP3A for clearance.

[0266] The following radiation therapies will be prohibited or restricted during the study: prior curative radiation therapy will be prohibited within 2 weeks of Day 1 of Cycle 1; concomitant radiation therapy to the tumor lesion(s) selected as the target lesion(s) will be prohibited from the start of study treatment until the completion of the treatment period; prior and concomitant palliative radiation therapy to non-target tumor lesions may be permitted at the investigator's discretion at any time before the start of study treatment and during the treatment period. [Table 4]

[0267] The list of drugs provided is not exhaustive. Please refer to the prescribing information for the accompanying medication to confirm CYP3A4 inhibition / induction risk or to contact the study medical monitor. [Table 5]

[0268] The list of drugs provided is not exhaustive. To confirm CYP2C8 or CYP2C9 substrates or to contact a study medical monitor, please refer to the prescribing information for the accompanying medication.

[0269] Study duration and length of participation Each study part consists of a screening, treatment, and safety follow-up period. The screening, treatment, and follow-up schedules will be the same for both parts of the study, as shown in the SOA (Table 1). The screening period will represent the period from the date of signing of the informed consent to the first administration of study medication (maximum of 28 days). The treatment periods for both the dose-finding and dose-expansion portions of the study will be as follows: Participants will receive repeated 28-day treatment cycles with the combination of Compound A and panitumumab. Participants will receive study medication until: · Clinical or radiological disease progression; Patients found to have clinically or radiologically progressive disease (PD) by RECIST v1.1 will discontinue the study Termination of study treatment due to death, intolerance, or withdrawal of consent to the study Complete 2 years of treatment (unless the investigator's benefit-risk assessment supports continuing treatment) The researcher decides; or The study is stopped by the sponsor for any reason.

[0270] All participants who discontinue participation in the study will complete all specified surveys, whenever possible, ahead of the end-of-treatment (EoT) visit, optimally within 7 days of the investigator's decision to no longer use the study medication.

[0271] Participants who discontinue study treatment early for reasons other than disease progression (e.g., toxicity) will continue to receive tumor assessments according to the procedural tumor response surveillance schedule until the participant begins subsequent anticancer treatment, experiences disease progression, withdraws consent, dies, or the study ends, whichever occurs first.

[0272] The safety follow-up period consisted of a follow-up on-site visit 30(+7) days after the last dose of study medication and another visit 60(+7) days after the last dose of panitumumab.

[0273] Note: After the defined safety follow-up period, investigators should continue to report any SAEs that they become aware of that are considered to be related to the study drug(s) as well as death, regardless of cause. Study participants who discontinue study drug due to a Grade 3 or higher drug-related AE may be followed until the AE has resolved (to Grade 1 or lower, baseline, or stabilized) or until they start a new anti-cancer treatment, whichever occurs first.

[0274] That is, additional, unscheduled investigations and visits may occur at the investigator's discretion if deemed necessary for clinical safety reasons.

[0275] Investigational products, dosages, and modes of administration Study agents include Compound A and panitumumab.

[0276] All participants will receive repeated 28-day Compound A plus panitumumab treatment cycles.

[0277] Two weeks before initiating study treatment, during the screening period, preventive care including humidifiers, sunscreen, oral antibiotics, and topical steroids should be initiated.

[0278] Compound A Compound A is supplied as an oral, solid, immediate-release capsule formulation in strengths of 5 mg and 10 mg.

[0279] Compound A capsules will be packaged in high-density polyethylene (HDPE) bottles and should be stored according to the conditions specified on the label. Compound A storage conditions will be supported by stability data conducted on the drug product. The starting dose of Compound A during the titration portion of the study will be 5 mg administered orally QD. The maximum dose of Compound A will not exceed 40 mg QD. Compound A will be administered orally 1 hour before or 2 hours after breakfast each day during the treatment period.

[0280] Panitumumab Panitumumab (Vectibix - Amgen Inc.) is supplied as a sterile, single-use vial and is administered at 6 mg / kg body weight via IV infusion Q2W via an infusion pump. Prior to infusion, panitumumab should be diluted in 9 mg / mL (0.9%) sodium chloride solution for injection to a final concentration not exceeding 10 mg / mL. Panitumumab should be administered via a peripheral line or indwelling catheter using a low-protein-binding 0.2 μm or 0.22 μm in-line filter. The recommended infusion time is approximately 60 minutes. Once the initial infusion is tolerated, subsequent infusions can be administered over 30–60 minutes. Doses greater than 1000 mg should be infused over approximately 90 minutes. The infusion rate may need to be reduced if an infusion-related reaction occurs.

[0281] Panitumumab infusion should be initiated within 60 minutes (+30 minutes) after oral administration of Compound A capsules. Please refer to the panitumumab Summary of Product Characteristics (SmPC) and United States (US) Prescribing Information (PI) for full preparation and administration instructions.

[0282] Safety evaluation Physical examination A complete and brief, symptom-directed physical examination will be performed by a qualified physician at the time specified in the SOA (Table 7). The complete physical examination will include: 1) head, eyes, ears, nose, and throat; 2) cardiovascular; 3) skin; 4) musculoskeletal; 5) respiratory; 6) gastrointestinal; and 7) nervous system examination. A limited, symptom-directed examination will be performed at the time specified or as indicated during clinical practice. Abnormalities observed at baseline will be recorded on the Medical History and Baseline Conditions eCRF. At subsequent visits, new or worsening CS abnormalities will be recorded on the AE eCRF.

[0283] Potential skin toxicity will be investigated by characterization and grading of the rash as part of the physical examination. Any abnormalities identified at baseline will be recorded in the Medical History eCRF with the appropriate disease / condition term. New or worsening CS abnormalities should be recorded as AEs in the eCRF.

[0284] Physical examinations should be conducted at various unscheduled time points if deemed necessary by the investigator.

[0285] Vital signs Vital signs will include measurements of body temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) after the participant has been seated for at least 5 minutes. Pulse oximetry will also be performed and documented. Blood pressure and heart rate measurements will be taken with fully automated equipment. Manual techniques will be used only if automated equipment is not available. Body temperature will be measured using a tympanic thermometer.

[0286] ECG monitoring 12-lead ECGs will be performed at screening, during the treatment period within 60 minutes prior to dosing, and 2-4 hours after Compound A administration on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 (see Table 7). ECGs at multiple time points after Cycle 2 Day 1 are not required but may be obtained if clinically indicated. ECGs are required at EoT and during the safety follow-up period. To reduce false readings, participants are encouraged to attempt to perform triplicate ECGs with 1-2 minutes between ECG readings. However, if necessary, i.e., due to a public health emergency, a single ECG is permitted. ECGs will be performed with participants in a supine or semi-recumbent position for at least 5 minutes before taking the reading. Heart rate, PR, QRS, QTcF, RR, and interpretation of results will be recorded. Additional ECG monitoring may be performed at other times if deemed necessary by the investigator. If the ECG study is to occur simultaneously with any other study procedures at the same time point, the ECG should be performed first, followed by vital signs, and then blood sample collection, at the nominal time the blood sample is collected.

[0287] For safety monitoring, the investigator or designer must review, sign, and date all ECG recordings. The investigator or designer will grade the overall ECG results as normal, not clinically significant abnormal (NCS), or abnormal CS. All abnormal CS ECG results must be reported as an AE or SAE. Paper or electronic copies of the ECG recordings will be kept at the site as part of the participant's permanent study file.

[0288] Central Examination This study will use a centralized ECG laboratory, with calibrated ECG machines located on-site, ECG recordings collected from the facility, and data reviewed and documented centrally.

[0289] Assessment of left ventricular ejection fraction Left ventricular ejection should be assessed at screening using an ECHO or MUGA scan, which constitutes the baseline assessment. Follow-up assessments should occur any time during the study when participants exhibit signs or symptoms that may be associated with heart failure (such as shortness of breath, exercise limitation, and peripheral edema). Assessments of left ventricular ejection that are scheduled to occur during safety follow-up should use the same modality as the baseline assessment performed at screening.

[0290] Ophthalmological examination Real-world data indicate that BRAF inhibitors can cause ocular side effects (Mettler et al., Ocular safety profile of BRAF and MEK inhibitors: data from the World Health Organization Pharmacovigilance Database. Ophthalmology. 2021;128:1748-55). Although there is currently no evidence to suggest that treatment with RAF dimer inhibitors, either as a class or specifically for Compound A, i.e., based on data emerging from current Compound A clinical studies, may result in an increased incidence of ocular AEs, it is recommended that a full ocular investigation, including visual acuity, intraocular pressure (as measured numerically), slit-lamp examination, cup-disc ratio, dilated fundus examination, and optical coherence tomography (OCT), be performed as indicated in this study. Other methods (e.g., fluorescein angiography) can be performed if indicated by the investigator, orthoptist, or ophthalmologist. Full ocular examinations should be performed at screening and approximately every 8 (± 1) weeks from the first dose of study medication during the first 12 months and approximately every 12 (± 1) weeks during the second year during the study. If participants remain in the study for more than 2 years, examinations may be performed approximately every 16 (± 2) weeks. If participants report new visual disturbances, such as decreased central vision, blurred vision, or one-time visual loss, a prompt ophthalmologic investigation is required, with follow-up as necessary. Participants who wear contact lenses should be evaluated for any signs or symptoms of keratitis. Any findings and symptoms of CS, including those confirmed by an ophthalmologist, should be reported as an AE.

[0291] ECOG PS monitoring is required throughout the study at the time points listed in the SOA (see Table 7). Clinical laboratory safety monitoring can be performed on-site using the results entered on the eCRF and local laboratory normal values. Blood sample collection for laboratory monitoring (serum chemistry, hematology, coagulation, and thyroid function), as well as urinalysis, will be performed at the time points indicated on the SOA (see Table 7). If safety laboratory screening tests are performed more than 96 hours after the first dose of study drug on Cycle 1 Day 1, these results must be repeated and confirmed within 48 hours prior to the first study drug administration.

[0292] Blood samples for CPK monitoring will be collected at screening; days 1, 8, and 15 of cycle 1; days 1 and thereafter of each subsequent treatment cycle of cycle 2; and at the EoT visit and safety follow-up visit.

[0293] All participants will need to have their electrolytes monitored (for hypomagnesemia and hypocalcemia) during treatment with panitumumab and for 8 weeks after completing panitumumab therapy.

[0294] Blood samples for coagulation parameters will be collected at screening; on Day 1 of Cycle 1; and thereafter on Day 1 of each cycle only if the participant is taking an anticoagulant and clinically indicated.

[0295] Thyroid function will be investigated from blood samples collected at screening and on day 1 of every 3 cycles after baseline (cycles 4, 7, 10, etc.), starting with cycle 4. On-site laboratory thyroid function testing will be performed based on analysis of thyroid-stimulating hormone (TSH), free T3, and free T4.

[0296] Additional blood draws for safety laboratory testing may be performed at other time points as deemed necessary by the investigator, in conjunction with the sponsor, i.e., for repeat laboratory or safety evaluations, including follow-up of AEs.

[0297] In safety laboratory studies, participants are not required to fast prior to collection of blood samples. Instructions for handling and processing of test specimens are provided in the research laboratory manual.

[0298] serology Hepatitis B surface antigen (HBsAg), antibodies to HBsAg, hepatitis core antibody (HBcAb), and HCV serology will be tested at screening. In addition, participants who are HBsAg-positive or HCV antibody-positive at screening will undergo viral load testing (HBV DNA or HCV RNA), respectively.

[0299] In patients with known HIV, a CD4+ T cell count should be performed at screening.

[0300] Human chorionic gonadotropin (HCG) pregnancy test A serum pregnancy test must be performed within 7 days prior to the first dose of study medication and documented as negative. A negative pregnancy test (serum or urine test) must be documented within 2 days prior to initiating treatment on Day 1 of each subsequent cycle. A serum pregnancy test will be performed at the EoT visit (and in the event of early discontinuation of study participation) and at the safety follow-up visit scheduled 30 + 7 days after the last dose of study medication. A positive urine pregnancy test must be confirmed by a serum pregnancy test. Menopausal status, if applicable, will be confirmed and documented by checking FSH levels at screening amenorrheal female participants.

[0301] Tumor response assessment Tumor response (antitumor efficacy) will be investigated by either computed tomography (CT) or magnetic resonance imaging (MRI), preferably CT (of the chest with or without contrast, and of the abdomen and pelvis with oral contrast, unless contraindicated). Positron emission tomography / CT (PET / CT) is permitted as an additional investigation if directed by the investigator. The same imaging modality and radiological procedures used to assess disease sites at screening must be used throughout the study (e.g., same contrast protocol for CT scans).

[0302] Tumor imaging will be performed within 28 days prior to the first dose of study medication and during the study, approximately every 8 (± 1) weeks from the first dose of study medication for the first 12 months, and approximately every 12 (± 1) weeks during the second year. If participants remain in the study for more than two years, scans may be performed approximately every 16 (± 2) weeks. In addition, participants will be required to undergo a CT / MRI scan of the brain at screening to confirm the presence or absence of CNS metastases. Participants with CNS metastases at baseline will be required to undergo a follow-up CT / MRI of the brain according to the scan schedule.

[0303] Tumor response and progression of cancer during the study will be monitored using RECIST v1.1. RECIST criteria will take precedence for participant treatment and discontinuation decisions. Patients found to have clinical or radiological PD per RECIST v1.1 will discontinue study treatment.

[0304] Participants who discontinue study treatment early for reasons other than RECIST-defined disease progression (e.g., toxicity) will continue to receive tumor assessments according to the Tumor Response Surveillance Schedule (see Table 7) until the participant begins subsequent anticancer therapy, experiences disease progression, withdraws consent, dies, or the study ends, whichever occurs first.

[0305] Central Examination Study imaging, including CT and / or MRI, must be performed at a qualified imaging facility according to the schedule in the SOA (see Table 7). For all participants in the dose expansion portion, sites will submit all CT and / or MRI scans to a central imaging core laboratory for central imaging review. The purpose of the central imaging review is to provide an independent, unbiased, and objective review of the CT and MRI data. Sites will be provided with an Imaging Acquisition Manual and an Imaging Submission Manual, which describe the imaging methodology and submission process that must be followed. All imaging data submitted to the central imaging core laboratory must be de-identified before submission. Participant identifiers in the imaging data must be consistent with all study-related documentation throughout the study. Study investigators can easily obtain details about de-identification requirements from the available imaging manual.

[0306] Pharmacokinetic assessment Blood samples for plasma PK analysis of Compound A and any associated metabolites (if applicable) will be obtained and processed according to the instructions provided in the study laboratory manual at the time points listed in the PK sampling table (see Table 7). The PK of panitumumab may be investigated in this study.

[0307] PK samples will be collected on Day 1 of Cycle 1 and Day 1 of Cycle 2 for quantification of Compound A and any associated metabolites, if applicable. On Day 1 of Cycle 1 and Cycle 2, samples for PK analysis will be collected prior to and 2-4 hours after administration of Compound A. Starting with Cycle 3, blood samples for analysis will be collected on Day 1 of each treatment cycle prior to administration of Compound A to measure steady-state Cthrough.

[0308] The timing of PK sample collection can be varied and / or PK samples can be obtained at additional time points to ensure adequate PK monitoring. The collection time for each sample must be recorded on the source of the collection tube and on the eCRF, which must be provided to the bioanalytical laboratory.

[0309] Plasma concentrations of Compound A and any associated metabolites (if applicable) will be measured in an accredited laboratory using appropriately qualified and validated chromatographic methods.

[0310] Shipping, storage, and handling of samples for PK assays will be managed through the bioanalytical laboratory. Instructions and supply kits will be provided for PK evaluation.

[0311] Pharmacokinetic assessment Mutation status for study eligibility Tumor tissue collection at the screening visit, either from archived tumor tissue or fresh tumor biopsy, is mandatory to establish baseline retrospective mutation status. Participants will be selected for screening and eligibility based on known mutation status from local molecular testing obtained through tumor tissue samples collected any time before screening. Participants with CRC who have a known mutation status and tumors harboring oncogenic mutations in BRAF, KRAS, or NRAS will be enrolled in Part 1 of the study. Participants with CRC harboring KRAS or NRAS mutations and participants with PDAC harboring KRAS mutations will be enrolled in Part 2 of the study.

[0312] In patients with readily accessible tumor lesions, it is highly recommended that a fresh baseline tumor biopsy be collected for analysis at the time of screening. All study participants will have their mutation status measured on-site using fresh or archived tissue at any time before screening.

[0313] Retrospective confirmatory mutation analysis Mutation results from local molecular testing assays should be confirmed by central analytical testing assays. Confirmatory mutation testing should be performed in a central laboratory at any time during the study to support study data analysis. When possible, tumor samples tested locally should be the same as those tested centrally.

[0314] Conclusive central laboratory mutation results (positive or negative) cannot be repeated. If central testing determines the sample is insufficient or the result is indeterminate, additional samples may be resubmitted to the central laboratory for retesting. If there is discordance between the local and central laboratory results, or if the local results cannot be confirmed by the central laboratory (e.g., inadequate sample or insufficient sample volume), the participant may continue receiving study treatment if there is no clinical deterioration or disease progression, as determined by the investigator and in consultation with the sponsor's medical monitor, and the participant is benefiting from study treatment. In such cases, the participant will be notified as soon as possible that their mutation status is unconfirmed, along with information explaining follow-up procedures and alternative treatment options.

[0315] Tumor tissue must be of good quality based on total viable tumor content. Fine needle aspirates, brushings, cell pellets from pleural effusions, and lavage samples are not acceptable.

[0316] Fresh biopsies should be limited to easily accessible tumor lesions (i.e., skin, peripheral lymph nodes, lung, liver, or internal lymph node metastases that can be easily explored using CT guidance). For acceptable biopsies, specimens include core needle biopsies for deep tumor tissue or excision, incision, punch, or forceps biopsies for skin, subcutaneous, or mucosal lesions. When performed, three to five tissue cylinders of appropriate size for histological examination and biomarker analysis should be obtained. A minimum of three cores per biopsy is required.

[0317] When available, freshly collected tumor biopsies and archived tumor tissue (tissue should be either formalin-fixed, paraffin-embedded blocks or approximately 15 unstained slides) will be sent to the central laboratory for mutation analysis. The panel of genes evaluated for baseline mutation testing for retrospective confirmatory analysis by the central laboratory is described in the laboratory manual.

[0318] Blood sampling for biomarker analysis Peripheral whole blood samples will be collected at the time points indicated in Table 7 for analysis of PDx biomarkers, including, but not limited to, mutation, amplification, transcription, and / or phosphorylation changes in MAPK pathway signaling. A central laboratory will manage the transportation, storage, and handling of tumor tissue and blood samples for biomarker evaluation. Sample handling and testing methods are readily available from general knowledge in the art.

[0319] Blood samples will also be collected to analyze the following tumor prognostic biomarkers in participants' serum samples: carcinoembryonic antigen (CEA) in all dose-finding cohorts in Part 1 and in dose-expansion arm 1 of Part 2 (participants with CRC harboring a KRAS or NRAS mutation); and carbohydrate antigen 19-9 (CA19-9) in dose-expansion arm 2 of Part 1 only (participants with PDAC harboring a KRAS mutation).

[0320] All blood samples for analysis of tumor prognostic biomarkers will be collected prior to administration of study drug during the treatment period and at other time points as indicated in Table 7. These blood samples will be analyzed on-site.

[0321] Statistical methods and sample size determination Statistical methods are outlined in the Statistical Analysis Plan (SAP) and will be completed before final database lock. Study results will be presented by study part and dose level cohort / group (if applicable). Study results may be described by participant, as appropriate. Generally, descriptive statistics (mean, standard deviation, median, minimum, and maximum) will be calculated for group metrics, and frequency counts and percentages (if appropriate) will be calculated for individual / categorical data. If participant safety, efficacy, PK, or PDx data are missing or uninterpretable, or if a participant withdraws from the study during the DLT period for reasons other than toxicity, the investigator, in consultation with the sponsor, may enroll additional participants to replace missing information and maintain the planned sample size for analysis. Baseline is defined as the last non-missing, evaluable measurement obtained before administration of study drug on Day 1 of Cycle 1. No statistical hypotheses will be formally evaluated in this study.

[0322] group Rational Dosing of Sample Size (Part 1): The sample size for Part 1 will consist of approximately 24 evaluable participants. The actual sample size will depend on the number of dose-escalation cohorts, as guided by the mTPI-2 model-assisted design.

[0323] Dose expansion (Part 2): The additional initial targets for the dose expansion portion of this study are 20 evaluable participants in each of Group 1 (CRC patients with KRAS or NRAS mutations who have been treated by RECIST criteria and have documented disease progression during or after at least one prior line of therapy) and Group 2 (PDAC patients with KRAS mutations who have been treated by RECIST criteria and have documented disease progression during or after at least one prior line of therapy).

[0324] Dose expansion arms 1 and 2 will be evaluated separately. If promising preliminary efficacy results are observed in either arm (e.g., based on high ORR or long PFS) after treating all planned participants, more participants may be enrolled in the relevant arm and efficacy may be further investigated before proceeding to Phase 2 / 3 clinical development.

[0325] Analysis population The analysis population defined for this study is shown in Table 6. Participant inclusion in each analysis population will be determined after database lock and before unblinding for final analysis. [Table 6]

[0326] statistical analysis Safety analysis Safety in Parts 1 and 2 will be measured by reporting AEs and safety laboratory values ​​(hematology, clinical chemistry, thyroid function tests, coagulation, and urinalysis). Vital signs, ECG, and ECHO / MUGA scan (if applicable) findings, physical and ophthalmologic examinations, and ECOG PS will also be used to measure the safety profile of the Compound A + panitumumab combination. Safety endpoints will be summarized using the safety population.

[0327] Incidence of AEs will be presented as the number (percentage (%)) of participants with TATEs by system organ class (SOC) and preferred term (PT) using the Current Medical Dictionary of Radiological Events (MedDRA) available at study entry. Additionally, the proportion of participants with dose interruptions or reductions of Compound A or panitumumab due to TATEs will be summarized. Descriptive summary statistics (i.e., n, mean, standard deviation, median, minimum, maximum for continuous variables; n [%] for categorical variables) and changes from baseline will be measured for laboratory parameters, ECG, ECHO / MUGA scan (if applicable), and vital signs. Shifts from baseline in ECOG PS will be summarized descriptively using frequency counts and percentages (%) at protocol-scheduled time points. New or worsening CS abnormalities identified on physical examination will be captured as AEs and will not be summarized or listed separately. For the ophthalmological examination, a general survey (normal, non-clinically significant abnormal (NCS), abnormal (CS)) is compiled by the ophthalmologist. If the ophthalmologist's survey reveals an abnormal result in only one eye, the result is compiled as abnormal in the general ophthalmological examination. The results of the ophthalmological examination are documented for each study method, by participant, and by eye.

[0328] Additionally, for Part 1, the MTD will be determined according to the mTPI-2 design and will be based on the occurrence of DLTs during the first 28 days of Cycle 1. This analysis will be performed in the DLT-evaluable population. At the end of Part 1, the MTD will be selected as the dose with the smallest difference between the isotonicity-transformed posterior mean of toxicity probability and the target toxicity rate between doses, with a posterior toxicity probability greater than 0.30.

[0329] During the dose-finding portion, participants will be closely monitored for AEs / SAEs. Recommendations according to the mTPI-2 design will be followed, with the lowest dose under investigation. If the maximum UPM is in the interval above (0.25, 0.33), the study will be terminated due to excessive toxicity. Furthermore, if the posterior probability of toxicity above 0.30 is greater than 95%, safety rule 1 will be used to terminate the study, and for the lowest dose, the study will be terminated due to excessive toxicity. Otherwise, the study will continue using the mTPI-2 recommendations and safety rules.

[0330] Efficacy analysis Efficacy analyses will be performed in the mITT population in Parts 1 and 2. Efficacy endpoints based on response surveys using RECIST 1.1 (i.e., ORR, DOR, DCR, and PFS) will be compiled to assess the antitumor activity of the combination of Compound A and panitumumab.

[0331] ORR is defined as the population of participants with confirmed CR or PR. DOR is defined as the time from first measurement of response in patients with confirmed response to first documentation of progression or death from any cause, whichever occurs first. DCR is defined as the population of patients with a best overall response (BOR) of 24 weeks or greater, with a confirmed CR, RP, or SD. PFS is defined as the time from the first dose of study drug to the date of first documentation of disease progression or death from any cause, whichever occurs first.

[0332] ORR and DCR will be summarized with two-sided exact (Clopper-Pearson) 95% CI. Time-to-event endpoints, including PFS and DOR, will be analyzed by the Kaplan-Meier method. Statistical methods for efficacy analyses are detailed in the SAP.

[0333] The efficacy-evaluable population includes all treated patients with radiologically evaluable disease confirmed at baseline and at least one post-baseline radiologically evaluable tumor response study.

[0334] Pharmacokinetic analysis PK blood samples are collected for quantification of Compound A and any associated metabolites (if appropriate) in plasma. Plasma concentration data for Compound A (and any associated metabolites) cannot be compiled but can be provided as a list. Additional PK analyses, including population PK (PopPK) analyses, can be performed as appropriate. These analyses can be reported separately from the CSR.

[0335] If supported by the data, exposure-response (efficacy or safety endpoint) analyses may be performed. Correlations between PK and biomarker endpoints may be explored, as appropriate. Results of such analyses may be reported separately from the CSR.

[0336] Pharmacokinetic and other exploratory analyses A summary of statistics for predictive and PDx biomarkers is provided, including but not limited to, assessment of the MAPK pathway for mutation, amplification, transcription, and / or phosphorylation status in baseline tumor tissue and peripheral blood samples. Depending on the available data, biomarker analysis may be descriptive in nature.

[0337] The results of the exploratory analysis may be reported separately from the CSR.

[0338] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0339] Abbreviations: AE = adverse event; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; CPK = creatine phosphokinase; CRC = colorectal cancer; CT = computed tomography; D / d = days; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; Eot = end of treatment; FSH = follicle-stimulating hormone; IV = intravenous; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition; PDx = pharmacokinetics; PDAC = pancreatic ductal adenocarcinoma; PK = pharmacokinetics; PO = per oral; Q2W = once every 2 weeks; QD = once daily; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; TC = telephone contact; WOCBP = women of childbearing potential.

[0340] Screening: For administrative reasons, individuals who do not meet the study entry criteria (screen failure) or have borderline test results may be rescreened once. Rescreened participants will be required to repeat all abnormal screening tests and procedures.

[0341] Informed consent must be documented before any study-specific procedures, including those for screening, are performed.

[0342] Demographics: Year of birth, age (in completed years), sex, and self-reported race / ethnicity will be recorded as part of the screening procedure. Female participants will be assessed as WOCBP or not of childbearing potential.

[0343] Medical history; including any history of clinically significant (CS) illness, surgery, and cancer.

[0344] Eligibility criteria, medical history, and previous / ongoing medication use: Review on Cycle 1 Day 1, prior to first dose of study medication, and document any changes since screening.

[0345] Pregnancy or FSH Test: A serum pregnancy test (for women of childbearing potential (WOCBP)) must be performed within 7 days prior to the first dose of study medication and documented as negative. A negative pregnancy test (serum or urine test) must be documented within 2 days prior to starting treatment on Day 1 of each subsequent cycle. A serum pregnancy test will be performed at the end of treatment (EoT) visit (and if study participation is discontinued early) and at the safety follow-up visit (30 + 7 days after the last dose of study medication). A positive urine pregnancy test must be confirmed by a serum pregnancy test. Postmenopausal status will be confirmed by testing follicle-stimulating hormone (FSH) levels (>30 IU / L) at screening for amenorrheic female participants.

[0346] Physical Examination: A complete and limited, symptom-directed physical examination will be performed by a qualified physician. A complete physical examination will include an examination of the 1) head, eyes, ears, nose, and throat, 2) cardiovascular, 3) skin, 4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) nervous system. Potential skin toxicity will be investigated by the nature and grading of any rash as part of the physical examination. A limited, symptom-directed examination will be performed at specified time points or as indicated during clinical visits. Physical examinations should be performed at various unscheduled time points if deemed necessary by the investigator.

[0347] Ophthalmologic Examination: A complete ocular examination, including visual acuity, intraocular pressure (expressed numerically), slit-lamp examination, cup-disc ratio, dilated fundus examination, and optical coherence tomography (OCT), should be performed at screening and throughout the study, approximately every 8 (± 1) weeks from the first dose of study medication for the first 12 months, and approximately every 12 (± 1) weeks in the second year. If participants remain in the study for more than two years, examinations may be performed approximately every 16 (± 2) weeks. Other methods (e.g., fluorescein angiography) may be performed if indicated by the investigator, orthoptist, or ophthalmologist. If a participant reports new visual disturbances at any time, such as decreased central vision, blurred vision, or vision loss, a prompt ophthalmologic examination is required, with follow-up, if necessary. For participants who wear contact lenses, careful identification of keratitis should be included in the evaluation. Any findings and symptoms of CS, including those confirmed by an ophthalmologist, should be reported as an AE.

[0348] Height and Weight: Height will be measured only at screening. Weight must be monitored throughout the study and recorded at each time point, using the same scale (if possible).

[0349] Vital signs will include measurements of temperature (tympanic), heart rate, respiratory rate, and blood pressure (systolic and diastolic) after the participant has been seated for at least 5 minutes. Pulse oximetry will also need to be performed and documented. At specific visits, vital signs will need to be obtained within 15 minutes before and within 15 minutes after each administration of study medication.

[0350] ECG: A 12-lead ECG will be performed at screening, during the treatment period within 60 minutes prior to dosing, and 2-4 hours after Compound A administration on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1. An ECG is required at EoT and during the safety follow-up period. ECGs are not required after Cycle 2 Day 1 but may be obtained if clinically indicated. To reduce false readings, participants are encouraged to attempt to perform triplicate ECGs with 1-2 minutes between ECG readings. However, if necessary, i.e., due to a public health emergency, a single ECG is permitted. ECGs will be performed with participants in a supine or semi-recumbent position for at least 5 minutes before taking the reading. All ECG tracings will be reviewed by the investigator or a qualified designer. Heart rate, PR, QRS, QTcF, RR, and interpretation of the results will be recorded. Additional ECG monitoring may be performed at other times if deemed necessary by the investigator.

[0351] ECHO / MUGA: Either ECHO or MUGA should be used consistently and the same method should be used throughout the study.

[0352] Viral Serology: HBV and HCV testing includes HBV and HCV serology (hepatitis B surface antigen (HBsAg), hepatitis B surface antigen (HBsAb), hepatitis B core antibody (HBcAb), and HCV antibody). In addition, viral load studies (HBV deoxyribonucleic acid (DNA) or HCV ribonucleic acid (RNA)) should be performed at screening for participants who are HBsAg-positive or HCV-antibody-positive, respectively. In patients with known HIV, a CD4+ T-cell count should be performed at screening.

[0353] Hematology, Chemistry, and Coagulation: Local laboratory investigations for hematology, serum chemistry, and coagulation parameters will be performed. If screening tests are performed more than 96 hours prior to the first dose of study drug on Cycle 1 Day 1, results must be repeated and confirmed within 48 hours prior to the first study drug administration. Local laboratory investigations can be performed up to 2 days (-2) prior to Day 1.

[0354] In addition: Blood samples for creatine phosphokinase (CPK) monitoring will be collected at screening; on days 1, 8, and 15 of cycle 1; from day 1 onwards of each subsequent treatment cycle in cycle 2; and at the EoT visit and safety follow-up visit (if applicable). All participants will need to have their electrolytes monitored (for hypomagnesemia and hypocalcemia) during treatment with panitumumab and for 8 weeks after completing panitumumab therapy. · In safety laboratory studies, participants are not required to fast before blood samples are collected.

[0355] Thyroid Function Tests: Local laboratory thyroid function tests for thyroid-stimulating hormone (TSH), free T3, and free T4.

[0356] Urinalysis: Perform local laboratory investigations of urinalysis parameters.

[0357] Eastern Cooperative Oncology Clinical Trials Group Tumor imaging—either computed tomography (CT) or magnetic resonance imaging (MRI) (preferably CT of the chest with or without contrast, and of the abdomen and pelvis with oral contrast)—will be performed within 28 days prior to the first dose of study medication and approximately every 8 (± 1) weeks during the first 12 months of the study and approximately every 12 (± 1) weeks during the second year. Positron emission tomography / CT (PET / CT) will be permitted as an additional investigation if directed by the investigator. Scans completed within the time window but before ICG signature can be used for baseline scans. If participants remain in the study for more than 2 years, scans may be performed approximately every 16 (± 2) weeks. The same imaging technology should be used for participants throughout the study. In addition, participants should undergo a brain CT / MRI scan at screening to confirm the presence or absence of CNS metastases. Participants with CNS metastases at baseline should undergo a follow-up brain CT / MRI according to the scan schedule.

[0358] Tumor tissue biopsy: Collection of tumor tissue at the screening visit, either from archived tumor tissue or a fresh tumor biopsy, is mandatory to establish baseline retrospective mutation status. In patients with easily accessible tumor lesions, collection of a fresh baseline tumor biopsy for analysis at the time of screening is highly recommended. Participants will be selected for screening and eligibility based on known mutation status from local molecular testing results obtained from tumor tissue samples collected any time before screening. Mutation results from local molecular testing will be confirmed by testing performed at a central laboratory. Central testing is retrospective and can occur any time during the study. Tumor samples should be submitted as either formalin-fixed, paraffin-embedded blocks or approximately 15 unstained slides. When possible, the tumor samples tested centrally should be the same as the samples tested locally.

[0359] Blood samples for carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) monitoring: Blood samples will be collected for CEA analysis in the dose-finding cohort and in dose expansion cohort 1 (participants with colorectal cancer (CRC) harboring KRAS or NRAS mutations). Blood samples will be collected for CA19-9 analysis in dose expansion cohort 2 only (participants with pancreatic ductal adenocarcinoma (PDAC) harboring KRAS mutations). All blood samples for tumor biomarker analysis will be collected prior to administration of study drug and at other indicated time points during the treatment period and will be analyzed on-site.

[0360] Study Medication Administration: Compound A will be administered orally (PO) once daily (QD). Panitumumab will be administered by intravenous (IV) infusion once every two weeks (Q2W; on days 1 and 15 of each treatment cycle) within 60 minutes (+30 minutes) after oral administration of Compound A. All participants will undergo repeated 28-day Compound A + panitumumab treatment cycles. Participants will receive study medication (Compound A, followed by panitumumab) on-site during study visits on days 1 and 15 of each treatment cycle. Participants will be instructed to self-administer their daily dose of Compound A on all other study days during the treatment period (i.e., days 2-14 and days 16-28 per treatment cycle).

[0361] PK: Blood samples for analysis of Compound A and any associated metabolites (if applicable) in plasma will be collected on Day 1 of Cycle 1 and Day 1 of Cycle 2 (pre-dose and 2-4 hours after Compound A administration), and on Day 1 of each subsequent cycle only (pre-dose of Compound A on these days).

[0362] Identification of AEs and Concomitant Medications: All elicitation of AEs, as well as use of concomitant medications, will occur from the time of informed consent through any interaction with the participant. Participants will also be instructed to inform the investigator or clinical staff of any AEs or intercurrent illnesses they experience during the study. For purposes of tolerability determination in Part 1, a DLT is defined in this study as any AE or abnormal laboratory value that occurs within the first 28-day cycle of treatment with study drug, meets at least one of the criteria, and is investigated as unrelated to the underlying disease, disease progression, intercurrent illness, or concomitant medication / treatment.

[0363] DLT Duration: The incidence of DLTs will be assessed during the first 28 days of Cycle 1 treatment with the Compound A + panitumumab combination in Part 1 (dose-finding portion).

[0364] Cycle 1 Day 22 Telephone Contact: Monitoring of AEs and concomitant medication use will be performed by a follow-up telephone contact (TC) between site staff and the study participant on Day 22 of the first treatment cycle. If necessary, at the investigator's discretion, an on-site visit will be scheduled after the TC.

[0365] End of Treatment: All patients will receive study drug until clinical or radiological disease progression; death, intolerance, or withdrawal of study consent; completion of 2 years of treatment (unless the investigator's benefit-risk assessment supports continuation of treatment); investigator decision; or the study is terminated by the sponsor for any reason. All participants who discontinue study participation will complete all specified surveys ahead of time, whenever possible, at the EoT visit. EoT debriefing is optimally conducted within 7 days of the investigator's decision to no longer use study drug. Participants who prematurely discontinue study treatment for reasons other than disease progression (e.g., toxicity) will continue to receive tumor evaluations according to the procedural tumor response surveillance schedule until the participant begins subsequent anticancer therapy, experiences disease progression, withdraws consent, dies, or the study is terminated, whichever occurs first.

[0366] Note: Investigators or participants may request additional, unscheduled on-site visits at any time throughout the study. Unscheduled visit investigations will be conducted as clinically indicated. If vital signs, 12-lead ECG, and PK / PDx biomarker blood draws are scheduled for the same nominal time, investigations should be performed in the following order: 12-lead ECG, vital signs, PK / PDx biomarker blood draws. This allows for study timing to ensure blood draws are performed at the strict nominal times. Participants who prematurely discontinue study drug treatment for reasons other than disease progression (e.g., toxicity) will continue to receive tumor assessments according to the procedural tumor response surveillance schedule until the participant begins subsequent anticancer treatment, experiences disease progression, withdraws consent, dies, or the study ends, whichever occurs first.

[0367] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. (i) 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or formula (I): 【Chemistry 5】 Compound A having the structure or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; (ii) an anti-EGFR antibody or antigen-binding fragment thereof; Combinations including:

2. The combination of claim 1 , wherein the combination comprises an anti-EGFR antibody.

3. The anti-EGFR antibody (a) panitumumab; or (b) a) a CDR1 comprising amino acids 8 to 15 of SEQ ID NO:3; b) a CDR2 comprising amino acids 29-45 of SEQ ID NO:3; and c) a CDR3 comprising amino acids 77-85 of SEQ ID NO:3 a heavy chain immunoglobulin molecule comprising: d) CDR1 comprising amino acids 5-15 of SEQ ID NO:4; e) CDR2 comprising amino acids 31-37 of SEQ ID NO:4; and f) a CDR3 comprising amino acids 70-78 of SEQ ID NO:4 a heavy chain immunoglobulin molecule comprising The combination of claim 2, wherein the antibody is an isolated human antibody comprising:

4. 3. The combination of claim 2, wherein compound A is in the form of Form F.

5. A combination kit comprising the combination according to any one of claims 1 to 4 together with one or more pharmaceutically acceptable carriers.

6. The combination kit of claim 5 , wherein the anti-EGFR antibody or antigen-binding fragment thereof is provided in a form suitable for IV administration.

7. The combination kit of claim 5 , wherein the anti-EGFR antibody or antigen-binding fragment thereof is provided in a form suitable for subcutaneous administration.

8. 8. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a combination or combination kit according to any one of claims 1 to 7.

9. 1. A method for treating cancer in a subject in need thereof, comprising administering to the subject: (i) 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or formula (I): 【Chemistry 6】 Compound A having the structure or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; (ii) an anti-EGFR antibody; and The method comprises simultaneously administering

10. 1. A method for treating cancer in a subject in need thereof, comprising administering to the subject: 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or formula (I): 【Chemistry 7】 Compound A having the structure or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof; The method, wherein the subject has received an anti-EGFR antibody.

11. 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject an anti-EGFR antibody; The subject matter may be identified by the name 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea, or by the formula (I): 【Chemistry 8】 Compound A having the structure or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

12. 8. A combination or combination kit according to any one of claims 1 to 7 for use in the treatment of cancer in a subject in need thereof.

13. 1. The name 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or a compound of formula (I): 【Chemistry 9】 Compound A having the structure Or the use of a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, wherein said agent is suitable for administration with panitumumab.

14. 1. Use of panitumumab in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is a compound known by the name 1-((1S,1aS,6bS)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthopyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-yl)-3-(2,4,5-trifluorophenyl)urea or by the formula (I): 【Chemistry 10】 Compound A having the structure or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.

15. 10. Use of a combination according to any one of claims 1 to 4 in the manufacture of a medicament for treating cancer in a subject in need thereof.

16. The method, combination, combination kit or use of any one of claims 8 to 15, wherein the cancer is colorectal cancer, pancreatic cancer or non-small cell lung cancer.

17. 17. The method, combination, combination kit or use of claim 16, wherein the cancer is colorectal cancer, metastatic colorectal cancer, BRAF mutant metastatic colorectal cancer, BRAF V600E mutant metastatic colorectal cancer, KRAS mutant colorectal cancer, KRAS G12C mutant colorectal cancer, KRAS G12D mutant colorectal cancer, KRAS G12V mutant colorectal cancer, NRAS mutant colorectal cancer, or TRP53 mutant colorectal cancer.

18. 16. The method, combination, combination kit or use of any one of claims 8 to 15, wherein the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), BRAF mutant pancreatic cancer, BRAF V600E mutant pancreatic cancer, KRAS mutant pancreatic cancer, KRAS G12C mutant pancreatic cancer, KRAS G12D mutant pancreatic cancer, KRAS G12V mutant pancreatic cancer, Trp53 mutant pancreatic cancer or NRAS mutant pancreatic cancer.

19. 16. The method, combination, combination kit or use of any one of claims 8 to 15, wherein the cancer is non-small cell lung cancer, BRAF mutant non-small cell lung cancer, BRAF V600E mutant non-small cell lung cancer, KRAS mutant non-small cell lung cancer, KRAS G12C mutant non-small cell lung cancer, KRAS G12D mutant non-small cell lung cancer, KRAS G12V mutant non-small cell lung cancer, Trp53 mutant non-small cell lung cancer or NRAS mutant non-small cell lung cancer.

20. 16. The method, combination, combination kit or use of any one of claims 8 to 15, wherein the cancer is colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, osteosarcoma, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma or thyroid cancer.

21. 16. The method, combination, combination kit or use of any one of claims 8 to 15, wherein the cancer is characterized by a mutation in a gene selected from RAS, NRAS, KRAS, RAF, BRAF, CRAF, ARAF, and any combination thereof.

22. 20. The method, combination, combination kit or use of claim 18, wherein the cancer is characterized by a mutation in a gene selected from RAS, NRAS, KRAS, RAF, BRAF, and any combination thereof.

23. 23. The method, combination, combination kit or use of claim 22, wherein the cancer is characterized by a mutation in a gene selected from NRAS, KRAS, BRAF, and any combination thereof.

24. The cancer is (i) a mutation in a gene selected from ARAF, BRAF, RAF1, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1, and any combination thereof; (iii)BRA_N20T、BRA_A33T、BRA_ S36A、BRD_____R99____ M53I、BRAFL64I、BRAFG69H、BR1IAD__380AeL、B1__M438ﺅeEBDDRERDDDLLLLLLLLL 162S、BR1FV569_G327ees、B19__381ees、111_ R188T、111Q201H、111__39111111111111111111111 E228V、BRAFR239Q、BA1DT241P、BA1DT241M、B11L245K、111111111111111111111 1259L、BRAKQ262R、BA1D H269Y、BA1D 219H、B1152155、111 D287H、111111111111911111111111 P341s 、 braf r347* 、 braf 、 、 s363f s363f 、 、 braf 、 braf p367s 、 braf p367r 、 、 braf 、 braf d380h 、 braf r389c 、 braf braf T401I、BRAIA404Cf*9、BRAF P407L、BA1L S419E、B11 G421E、111D1**211 E451K、BRAFE451Q、BRAD P453T、BD1D 4459L、BD1IHIE、B15IHIHIH G464R、BRLEG464E、BRLE G464A、BR5D G464U、B15 S465D、B15 S465M、B55 S465A、B55 G466R、1553665V、BR15H467A、B11D S467L、B11 F468C、111111931111 G669V、BRAFT470K、BRA5T471I、BA15 V471K、A15 Y4725、A15 Y472S、A15 Y472C、A1F520D L485_A990em、BRAFL485Y、B85_L485__D990eesI、B85_L485S、BD5L8DD N486_QD94de、BR5_N486da、Bｲu_ N486_T488dd、des__T491dd、did__L99ddss N\86_PC90de-、BR5FN486_AO89demsKBR5__486_TT991dessthti T488_Q493delinsK、BR1_A489_>990em、BR1_ P490es、B11 P490_Q494eE、B11E199E 4504_R50650、BR555555、B1555555555、555555555555555555555555555555555555555 T529M、BRAFT529N、BA1TT529I、BA1 W531C、B11 G534D、111 Y538H、111 R558Q、11111111111 H574Y、BRATH571Q、BR15 N581D、B115 N581Y、B115 N581T、B15 N581I、B115 N581IID82M、BRAFDD83C、BDDGL84D、BDD H585Y、BDDEDDVK、DDDDDDDED - DD94E、BRAFDD95L、BDDDD9Y5、BDD G596H、BDD G596>、BDD G596C、BDD G596D、BDDDD9DDDDDD L597Q、BRAFL597P、BA1DL998、BDDDD98T、BDD_D98T、BDD_D9EEDD T599A、BRAFT599K、BRAFT599R、BRDIT999I、B99_____DDTDTD T599_V6000EET、BRAF V00__56010000EN、0000000000000000000000000 4600delinsYM、BRAM V600M、BRA5 600L、BR10 V600、310__I500EE200E20012000 K601Q、BRAF560E、B01E560__T601ees、B01_501T、101_5019、111 S602f 、 braf r603* 、 braf w604dateriall 、 braf w604r 、 braf 、 、 s605a 、 braf 、 、 braf brafS605E, BRAF S605G, BRAF S605N, BRAF S605I, BRAF G606W, BRAF G606E, BRAF G606A, BRAF G606V, BRAF S607P, BRAF S607F, BRAF H608R, BRAF Q609E, BRAF Q609L, BRAF Q609H, BRAF E611D, BRAF L613F, BRAF G615R, BRAF L618F, BRAF W619R, BRAF S637*, BRAF V639I, BRAF E648Q, BRAF Y656D, BRAF R671Q, BRAF P676S, BRAF L678I, BRAF V681I, BRAF E695K, BRAF K698R, BRAF L711F, BRAF A712T, BRAF R719S, BRAF H725Y, BRAF A728V, BRAF P731T, BRAF P731S, BRAF P731L, BRAF A762E, BRAF A762V, and any combination thereof; (iii) KIAA1549-BRAF fusion, BCAS1-BRAF fusion, CCDC6-BRAF fusion, CDC42BPB-BRAF fusion, FAM131B-BRAF fusion, FXR1-BRAF fusion , GIT2-BRAF fusion, KLHL7-BRAF fusion, RNF130-BRAF fusion, TMEM106B-BRAF fusion, MKRN1-BRAF fusion, AGAP3-BRAF fusion, AGK-BRA a mutation selected from an F fusion, an AKAP9-BRAF fusion, an ARMC10-BRAF fusion, a CUL1-BRAF fusion, a GTF2I-BRAF fusion, a PAPSS1-BRAF fusion, a PCBP2-BRAF fusion, a PPFIBP2-BRAF fusion, a SND1-BRAF fusion, a TRIM24-BRAF fusion, a ZKSCAN1-BRAF fusion, a SEPT3-BRAF fusion, and any combination thereof; (iv) NRAS G12A, NRAS G12C, NRAS G12D, NRAS G12N, NRAS G12P, NRAS G12R, NRAS G12S, NRAS G12V, NRAS G12Y, NRAS G13A, NRAS G13C, NRAS G13D, NRAS G13E, NRAS G13N, NRAS G13R, NRAS G13S, NRAS G13V, NRAS A18T, NRAS I24N, NRAS P34L, NRAS Y40*, NRAS Q43*, NRAS T50I, NRAS T58I, NRAS A59G, NRAS A59D, NRAS A59T, NRAS G60E, NRAS G60R, NRAS Q61E, NRAS Q61H, NRAS Q61H, NRAS Q61K, NRAS Q61L, NRAS Q61L, NRAS Q61P, NRAS Q61R, NRAS Q61R, NRAS Q61R, NRAS Q61*, NRAS E63K, NRAS Y64D, NRAS S65C, NRAS R68S, NRAS S89A, NRAS G115Efs*46, NRAS 16. The method, combination, combination kit or use of any one of claims 8 to 15, characterized by a mutation selected from the group consisting of: NRAS E132K, NRAS K135N, NRAS A146P, NRAS A146T, NRAS A146V, NRAS E162*, and any combination thereof.

25. 16. The method, combination, combination kit or use of any one of claims 8 to 15, wherein the cancer is characterized by a mutation selected from NRAS Q61R, NRAS Q61K, NRAS Q61L, NRAS G12S, NRAS G13R, KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusions, and any combination thereof.

26. 26. The method, combination, combination kit, or use of claim 25, wherein the cancer is characterized by a mutation selected from NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and any combination thereof.

27. 27. The method, combination, combination kit, or use of claim 26, wherein the cancer is characterized by a mutation selected from NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and any combination thereof.

28. The method of any one of claims 8 to 11, wherein the cancer is characterized by a MAPK pathway genomic abnormality.

29. 12. The method of any one of claims 8 to 11, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered three times daily.

30. 12. The method of any one of claims 8 to 11, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered once daily.

31. 12. The method of any one of claims 8 to 11, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered in an amount of about 5 mg to about 60 mg per day.

32. 32. The method of claim 31, wherein Compound A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof, is administered at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg per day.

33. The method includes increasing a plasma Compound A AUC in the subject from about 2,128 ng*h / mL to about 45,000 ng*h / mL. ８ｈ The method according to any one of claims 8 to 11, wherein

34. The method of any one of claims 8 to 11, wherein panitumumab is administered in an amount of about 6 mg / kg.

35. 35. The method of claim 34, wherein panitumumab is administered in an amount of about 6 mg / kg administered as an intravenous infusion over 60 minutes.

36. 36. The method of claim 35, wherein panitumumab is administered in an amount of about 6 mg / kg administered as an intravenous infusion over about 60 minutes every two weeks.

37. 37. The method of any one of claims 34 to 36, wherein panitumumab is co-administered with Compound A, or a pharmaceutically acceptable salt or solvate thereof.

38. The method of any one of claims 8 to 11, wherein the subject achieves stable disease, a partial response, or a complete response.

39. 39. The method, combination, combination kit, or use of any one of claims 8 to 38, wherein panitumumab is administered intravenously in an amount of about 6 mg / kg every 14 days as an intravenous infusion over about 60 minutes when the amount of panitumumab administered in 14 days is about 1000 mg or less, or over about 90 minutes when the amount of panitumumab administered in 14 days is more than about 1000 mg, and Compound A is administered orally once daily at about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

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