Combination of B-RAF inhibitor and anti-EGFR antibody for treatment of cancer

Abstract

Provided herein are combinations comprising: (i) a compound having the name of 1-((1S, 1aS, 6bS)-5-((7-oxo-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy)-1a, 6b-dihydro-1H-cyclopropyl [b] benzofuran-1-yl)-3-(2, 4, 5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-4-yl) oxy)-1a, 6b-dihydro-1H-cyclopropyl [b] benzofuran-1-yl)-3-(2, 4, 6, 7, 8-tetrahydro-1, 8-naphthyridin-4-yl)-3-(2, 4, 6, 7 The invention relates to a compound A with a structure shown in a formula (I), or pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopic body, solvate or prodrug thereof, and an anti-EGFR antibody, such as panitumab. Compositions comprising the same; and methods of using these combinations and compositions in the treatment of cancer, such as colorectal cancer, pancreatic cancer, and non-small cell lung cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention provides novel combinations comprising a B-Raf inhibitor (in particular 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 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 (e.g., cancer) in which inhibition of B-Raf, KRAS, NRAS, and / or EGFR is beneficial. Background Art

[0002] Effectively treating hyperproliferative diseases, including cancer, is an ongoing goal in the field of oncology. Generally, cancer is caused by a dysregulation of the normal processes that control cell division, differentiation, and apoptotic cell death, and is characterized by the proliferation of malignant cells, which have the potential for unlimited growth, local expansion, and systemic metastasis. Dysregulation of the normal processes includes abnormalities in signal transduction pathways and responses to factors different from those present in normal cells.

[0003] The protein kinase family is an important and large family of enzymes. Currently, there are approximately 500 different known protein kinases. Protein kinases catalyze the phosphorylation of amino acid side chains in a variety of proteins by transferring the γ-phosphate of an ATP-Mg 2+ complex to the amino acid side chain. These enzymes control most signal transduction processes within cells by reversibly phosphorylating the hydroxyl groups of serine, threonine, and tyrosine residues in proteins, thereby controlling cell function, growth, differentiation, and destruction (apoptosis). Studies have shown that protein kinases are key regulators of many cellular functions, including signal transduction, transcriptional regulation, cell motility, and cell division. It has also been demonstrated that some oncogenes encode protein kinases, indicating that kinases play a role in tumorigenesis. These processes are highly regulated, typically through complex and intertwined pathways, in which each kinase is regulated by one or more kinases. Thus, abnormal or inappropriate protein kinase activity can lead to the emergence of disease states associated with such abnormal kinase activity, including benign and malignant proliferative diseases and diseases caused by inappropriate activation of the immune and nervous systems. Due to the physiological relevance, diversity, and ubiquity of protein kinases, they have become one of the most important and widely studied enzyme families in biochemistry and medical research.

[0004] The protein kinase family of enzymes is generally divided into two main 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- and cyclic GMP-dependent protein kinases, calcium- and phospholipid-dependent protein kinases, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases, etc. These kinases are usually cytoplasmic or may be associated with the particulate fraction of the cell through ankyrin proteins. Aberrant protein serine / threonine kinase activity is associated with or suspected to be associated with many pathologies, such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers, and other proliferative diseases. Therefore, serine / threonine kinases and the signal transduction pathways they are involved in are important targets for drug design. Tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play equally important roles in cell 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. Studies have shown that many tyrosine kinases are transmembrane proteins with their receptor domains on the outside of the cell and their kinase domains on the inside of the cell. Considerable work is still underway to identify modulators of tyrosine kinases.

[0005] Receptor tyrosine kinases (RTKs) catalyze the phosphorylation of certain tyrosine residues in a variety of proteins, including themselves, thereby controlling cell growth, proliferation, and differentiation.

[0006] There are multiple signal transduction pathways downstream of several RTKs; among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that the Ras GTPase protein is activated in response to growth factors, hormones, cytokines, etc., stimulating 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 2. This signal transduction pathway is also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, which mediates the cell's response to growth signals. Its ultimate function is to link receptor activity on the cell membrane to the modification of cytoplasmic or nuclear targets that control cell proliferation, differentiation, and survival.

[0007] Constitutive activation of this pathway is sufficient to induce cell transformation. Dysregulation of MAP kinase pathway activation due to aberrant receptor tyrosine kinase activation, Ras mutations, or Raf mutations is common in human cancers and is a major factor determining abnormal growth control. Ras mutations are relatively common in human malignancies and have been found in approximately 30% of cancers. GTPase proteins of the Ras family (proteins that convert guanosine triphosphate to guanosine diphosphate) transmit signals from activated growth factor receptors to downstream intracellular partners. The targets recruited by active membrane-bound Ras are mainly serine / threonine protein kinases of the Raf family. The Raf family consists of three related kinases (A-Raf, B-Raf, and C-Raf) and serves as downstream effectors of Ras. Ras-mediated activation of Raf then triggers the 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 a variety of Ras GTPases and B-Raf kinases have been found to result in sustained and constitutive activation of the MAPK pathway, ultimately leading to increased cell division and survival. Thus, these mutations are closely associated with the establishment, development, and progression of a variety of human cancers. The biological role of Raf kinases, particularly B-Raf, in signal transduction has been described in the following references: Davies, H. et al., Nature (2002) 9:1-6; Garnett, M.J. and Marais, R., Cancer Cell (2004) 6:313-319; Zebisch, A. and Troppmair, J., Cell. Mol. Life Sci. (2006) 63:1314-1330; Midgley, R.S. and Kerr, D.J., Crit. Rev. Onc / Hematol. (2002) 44:109-120; Smith, R.A. 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 the B-Raf kinase that activate MAPK pathway signaling have been found in the majority of human melanomas (Davies (2002) supra) and thyroid cancers (Cohen et al. J. Nat. Cancer Inst. [Journal of the National Cancer Institute] (2003) 95(8) 625-627 and Kimura et al. Cancer Res. [Cancer Research] (2003) 63(7) 1454-1457), and are less frequent but still significant in the following cancers:

[0010] Barrett's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6: 313 - 319 and Sommerer et al., Oncogene (2004) 23(2): 554 - 558), biliary tract malignancies (Zebisch et al., Cell. Mol. Life Sci. (2006) 63: 1314 - 1330), breast cancer (Davies (2002) see above), cervical cancer (Moreno - Bueno et al., Clin. Cancer Res. (2006) 12(12): 3865 - 3866), cholangiocarcinoma (Tannapfel et al., Gut (2003) 52(5): 706 - 712), central nervous system tumors (including primary CNS tumors such as glioblastoma, astrocytoma, and ependymoma (Knobbe et al., Acta Neuropathol. (Berl.) (2004) 108(6): 467 - 470, Davies (2002) see above and Garnett et al., Cancer Cell (2004) see above) and secondary CNS tumors (i.e., tumors that metastasize to the central nervous system from outside the central nervous system)), colorectal cancer (including colon cancer (Yuen et al., Cancer Res. (2002) 62(22): 6451 - 6455, Davies (2002) see above 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 head and neck squamous cell carcinoma (Cohen et al., J. Nat. Cancer Inst.[Journal of the National Cancer Institute](2003) 95(8) 625 - 627 and Weber et al., Oncogene (2003) 22(30) 4757 - 4759), hematological cancers (including leukemia (Garnett et al., Cancer Cell (2004), see above), especially acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004), see above 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 syndromes (Christiansen et al., Leukemia (2005), see above) and chronic myelogenous leukemia (Mizuchi et al., Biochem. Biophys. Res. Commun. (2005) 326(3) 645 - 651)); Hodgkin lymphoma (Figl et al., Arch. Dermatol. (2007) 143(4) 495 - 499), non - Hodgkin lymphoma (Lee et al., Br. J. Cancer (2003) 89(10) 1958 - 1960), megakaryocytic leukemia (Eychene et al., Oncogene (1995) 10(6) 1159 - 1165) and multiple myeloma (Ng et al., Br. J. Haematol. (2003) 123(4) 637 - 645), hepatocellular carcinoma (Garnett et al., Cancer Cell (2004)), lung cancer (Brose et al., Cancer Res. (2002) 62(23) 6997 - 7000, Cohen et al., J. Nat. Cancer Inst. (2003), see above and Davies (2002), see above) (including small cell lung cancer (Pardo et al., EMBO J (2006) 25(13) 3078 - 3088) and non - small cell lung cancer (Davies (2002), see above)), ovarian cancer (Russell and McCluggage J. Pathol.[Journal of Pathology](2004) 203(2) 617 - 619 and Davies (2002) (see above), endometrial cancer (Garnett et al., *Cancer Cell* (2004) see above, and Moreno - Bueno et al., *Clin. Cancer Res.* (2006) see above), 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. J. Cancer* (2003) 106(6) 980 - 981), sarcoma (Davies (2002) see above) and skin cancer (Rodriguez - Viciana et al., *Science* (2006) 311(5765) 1287 - 1290 and Davies (2002) see above). Overexpression of c - Raf is 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. Upon activation, EGFR is converted from an inactive monomeric form to an active homodimer (Yarden et al., *Biochemistry*, 26(5) 1443 - 1451). The homodimer stimulates intracellular protein tyrosine kinase activity. As a result, several tyrosine residues in the EGFR C - terminal domain are phosphorylated (Downward et al., *Nature* 311(5985) 483 - 485). This phosphorylation causes downstream activation and initiates multiple signal transduction cascades, mainly 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 many cancers, including lung cancer, anal cancer, and glioblastoma (Walker et al., Hum. Pathol. 40(11) 1517 - 1527). Inhibiting EGFR is an effective approach for treating 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 use in combination with FOLFOX as first - line treatment for wild - type RAS metastatic colorectal cancer (mCRC), and as monotherapy after disease progression following prior chemotherapy with fluoropyrimidine, oxaliplatin, and irinotecan. Panitumumab is marketed by Amgen Inc. under the trade name Vectibix. Other anti - EGFR antibodies include, but are not limited to, cetuximab, zalutumumab, nimotuzumab, and matuzumab.

[0014] Despite many recent advances in cancer treatment, there is still a need for more effective and / or alternative treatments for individuals affected by cancer (e.g., individuals with B - Raf, KRAS, or NRAS mutations).

[0015] The citation or identification of any reference in this section should not be construed as an admission that the reference is prior art to this application. Summary of the Invention

[0016] Provided herein is a compound A 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 a structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof and a combination of 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 can be used to treat cancer. In one embodiment, provided herein is a method of treating cancer in a mammal (e.g., a human) in need thereof, the method comprising administering a therapeutically effective amount of the 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 daily. In one embodiment, panitumumab is administered at a dose 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-mutated metastatic colorectal cancer. In one embodiment, the cancer is BRAF V600E-mutated metastatic colorectal cancer. In one embodiment, the cancer is KRAS-mutated colorectal cancer. In one embodiment, the cancer is KRAS G12C-mutated colorectal cancer. In one embodiment, the cancer is KRAS G12D-mutated colorectal cancer. In one embodiment, the cancer is KRAS G12V-mutated colorectal cancer. In one embodiment, the cancer is Trp53-mutated colorectal cancer. In one embodiment, the cancer is NRAS-mutated colorectal cancer. In one embodiment, the cancer is KRAS / NRAS-mutated 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-mutated pancreatic cancer. In one embodiment, the cancer is BRAF V600E-mutated pancreatic cancer. In one embodiment, the cancer is KRAS-mutated pancreatic cancer. In one embodiment, the cancer is KRAS G12C-mutated pancreatic cancer. In one embodiment, the cancer is KRAS G12D-mutated pancreatic cancer. In one embodiment, the cancer is KRAS G12V-mutated pancreatic cancer. In one embodiment, the cancer is Trp53-mutated pancreatic cancer. In one embodiment, the cancer is NRAS-mutated pancreatic cancer.

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

[0021] In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 2,128 ng*h / ml and about 3,192 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 4,576 ng*h / ml and about 6,864 ng*h / ml. In one embodiment, the plasma compound A AUC provided by the methods described herein in a subject 8h is between about 7,944 ng*h / ml and about 11,916 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 9,840 ng*h / ml and about 14,760 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 12,640 ng*h / ml and about 18,960 ng*h / ml. In one embodiment, the plasma compound A AUC provided by the methods described herein in a subject 8h is between about 30,000 ng*h / ml and about 45,000 ng*h / ml.

[0022] In one embodiment, the subject achieves disease stabilization, partial remission, or complete remission. In one embodiment, the subject does not experience disease progression.

[0023] In one embodiment, provided herein is the use of Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, 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, isotopomer, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is adapted to be administered 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 adapted to be administered together with Compound A. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The safety run-in and dose escalation schedule are described.

[0025] Figure 2 The study design is described: Part 1 (dose exploration) and Part 2 (dose expansion).

[0026] Figure 3 The study phases are described. DETAILED DESCRIPTION DEFINITIONS

[0027] As used herein, "Compound A" refers to 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 a compound having the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof. Compounds A and pharmaceutically acceptable salts and solvates thereof are disclosed and claimed in WO 2014206343 and WO 2020151756 as being useful as inhibitors of BRAF activity, particularly in cancer treatment, the entire disclosures of which are incorporated herein by reference. Compound A is Compound 1.49 in WO 2014206343 and Compound 1 in WO 2020151756. Compound A can be prepared as described in WO 2014206343 and WO 2020151756. 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, isotopomer, solvate or prodrug thereof.

[0028] As used herein, the term "antibody" generally refers to immunoglobulins or immunoglobulin-like molecules, including, for example, but not limited to, IgA, IgD, IgE, IgG, and IgM, their combinations, and similar molecules produced during any vertebrate immune response, such as immunoglobulins in mammals such as humans, goats, rabbits, and mice, and in non-mammalian species such as sharks. The term "antibody" includes intact immunoglobulins and "antibody fragments" or "antigen-binding fragments" that specifically bind to a molecule of interest (or a group of highly similar molecules of interest), substantially excluding binding to other molecules (e.g., the binding constant of an antibody and antibody fragment to a molecule of interest is at least 10 3 M -1 times, at least 10 4 M -1 times, or at least 10 5 M -1 ) greater than their binding constants to other molecules in a biological sample). The term "antibody" also includes genetically engineered forms, such as chimeric antibodies (e.g., humanized murine antibodies), heteroconjugate antibodies (e.g., bispecific antibodies). See also Pierce Catalog and Handbook, 1994 - 1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J., Immunology 3 rd [[Immunology, 3rd Ed., W.H. Freeman & Co., New York, 1997]].

[0029] More particularly, an "antibody" refers to a polypeptide ligand that at least includes the immunoglobulin variable regions of the light or heavy chain that specifically recognize and bind to an epitope. An antibody consists of a heavy chain and a light chain, each having a variable region, called the heavy chain variable region (V H ) and the light chain variable region (V L ). The V H region and the V L region together are responsible for binding the antigen recognized by the antibody.

[0030] Typically, an immunoglobulin has heavy (H) and light (L) chains interconnected by disulfide bonds. There are two types of light chains, lambda (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) that determine the functional activity of the antibody molecule: IgM, IgD, IgG, IgA, and IgE. Each heavy and light chain contains a constant region and a variable region (these regions are also referred to as "domains"). In combination, the heavy and light chain variable regions specifically bind antigen. The light and heavy chain variable regions contain "framework" regions interrupted by three hypervariable regions (also called "complementary determining regions" or "CDRs"). The ranges of the framework regions and CDRs have been defined (see Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991, which is hereby incorporated by reference). The Kabat database is now maintained online. The framework region sequences of different light or heavy chains are relatively conserved within a species. The framework regions of an antibody, i.e., the combined framework regions that make up the light and heavy chains, predominantly adopt a β-sheet conformation, and the CDRs form loops that connect the β-sheet structures and in some cases form part of the β-sheet structure. Thus, the framework regions serve to form a scaffold that positions the CDRs in the correct orientation through interchain non-covalent interactions.

[0031] The CDRs are primarily responsible for binding to the epitopes of the antigen. The CDRs of each chain are typically designated CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are usually also identified by the chain in which the particular CDR is located. Thus, V H CDR3 is located in the variable domain of the heavy chain of the antibody in which it is found, while V L CDR1 is CDR1 of the variable domain of the light chain of the antibody in which it is found. Antibodies with different specificities (i.e., different combinations of sites for different antigens) have different CDRs. Although the CDRs vary among antibodies, 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).

[0032] The term "antibody" is further intended to cover its digestive fragments, specific parts, derivatives, and variants, including antibody analogs or antibody portions that incorporate structures and / or functions that mimic an antibody or its specific fragments or parts, including single-chain antibodies and their fragments. Examples of binding fragments covered by the "antigen-binding portion" of the term antibody include Fab fragments, which are composed of V L 、V H 、C L and C HA monovalent fragment consisting of domains; an F(ab′)2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bond in the hinge region; an F H fragment consisting of V H and C d domains; an F L fragment consisting of the V H and V v domains of a single arm of an antibody; a dAb fragment (Ward et al. (1989) Nature 341:544-546), which consists of a V H domain; and a separated complementarity-determining region (CDR). In addition, although the two domains V v and V L of the F H fragment are encoded by separate genes, they can be joined by recombinant methods using a synthetic linker so that they can form a single protein chain, in which the V L and V H regions pair to form a monovalent molecule (referred to as single-chain F v (scF v ). Bird et al. (1988) Science 242:423-426 and Huston et al. 1988 Proc. Natl. Acad. Sci. USA 85:5879-5883. The term "antibody fragment" is also intended to cover single-chain antibodies. Any of the above antibody fragments are obtained using conventional techniques known to those skilled in the art, and these fragments are screened for binding specificity and neutralizing activity in the same manner as intact antibodies.

[0033] "Antibody fragment" or "antigen-binding fragment" includes proteolytic antibody fragments (such as F(ab′)2 fragments, Fab' fragments, Fab'-SH fragments, and Fab fragments known in the art), recombinant antibody fragments (such as sF v fragments, dsF v fragments, bispecific sF v fragments, bispecific dsF v fragments, F(ab)′2 fragments, single-chain Fv proteins ("scF v "), disulfide-stabilized F v proteins ("dsF v "), diabodies, and triabodies), and camelid antibodies (see, for example, U.S. Patent Nos. 6,015,695; 6,005,079; 5,874,541; 5,840,526; 5,800,988; and 5,759,808). scF vThe protein is a fusion protein in which the variable region of the light chain of an immunoglobulin and the variable region of the heavy chain of an immunoglobulin are joined together by a linker, and in dsF v the chain is mutated to introduce a disulfide bond to stabilize the binding of the chain.

[0034] As used herein, the term "anti-EGFR antibody" generally refers to an antibody or an antigen-binding fragment thereof that specifically or preferentially binds to EGFR. In some cases, an anti-EGFR antibody can bind to a mutant form of EGFR (e.g., EGFR variant III (also known as EGFRvIII), which is the most common extracellular domain mutation of EGFR; this mutation results in the deletion of exons 2-7 of the EGFR gene and renders the mutant receptor unable to bind any known ligand). For example, an anti-EGFR antibody can be panitumumab, cetuximab, zalutumumab, nimotuzumab, or matuzumab.

[0035] Panitumumab (Vectibix) is a recombinant human IgG2 monoclonal antibody that specifically binds to human EGFR and can be prepared according to the procedures described in U.S. Patent Publication No. 2015 / 0152184, which is incorporated herein by reference in its entirety. The sequences of the heavy and light chains of 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 product marketed by Amgen as Vectibix and the generic, pharmacopeial, nonproprietary, or official FDA name of a product that is interchangeable or equivalent to the product marketed as Vectibix.

[0036] In one embodiment, panitumumab is a recombinant human IgG2 monoclonal antibody that specifically binds to human EGFR. Panitumumab contains a variable region of the heavy chain and a variable region of the light chain and can be prepared according to the procedures described in U.S. Patent No. 6,235,883. The sequences of the heavy chain of panitumumab and its matching light chain disclosed in U.S. Patent No. 6,235,883 are as follows:

[0037] Heavy chain 1

[0038] VSGGSVSSGD YYWTWIRQSP GKGLEWIGHI YYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTA IYYCVRDRVT GAFDIWGQGT MVTSS (SEQ ID NO:1)

[0039] Light chain 1

[0040] TITCQASQDI SNYLNWYQQK PGKAPKLLIY DASNLETGVPSRFSGSGSGT DFTFTISSLQPEDIATYFCQ HFDHLPLAFG GGTKVEIKRTVAAPSVFIFP PSDEQ(SEQ ID NO:2)

[0041] The above heavy chain 1 and light chain 1 correspond to Sequences 37 and 38 in U.S. Patent No. 6,235,883, which is incorporated herein by reference in its entirety.

[0042] Heavy chain 2 VSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS(SEQ ID NO:3)

[0043] Light chain 2

[0044] TITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQ(SEQ ID NO:4)

[0045] The above heavy chain 2 and light chain 2 correspond to Sequences 76 and 54 in U.S. Patent No. 7,807,798, which is incorporated herein by reference in its entirety.

[0046] In one embodiment, panitumumab is an isolated human antibody, as disclosed in U.S. Patent No. 7,807,798, which binds to the human epidermal growth factor receptor (EGF-r). In one embodiment, panitumumab is an isolated human antibody, and the isolated human antibody comprises a heavy chain immunoglobulin molecule and a light chain immunoglobulin molecule. The heavy chain immunoglobulin molecule comprises: 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 the light chain immunoglobulin molecule comprises: 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:

[0047] The sequences of cetuximab, zalutumumab, nimotuzumab, and matuzumab are also 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 readily prepared by common general knowledge in the art. In one embodiment, cetuximab is the anti-epidermal growth factor receptor monoclonal antibody Mab C225 as defined in US7960516 B2, which patent is incorporated herein by reference in its entirety. In one embodiment, cetuximab is the anti-EGFR antibody described in US 4,943,533 and WO 96 / 40210. In one embodiment, zalutumumab (Humax-EGFR) is the anti-EGFR antibody described in WO 02 / 100348 and WO2004 / 056847. In one embodiment, nimotuzumab (TheraCIM hR3) is the anti-EGFR antibody described in US 5,891,996 and US 6,506,883. In one embodiment, matuzumab (EMD72000) is the anti-EGFR antibody described in WO 02 / 66058. The disclosures of these references are incorporated herein by reference in their entireties.

[0048] In one embodiment, a solid form of Compound A is used for the treatment provided herein. In one embodiment, a crystalline form of Compound A is used for the treatment provided herein. In one embodiment, an amorphous form of Compound A is used for the treatment provided herein. In one embodiment, the free base of Compound A is used for the treatment provided herein. In one embodiment, the hydrochloride salt of Compound A is used for the treatment provided herein. In one embodiment, the solid form of Compound A described in WO 2020151756 is used for the treatment provided herein. In one embodiment, the solid form of Compound A described in WO 2020151756 is used for the treatment 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 WO 2020151756 is used for the treatment provided herein. In one embodiment, Form F of Compound A described in WO 2020151756 is used for the treatment provided herein. In one embodiment, Form F of Compound A described in Example 7 of WO 2020151756 is used for the treatment provided herein. The disclosure of WO 2020151756 is incorporated herein by reference in its entirety.

[0049] As used herein, the term "tumor" refers to the abnormal growth of cells or tissues and is understood to include both benign (i.e., non-cancerous growth) and malignant (i.e., cancerous growth). The term "tumoral" means relating to a tumor or associated with a tumor.

[0050] As used herein, the term "agent" 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 "agent" can be a single compound or a combination or composition of two or more compounds.

[0051] The term "treatment" and its derivatives as used herein refer to therapeutic treatment. For a particular condition, treatment means: (1) improving the condition or one or more biological manifestations of the condition; (2) interfering with (a) one or more points in the biological cascade that causes or contributes to the condition, or (b) one or more biological manifestations 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 biological manifestations of the condition.

[0052] As used herein, "prevention" is understood to refer to the prophylactic administration of a drug to significantly 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. For example, prophylactic treatment is appropriate when a subject is considered to be at high risk of developing cancer, such as when the subject has a strong family history of cancer or when the subject has been exposed to a carcinogen.

[0053] As used herein, the term "effective amount" means the amount of a drug or agent that elicits a biological or medical response in a tissue, system, animal, or human, i.e., the amount that a researcher or clinician is seeking, for example. In addition, the term "therapeutically effective amount" means any amount that results in an improvement in the treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not receiving such amount. The term also includes amounts that are effective within its scope to enhance normal physiological functions.

[0054] Compound A disclosed herein may contain one or more chiral atoms or may otherwise exist as enantiomers. Thus, the compounds of the invention include mixtures of enantiomers as well as purified enantiomers or enantiomer-enriched mixtures. In addition, it should be understood that all tautomers and mixtures of tautomers are included within the scope of Compound A.

[0055] As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in the present invention, a compound of formula (I) or a salt and a solvent thereof). In addition, it is to be understood that compound A may exist alone or together with its solvate. Such solvents for the purposes of the present invention do not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, dimethyl sulfoxide, ethanol, and acetic acid. In one embodiment, the solvent used is a pharmaceutically acceptable solvent. 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).

[0056] Compound A may have the ability to crystallize in more than one form, which is a characteristic of known polymorphs, and it is to be understood that such polymorphs ("polymorphs") are within the scope of compound A. Polymorphs generally can occur as a reaction to changes in temperature or pressure or both, and can also be caused by changes during the crystallization process. Polymorphs can be distinguished by a variety of physical properties known in the art, such as x-ray diffraction patterns, solubility, and melting point.

[0057] As used herein, and in the 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.

[0058] As used herein and unless otherwise specified, the terms "about" and "approximately", when used in connection with the dose, amount, or weight percentage of a component of a composition or dosage form, mean the dose, amount, or weight percentage known to a person of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage. In certain embodiments, the terms "about" and "approximately", when used in this context, contemplate a dose, amount, or weight percentage within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percentage.

[0059] As used herein and unless otherwise indicated, the terms "about" and "approximately," when used in reference to a numerical value or range of values provided to characterize a particular solid form, such as with respect to a particular temperature or temperature range, e.g., as describing a melting, dehydration, desolvation, or glass transition temperature; a mass change, e.g., as a function of temperature or humidity; a solvent or water content, e.g., expressed as a mass or percentage; or a peak position, e.g., in an analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values can vary to the extent considered reasonable by a person of ordinary skill in the art while still describing 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 diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (e.g., 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 certain embodiments, the terms "about" and "approximately," when used in this context, indicate that the numerical value or range of values can 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° 2θ (or ±0.2 degrees 2θ) while still describing a particular XRPD peak.

[0060] As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic and organic acids and bases). Suitable pharmaceutically acceptable base addition salts of the compounds provided herein include, but are not limited to, those well known in the art, see, e.g., Remington’s Pharmaceutical Sciences, 18 th eds. [Remington's Pharmaceutical Sciences, 18th Edition], Mack Publishing, Easton PA (1990) [Mack Publishing Company, Easton, Pennsylvania, 1990] or Remington: The Science and Practice of Pharmacy, 19 th eds. [Remington: The Science and Practice of Pharmacy, 19th Edition], Mack Publishing, Easton PA (1995) [Mack Publishing Company, Easton, Pennsylvania, 1995].

[0061] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" means a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. Representative stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the 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 the compound. These compounds may have 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.

[0062] The use of stereoisomerically pure forms of these compounds and the use of mixtures of these forms are covered in 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. Standard techniques (such as chiral columns or chiral resolving agents) can be used to asymmetrically synthesize or resolve these isomers. See, e.g., Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions, page 268 (edited by E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, Indiana, 1972).

[0063] 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 separated as the E or Z isomer. In other embodiments, the compounds are a mixture of the E and Z isomers.

[0064] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms depends on the environment in which the compound is present and may vary, for example, depending on whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, pyrazole can exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0065] As will be readily understood by those skilled in the art, multiple functional groups and other structures can exhibit tautomerism and all tautomers of the compounds provided herein are within the scope of the present invention.

[0066] It should also be noted that the compounds can contain non-natural proportions of atomic isotopes at one or more atoms. For example, the compounds can be radiolabeled with a radioactive isotope, such as with tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or can be isotope-enriched, such as enriched with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N). As used herein, "isotopologues" are isotope-enriched compounds. The term "isotope-enriched" refers to atoms having an isotopic composition different from the natural isotopic composition of the atom. "Isotope-enriched" can also refer to a compound that contains at least one atom having an isotopic composition different from the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope of a given atom. Radiolabeled and isotope-enriched compounds can be used as therapeutic agents (e.g., for the treatment of cancer and inflammation), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of the compounds described herein (whether radioactive or not) should be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds are provided, for example, these isotopologues are compounds enriched with deuterium, carbon-13, or nitrogen-15.

[0067] The term "subject" includes animals, including but not limited to, for example, primates, cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs. In some embodiments, the subject is a mammal, such as a human.

[0068] For use in therapy, while compound A may be administered as the raw chemical, the active ingredient may also be presented 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 one or more carriers, diluents or excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation (which can be a pharmaceutical formulation) and not injurious to its recipient. According to another aspect of the present invention, there is also provided a process for preparing a pharmaceutical composition which comprises mixing compound A with one or more pharmaceutically acceptable carriers, diluents or excipients. Such ingredients of the pharmaceutical composition used may be present in different pharmaceutical combinations or formulated together in one pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising compound A and one or more pharmaceutically acceptable carriers, diluents or excipients. The above-mentioned compound A can be used in any of the above compositions.

[0069] The pharmaceutical composition may be in unit dosage form, each unit dosage containing a predetermined amount of the active ingredient. As is known to those skilled in the art, the amount of the active ingredient per dosage depends on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage compositions are those containing the daily dose or a sub-dose or an appropriate fraction thereof of the active ingredient. In addition, such pharmaceutical compositions can be prepared by any method well known in the pharmaceutical art.

[0070] The combination can be administered by any suitable route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). It is to be understood that the preferred route may vary depending, for example, on the condition of the recipient of the combination and the cancer to be treated. It is also to be understood that each agent administered can be administered by the same or different routes and that the combinations provided herein can be compounded together in a pharmaceutical composition or separately in two pharmaceutical compositions.

[0071] A pharmaceutical composition suitable for oral administration may be presented in discrete unit form, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or water-in-oil liquid emulsions or oil-in-water liquid emulsions.

[0072] Unless otherwise defined, in all dosing regimens described herein, the regimen of the compound administered need not start at the beginning of the treatment nor end at the end of the treatment; it is only required that the consecutive days of administration of the two compounds and the optional consecutive days or specified dosing regimen (including the amount of the compound administered) of administration of only one of the component compounds occur at some point during the course of the treatment.

[0073] Compound A can be used in combination with an anti-EGFR antibody or an antigen-binding fragment thereof according to the present disclosure by simultaneous administration in a unit pharmaceutical composition comprising the two compounds.

[0074] Furthermore, it is not important whether the compounds are administered in the same dosage form. For example, Compound A can be administered orally, while the anti-EGFR antibody or an antigen-binding fragment thereof can be administered intravenously.

[0075] As used herein, the term "kit" or "package kit" refers to a pharmaceutical composition or combination for administering the combination according to the present disclosure. In one embodiment, the combination contained in the kit can be in a single pharmaceutical composition (such as a tablet) or in different pharmaceutical compositions. In one aspect, a package kit is provided that contains the following components: a combination in association with a pharmaceutically acceptable excipient, diluent, or carrier. The kit can also provide instructions, such as dosage instructions and administration instructions. Such dosage instructions and administration instructions can be of the kind provided to a doctor (such as through a pharmaceutical product label), or they can be of the kind provided by a doctor (such as instructions to a patient).

[0076] As used herein, the term "dose" should be understood to mean a dose intended to slowly increase the plasma or blood concentration level of a compound to a therapeutically effective level or to maintain such a therapeutically effective level.

[0077] In certain embodiments, the treatment of cancer can be evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Therasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. [New Guidelines for Evaluating the Response to Treatment in Solid Tumors] J. of the National Cancer Institute [Journal of the National Cancer Institute]; 2000; (92) 205 - 216 and Eisenhauer, Elizabeth A., et al., European journal of cancer [European Journal of Cancer] 45.2 (2009): 228 - 247). New Response Evaluation Criteria for Solid Tumors: Revised RECIST Guidelines (version 1.1). European J. Cancer [European Journal of Cancer]; 2009; (45) 228–247). In the presence or absence of new lesions, the overall response of all possible combinations of tumor responses in target and non-target lesions is as follows: Target lesion Non-target lesion New lesion Overall response CR CR No CR CR Partial response / SD No PR PR No PD No PR SD No PD No SD PD Any Yes or no PD Any PD Yes or no PD Any Any Yes PD CR = Complete Response; PR = Partial Response; SD = Stable Disease; and PD = Progressive Disease.

[0078] For the assessment of target lesions, a Complete Response (CR) is defined as the disappearance of all target lesions; a Partial Response (PR) is defined as a decrease of at least 30% in the sum of the longest diameters of target lesions, as compared to the baseline sum of the longest diameters; Progressive Disease (PD) is defined as an increase of at least 20% in the sum of the longest diameters of target lesions, as compared to the smallest sum of the longest diameters recorded since the start of treatment or the appearance of one or more new lesions; and Stable Disease (SD) is defined as neither sufficient shrinkage to meet the criteria for a partial response nor sufficient increase to meet the criteria for progressive disease, as compared to the smallest sum of the longest diameters since the start of treatment.

[0079] For the assessment of non-target lesions, a Complete Response (CR) is defined as the disappearance of all non-target lesions and normalization of tumor marker levels; Incomplete Response / Stable Disease (SD) is defined as the persistence of one or more non-target lesions and / or the maintenance of tumor marker levels above the normal limits; and Progressive Disease (PD) is defined as the appearance of one or more new lesions and / or definite progression of existing non-target lesions.

[0080] The procedures, practices, and definitions described below provide guidelines for implementing the recommendations of the Response Assessment in Neuro-Oncology (RANO) Working Group regarding response criteria for high-grade gliomas (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. [Journal of Clinical Oncology] 2010; 28:1963-1972). The major modifications to the RANO criteria for Time Point Response (TPR) criteria may include adding practices for defining changes in glucocorticoid dose and removing the section on clinical deterioration of the subject to focus on objective radiological assessment. The baseline MRI scan is defined as the assessment performed at the end of the postoperative rest period, before starting or restarting compound treatment. The baseline MRI is used as a reference for assessing Complete Response (CR) and Partial Response (PR). The minimum SPD (Sum of Products of Perpendicular Diameters) obtained at baseline or subsequent assessments is designated as the nadir assessment and used as a reference for determining progression. Five days before any protocol-defined MRI scan, the subject does not receive glucocorticoids or receives a stable dose of glucocorticoids. A stable dose is defined as the same daily dose for five consecutive days before the MRI scan. If the prescribed glucocorticoid dose is changed within five days before the baseline scan, a new baseline scan is required and the use of glucocorticoids meets the above criteria. The following definitions are used.

[0081] Measurable lesion: A measurable lesion is a contrast-enhanced lesion that can be measured two-dimensionally. Measure the maximum enhanced tumor diameter (also known as the longest diameter, LD). Measure the maximum perpendicular diameter on the same image. The crosshairs for the two-dimensional measurement should cross, and the product of these diameters is calculated.

[0082] Minimum diameter: T1-weighted images with a section thickness of 5 mm and an interval of 1 mm. The minimum LD of 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, for target lesions that become smaller than the measurement minimum requirement or are no longer suitable for two-dimensional measurement, each diameter less than 5 mm is recorded as 5 mm by default. Lesions that disappear are recorded as 0 mm x 0 mm.

[0083] Multicentric lesions: Lesions considered to be multicentric (as opposed to contiguous) are those in which normal brain tissue intervenes between two (or more) lesions. For multicentric lesions that are discrete 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 to be the same lesion.

[0084] Non-measurable lesions: All lesions that do not meet the criteria for measurable disease as defined above, as well as all non-enhancing lesions and other truly non-measurable lesions, are considered non-measurable lesions. Non-measurable lesions include enhancing foci smaller than the specified minimum diameter (i.e., smaller than 5 mm x 5 mm), non-enhancing lesions (e.g., as seen on T1-weighted post-contrast, T2-weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumors. Hemorrhagic lesions typically have an inherent high density on T1-weighted images and may be misinterpreted as enhancing tumors. Therefore, pre-contrast T1-weighted images can be examined to exclude baseline or interval subacute hemorrhage.

[0085] At baseline, lesions are classified as follows: Target lesions: Up to 5 measurable lesions can be selected as target lesions, each with a size of at least 10 mm x 5 mm and representative of the subject's disease; 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 measurable lesions, and the SPD of all target lesions is determined. All other lesions present should be recorded. In all post-treatment evaluations, the baseline classification of lesions as target and non-target lesions remains unchanged, and lesions are recorded and described in a consistent manner over time (e.g., recorded in the same order in the source document and eCRF). Throughout the study, all measurable and non-measurable lesions must be evaluated using the same technique as at baseline (e.g., the subject should be imaged on the same MRI scanner or at least using the same magnet strength) to reduce the difficulty of interpretation variability. At each evaluation, target lesions are measured and the SPD is calculated. Non-target lesions are qualitatively evaluated, and new lesions (if any) are recorded separately. At each evaluation, the time-point response of target lesions, non-target lesions, and new lesions is determined. Tumor progression can be determined even if only a subset of lesions is evaluated. However, unless progression is observed, the objective status (stable disease, PR, or CR) can only be determined after all lesions have been evaluated.

[0086] The confirmatory assessment of the overall time-point response for CR and PR is performed at the next scheduled evaluation, but may not be performed if the scan interval < 28 days. The best response plus the confirmation requirement is derived from a series of time points.

[0087] As used herein, "in some embodiments", "in one embodiment", and "in certain embodiments" are used interchangeably. In some embodiments, the recitation of Compound A may 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", and vice versa.

[0088] As used herein, all amounts specified for Compound A or panitumumab are expressed as the amount of the free or unsalted compound. Combination

[0089] Provided herein is 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 Compound A having the structure of formula (I): Or a combination of a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof and an anti-EGFR antibody or an antigen-binding fragment thereof. The combination is used for treating 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 comprises an anti-EGFR antibody. In one embodiment, the combination comprises anti-panitumumab.

[0090] In one embodiment, the solid form of Compound A described in WO 2020151756 is used for the treatment 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 WO 2020151756 is used for the treatment provided herein. In one embodiment, Form F of Compound A described in WO 2020151756 is used for the treatment provided herein. In one embodiment, Compound A is Form F.

[0091] In one embodiment, the combination kit comprises the combination provided herein and one or more pharmaceutically acceptable carriers. In one embodiment, provided herein is a method of using the combination kit comprising the combination provided herein for the treatment provided herein. In one embodiment, provided herein is the use of the combination kit comprising the combination provided herein as provided herein.

[0092] In one embodiment, the anti-EGFR antibody (e.g., panitumumab) is provided in a form suitable for IV administration.

[0093] In one embodiment, the anti-EGFR antibody (e.g., panitumumab) is provided in a form suitable for subcutaneous administration. Methods of treatment

[0094] Provided herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination disclosed herein. Provided herein is the use of a combination disclosed herein in the treatment or prevention of cancer. Provided herein is the use of a combination disclosed herein in the manufacture of a medicament for the treatment or prevention of cancer.

[0095] Also provided herein is compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof, for the treatment or prevention (e.g., treatment) of cancer in a subject, wherein compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof is administered in combination with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab.

[0096] Also provided herein is a pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof, for the treatment or prevention (e.g., treatment) of cancer in a subject, wherein compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof is administered in combination with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab.

[0097] Also provided herein is an anti-EGFR antibody, for the treatment or prevention (e.g., treatment) of cancer, wherein the anti-EGFR antibody is administered in combination with compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof. In some embodiments, the anti-EGFR antibody is panitumumab.

[0098] Also provided herein is a pharmaceutical composition comprising an anti-EGFR antibody, for the treatment or prevention (e.g., treatment) of cancer, wherein the anti-EGFR antibody is administered in combination with compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof. In some embodiments, the anti-EGFR antibody is panitumumab.

[0099] The present invention also provides the use of compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof in the manufacture of a medicament for the treatment or prophylaxis (e.g., treatment) of cancer, wherein the medicament is administered together with an anti-EGFR antibody. In some embodiments, the anti-EGFR antibody is panitumumab.

[0100] The present invention also provides the use of an anti-EGFR antibody in the manufacture of a medicament for the treatment or prophylaxis (e.g., treatment) of cancer, wherein the medicament is administered together with compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof. In some embodiments, the anti-EGFR antibody is panitumumab.

[0101] The present invention further provides a method of treating cancer in a subject in need thereof, the method 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.

[0102] In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily 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. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered orally daily 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. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily 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. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily 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. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily 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. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily at a dose between about 5 mg and about 60 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily at a dose between about 5 mg and about 40 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily at about 5 mg. In some embodiments, Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof is administered daily at about 10 mg.In some embodiments, compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate or prodrug thereof is administered at 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 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 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 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 about 35 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 40 mg per day. In some embodiments, the administration is oral administration.

[0103] In some embodiments, compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate or prodrug thereof is administered once a day. In some embodiments, compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate or prodrug thereof is administered twice a day. In some embodiments, compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate or prodrug thereof is administered three times a day.

[0104] 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 as an intravenous infusion in an amount of about 6 mg / kg over about 60 minutes. In one embodiment, panitumumab is administered as an intravenous infusion in an amount of about 6 mg / kg over about 60 minutes once every two weeks.

[0105] 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, approximately once 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, approximately once 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, approximately once 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, approximately once every two weeks.

[0106] In one embodiment, panitumumab is administered as an intravenous infusion approximately once every two weeks over about 60 minutes at a dose 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. In one embodiment, panitumumab is administered as an intravenous infusion approximately once every two weeks over about 60 minutes at a dose 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. In one embodiment, panitumumab is administered as an intravenous infusion approximately once every two weeks over about 60 minutes at a dose 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. In one embodiment, panitumumab is administered as an intravenous infusion approximately once every two weeks over about 60 minutes at a dose 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.

[0107] In some embodiments, panitumumab is administered as an intravenous infusion at a dose of about 6 mg / kg once every 14 days. When the amount of panitumumab administered within 14 days does not exceed about 1000 mg, it is administered over about 60 minutes, or when the amount of panitumumab administered within 14 days exceeds about 1000 mg, it is administered over about 90 minutes. In some embodiments, panitumumab is administered as an intravenous infusion at a dose of about 6 mg / kg once every 14 days. When the amount of panitumumab administered within 14 days does not exceed about 1000 mg, it is administered over about 60 minutes, or when the amount of panitumumab administered within 14 days exceeds about 1000 mg, it is administered over about 90 minutes.

[0108] 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 to each other within about 30 minutes. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of 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 once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 5 mg. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 10 mg. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 15 mg. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 20 mg. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 25 mg.In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered over about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or administered over about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 30 mg. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered over about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or administered over about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 35 mg. In some embodiments, panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered over about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or administered over about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and Compound A is administered orally once daily at a dose of about 40 mg.

[0109] 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-mutated metastatic colorectal cancer. In one embodiment, the cancer is BRAF V600E-mutated metastatic colorectal cancer. In one embodiment, the cancer is KRAS-mutated colorectal cancer. In one embodiment, the cancer is KRAS G12C-mutated colorectal cancer. In one embodiment, the cancer is KRAS G12D-mutated colorectal cancer. In one embodiment, the cancer is KRAS G12V-mutated colorectal cancer. In one embodiment, the cancer is Trp53-mutated colorectal cancer. In one embodiment, the cancer is NRAS-mutated colorectal cancer.

[0110] In some embodiments, provided herein are methods of treating colorectal cancer in a subject by administering an anti-EGFR antibody and Compound A to the subject. 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 following said other therapy.

[0111] 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-mutated pancreatic cancer. In one embodiment, the cancer is BRAF V600E-mutated pancreatic cancer. In one embodiment, the cancer is KRAS-mutated pancreatic cancer. In one embodiment, the cancer is KRAS G12C-mutated pancreatic cancer. In one embodiment, the cancer is KRAS G12D-mutated pancreatic cancer. In one embodiment, the cancer is KRAS G12V-mutated pancreatic cancer. In one embodiment, the cancer is Trp53-mutated pancreatic cancer. In one embodiment, the cancer is NRAS-mutated pancreatic cancer.

[0112] In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is BRAF-mutated non-small cell lung cancer. In one embodiment, the cancer is BRAF V600E-mutated non-small cell lung cancer. In one embodiment, the cancer is KRAS-mutated non-small cell lung cancer. In one embodiment, the cancer is KRAS G12C-mutated non-small cell lung cancer. In one embodiment, the cancer is KRAS G12D-mutated non-small cell lung cancer. In one embodiment, the cancer is KRAS G12V-mutated non-small cell lung cancer. In one embodiment, the cancer is Trp53-mutated non-small cell lung cancer. In one embodiment, the cancer is NRAS-mutated non-small cell lung cancer.

[0113] In some embodiments, the cancer is colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, brain cancer, lung cancer, kidney cancer, bone cancer, 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 after one or more prior treatments.

[0114] 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, wherein the patient has progressed after one or more prior treatments.

[0115] 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 fusion, and any combination thereof; preferably a mutation of NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and any combination thereof; more preferably a mutation of NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and any combination thereof.

[0116] In one embodiment, the cancer is characterized by other genomic aberrations of the MAPK pathway. In one embodiment, the other genomic aberration of the MAPK pathway is the RAS A1 splice variant.

[0117] 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.

[0118] In some embodiments, cancer is characterized by being selected from 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, BRAF G466A, BRAFG466V, BRAF S467A, BRAF S467L, BRAF F468C, BRAF G469L, BRAF G469del, BRAF G469S, BRAF G469R, BRAF G469E, BRAF G469A, BRAFG469V, BRAF T470K, BRAF V471I, BRAF V471F, BRAF Y472dup, BRAF Y472S, BRAFY472C, BRAF G478C, BRAF K483E, BRAF K483M, BRAF L485_P490del, BRAF L485Y, BRAFL485_P490delinsY, BRAF L485S, BRAF L485W, BRAF L485F, BRAF L485_P490delinsF, BRAFN486_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, BRAFV487_P490del, BRAF V487_P492delinsA, BRAF T488_P492del, BRAFT488_Q493delinsK, BRAF A489_P490del, BRAF P490del, BRAF P490_Q494del, BRAFK499E, BRAF K499N, BRAF E501K, BRAF E501G, BRAF V504_R506dup, BRAFV504I, 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, BRAFH568D, BRAF H574N, BRAF H574Y, BRAF H574Q, BRAF N581D, BRAF N581Y, BRAF N581T, BRAF N581S, BRAF N581I, BRAF N581K, BRAF I582M, BRAFF583C, 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, BRAF S605A, BRAF S605F, BRAF S605E, BRAF S605G, BRAFMutations of 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.

[0119] In some embodiments, the cancer is characterized by mutations selected from 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-BRAF fusion, AKAP9-BRAF fusion, ARMC10-BRAF fusion, CUL1-BRAF fusion, GTF2I-BRAF fusion, PAPSS1-BRAF fusion, PCBP2-BRAF fusion, PPFIBP2-BRAF fusion, SND1-BRAF fusion, TRIM24-BRAF fusion, ZKSCAN1-BRAF fusion, SEPT3-BRAF fusion and any combination thereof.

[0120] In some embodiments, the cancer is characterized by a mutation selected from 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 E132K, NRAS K135N, NRAS A146P, NRAS A146T, NRAS A146V, NRAS E162* and any combination thereof.

[0121] In some embodiments, the cancer carries one or more of the mutations described herein. In some embodiments, the subject has a cancer carrying one or more of the mutations described herein.

[0122] In some embodiments, Compound A is administered one to three times per day. In one embodiment, Compound A is administered three times per day. In one embodiment, Compound A is administered twice per day. In one embodiment, Compound A is administered once per day.

[0123] In some embodiments, the plasma Compound A AUC provided by the methods described herein in a subject 8h is between about 2,000 ng*h / ml and about 3,200 ng*h / ml. In one embodiment, the plasma Compound A AUC provided by the methods described herein in a subject 8h is between about 2,128 ng*h / ml and about 3,192 ng*h / ml. In one embodiment, the plasma Compound A AUC provided by the methods described herein in a subject 8h is between about 2,400 ng*h / ml and about 2,900 ng*h / ml.

[0124] In some embodiments, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 4,600 ng*h / ml and about 6,900 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 4,576 ng*h / ml and about 6,864 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 5,100 ng*h / ml and about 6,300 ng*h / ml.

[0125] In some embodiments, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 8,000 ng*h / ml and about 12,000 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 7,944 ng*h / ml and about 11,916 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 8,900 ng*h / ml and about 10,900 ng*h / ml.

[0126] In some embodiments, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 10,000 ng*h / ml and about 14,800 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 9,840 ng*h / ml and about 14,760 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 11,100 ng*h / ml and about 13,500 ng*h / ml.

[0127] In some embodiments, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 12,700 ng*h / ml and about 19,000 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8h is between about 12,640 ng*h / ml and about 18,960 ng*h / ml. In one embodiment, the plasma compound AAUC provided by the methods described herein in a subject 8hBetween about 14,200 ng*h / ml and about 17,400 ng*h / ml.

[0128] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject 8h Between about 30,000 ng*h / ml and about 45,000 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject 8h Between about 33,800 ng*h / ml and about 41,300 ng*h / ml.

[0129] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 5 mg / day 8h Between about 2,000 ng*h / ml and about 3,200 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 5 mg / day 8h Between about 2,128 ng*h / ml and about 3,192 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 5 mg / day 8h Between about 2,400 ng*h / ml and about 2,900 ng*h / ml.

[0130] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 10 mg / day 8h Between about 4,600 ng*h / ml and about 6,900 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 10 mg / day 8h Between about 4,576 ng*h / ml and about 6,864 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 10 mg / day 8h Between about 5,100 ng*h / ml and about 6,300 ng*h / ml.

[0131] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 15 mg / day 8h Between about 8,000 ng*h / ml and about 12,000 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 15 mg / day 8hBetween about 7,944 ng*h / ml and about 11,916 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 15 mg / day 8h Between about 8,900 ng*h / ml and about 10,900 ng*h / ml.

[0132] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 25 mg / day 8h Between about 10,000 ng*h / ml and about 14,800 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 25 mg / day 8h Between about 9,840 ng*h / ml and about 14,760 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 25 mg / day 8h Between about 11,100 ng*h / ml and about 13,500 ng*h / ml.

[0133] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 40 mg / day 8h Between about 12,700 ng*h / ml and about 19,000 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 40 mg / day 8h Between about 12,640 ng*h / ml and about 18,960 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 40 mg / day 8h Between about 14,200 ng*h / ml and about 17,400 ng*h / ml.

[0134] In some embodiments, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 60 mg / day 8h Between about 30,000 ng*h / ml and about 45,000 ng*h / ml. In one embodiment, the methods described herein provide a plasma compound A AUC in a subject receiving compound A at about 60 mg / day 8h Between about 33,800 ng*h / ml and about 41,300 ng*h / ml.

[0135] In some embodiments, the AUC is measured in the plasma of the subject8h 。In some embodiments, AUC is measured in the blood of the subject 8h 。In some embodiments, AUC is measured in the plasma or blood of the subject on Day 1 of Cycle 2 8h 。In some embodiments, AUC is measured in the plasma or blood of the subject at about Day 29 of treatment with Compound A 8h 。

[0136] In one embodiment, the subject receives 1 to 12 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 1 to 12 cycles of the treatment provided herein, where each cycle consists of about 21 days. In one embodiment, the subject receives 1 to 12 cycles of the treatment provided herein, where each cycle consists of about 14 days. In one embodiment, the subject receives 1 to 12 cycles of the treatment provided herein, where each cycle consists of about 7 days.

[0137] In one embodiment, the subject receives 1 to 12 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 1 to 10 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 1 to 8 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 1 to 6 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 1 to 4 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 4 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 3 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 2 cycles of the treatment provided herein, where each cycle consists of about 28 days. In one embodiment, the subject receives 1 cycle of the treatment provided herein, where each cycle consists of about 28 days.

[0138] In one embodiment, the subject achieves disease stabilization, partial remission, or complete remission. In one embodiment, the subject achieves partial remission or complete remission. In one embodiment, the subject achieves complete remission. In one embodiment, the subject does not experience disease progression. In one embodiment, the subject achieves disease stabilization. In one embodiment, the subject achieves partial remission. In one embodiment, the subject achieves disease stabilization, partial remission, or complete remission for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the subject achieves disease stabilization, partial remission, or complete remission for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months. In one embodiment, the subject achieves disease stabilization, partial remission, or complete remission for 1 year, 2 years, 3 years, or 4 years.

[0139] Provided herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject the combination provided herein, wherein the cancer is characterized by a mutation selected from BRAF, RAS, NRAS, KRAS, and combinations thereof; preferably NRAS and KRAS and combinations thereof; more preferably KRAS. Provided herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an inhibitor of BRAF, wherein the cancer is characterized by a mutation in KRAS. In one embodiment, the cancer is colorectal cancer (CRC). In one embodiment, the cancer is PDAC.

[0140] In some embodiments, the cancer is colorectal cancer, pancreatic cancer, melanoma, non-small cell lung cancer, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, or thyroid cancer.

[0141] 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 fusion, and any combination thereof; preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, BRAF V600E, BRAF fusion, and any combination thereof; more preferably NRAS Q61R, NRAS Q61K, NRAS Q61L, KRAS G12D, KRAS G12V, and any combination thereof. In one embodiment, the cancer is characterized by the mutations provided herein.

[0142] In certain embodiments, the patient has colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, skin cancer, adrenal cancer, cervical cancer, lymphoma, or thyroid cancer. In specific embodiments, the measured patient response is inhibition of disease progression, inhibition of tumor growth, reduction of primary and / or secondary tumors, 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, slowing or reduction in severity of secondary effects of the disease, tumor growth arrest, or tumor regression.

[0143] Provided herein are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject the combination provided herein, wherein the cancer is metastatic cancer, resistant cancer, recurrent cancer, and / or unresectable cancer. In some embodiments, the subject is an adult patient, e.g., a patient 18 years of age or older.

[0144] In one embodiment, Form F is in powder form with a particle size of D90 < about 200 μm. In one embodiment, Form F is in powder form with a particle size of D90 < about 400 μm. In one embodiment, Form F is in powder form with a particle size of D90 < about 600 μm. In one embodiment, Form F is in powder form with a particle size of D90 < about 100 μm. In one embodiment, Form F is in powder form with a particle size of D90 < 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%. Kit

[0145] Provided herein are kits that comprise Compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate, or prodrug thereof and an anti-EGFR antibody, and instructions for effective administration. For example, in some embodiments, the kit comprises Compound A and panitumumab and instructions for effective administration. In some embodiments, the kit is for use in the methods described herein (e.g., methods of treating cancer).

[0146] Provided herein are kits that comprise the combination provided herein and a method for monitoring a patient's response to administration of the compounds provided herein.

[0147] In other embodiments, provided herein are pharmaceutical kits that contain the combinations provided herein and methods for measuring the amount of B-RAF, KRAS, NRAS, or MEK inhibition in a patient. In certain embodiments, the pharmaceutical kit contains a method for measuring B-RAF or MEK inhibition in a patient's circulating plasma, blood, or tumor cells and / or skin biopsy or tumor biopsy / aspirate. In certain embodiments, provided herein are pharmaceutical kits that contain the compounds provided herein and methods for measuring the amount of B-RAF, KRAS, NRAS, or MEK inhibition before, during, and / or after administration of the compounds provided herein. In certain embodiments, the patient has colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, or ovarian cancer.

[0148] In certain embodiments, the pharmaceutical kits provided herein contain an amount of the combinations provided herein effective to treat or prevent the following cancers: colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, brain cancer, lung cancer, kidney cancer, bone cancer, 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 pharmaceutical kits provided herein contain an amount of the compounds provided herein effective to treat or prevent colorectal cancer, pancreatic cancer, non-small cell lung cancer, melanoma, or ovarian cancer.

[0149] In certain embodiments, the pharmaceutical kits provided herein further contain one or more pharmaceutically acceptable carriers.

[0150] In certain embodiments, the pharmaceutical kits provided herein further contain instructions for use, such as instructions for administering the compounds provided herein and / or monitoring the patient's response to the administered compounds. Examples

[0151] The following examples are intended to be purely exemplary and should not be regarded as limiting in any way. Unless otherwise noted, the experimental methods in the examples described below are conventional methods.

[0152] Table 1. List of Abbreviations and Terms Example 1

[0153] The investigational product was Compound A and panitumumab. The study title was "A First-in-Human 1a / 1b Phase, Open-Label, Dose Escalation and Expansion Study of the RAF Dimer Inhibitor Compound A in Patients with Advanced or Refractory Tumors".

[0154] This study is a multicenter, open-label, two-part (safety run-in and dose expansion) Phase 1a / 1b study of Compound A and panitumumab in tumor patients with B-RAF or K-RAS / N-RAS mutations that may respond to RAF dimer inhibitors.

[0155] The number of patients is approximately 64 patients in total. Part 1 (safety run-in) is approximately 24 patients. Part 2 (dose expansion) has approximately 40 patients.

[0156] Objectives and Endpoints

[0157] The study objectives for the safety run-in include primary, secondary, and exploratory objectives. The primary objective is to evaluate the safety and tolerability of the combination of Compound A and panitumumab and to determine the recommended Phase 1b / 2 dose of the combination. The secondary objectives are to characterize the pharmacokinetics (PK) of the combination of Compound A and panitumumab and to evaluate the preliminary anti-tumor activity of the combination of Compound A and panitumumab. The exploratory objectives are to identify potential predictive biomarkers of efficacy, to evaluate potential pharmacodynamic (PD) biomarkers of target engagement, biological activity, and mechanism of action, and to explore the mechanisms of treatment resistance in patients who do not respond or develop resistance.

[0158] The study objectives for the dose expansion include primary, secondary, and exploratory objectives. The primary objective is to evaluate the preliminary anti-tumor activity of the combination of Compound A and panitumumab. The secondary objectives are to further evaluate 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 identify potential predictive biomarkers of efficacy, to evaluate potential PD biomarkers of target engagement, biological activity, and mechanism of action, and to explore the resistance mechanisms in patients who do not respond or develop resistance.

[0159] Study Endpoints for the Safety Run-in

[0160] The primary endpoint is the safety and tolerability of the combination of Compound A and panitumumab, evaluated by the incidence and severity of AEs and SAEs (coded to System Organ Classifications (SOC) and Preferred Terms (PT) 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 examinations, ophthalmological examinations, vital signs, electrocardiograms (ECGs), echocardiograms (ECHOs), and laboratory tests. The recommended Phase 1b / 2 dose is determined based on safety, tolerability, PK, preliminary efficacy, and other available data.

[0161] Secondary endpoints include determining the pharmacokinetic characteristics of the combination of Compound A and panitumumab. This may include PK parameters, including but not limited to single dose: area under the plasma concentration curve (AUC), maximum observed plasma concentration (Cmax ) Time to reach maximum observed plasma concentration (T max ); Steady state: AUC last,ss , C max,ss and T max,ss . This may also include efficacy parameters, including 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 mitogen-activated 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 amplifications, and other aberrations in or affecting the MAPK pathway.

[0162] Study endpoints for dose escalation

[0163] The primary endpoints are 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 are: safety and tolerability assessment of AEs, physical examination, ophthalmic examination, vital signs, ECG, ECHO, and laboratory measurements as described in safety run-in; PK parameters of Compound A, including but not limited to: AUC, C max and T max ; and PK parameters of panitumumab, including but not limited to: AUC, Cmax, and Tmax.

[0164] Exploratory endpoints are predictive biomarkers of efficacy, including but not limited to mitogen-activated 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 amplifications, and other aberrations in or affecting the MAPK pathway.

[0165] Study design

[0166] This is a two-part, phase 1b study of the combination of Compound A and panitumumab in tumor patients with oncogenic K-RAS / N-RAS or B-RAF mutations in metastatic colorectal cancer (CRC) and KRAS mutations in pancreatic cancer. The combination of Compound A and panitumumab may increase anti-tumor activity in patients with CRC K-RAS / N-RAS or B-RAF and pancreatic K-RAS mutations, and address the far-from-met medical needs in these patient populations.

[0167] This safety run-in is a multicenter, open-label, multi-dose, dose-escalation study in tumor patients with oncogenic B-RAF or K-RAS / N-RAS mutations in metastatic colorectal or pancreatic cancer. Three combination dose levels are used. The Safety Monitoring Committee (SMC) evaluates safety data after patients complete at least 1 cycle of treatment and determines subsequent dose levels. The number of pancreatic patients cannot exceed one-third of the safety run-in cohort.

[0168] Dose expansion is a multicenter, open-label, multi-arm, non-comparative, indication-expansion study in metastatic colorectal cancer (approximately 20 patients) with confirmed K-RAS / N-RAS mutations and pancreatic cancer (approximately 20 patients) with confirmed KRAS mutations. Additional arms may be added to the study as recommended by the SMC and approved by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) to investigate emerging signals, if necessary.

[0169] Patients are monitored for safety, tolerability, and efficacy throughout the study from the day of the first administration of the investigational medicinal product (IMP) until 30 days after the last administration of study medication. Radiological assessments of tumor response are performed approximately every 6 (±1) weeks during the first six months, every 8 (±1) weeks thereafter, and may be adjusted to every 12 (±1) weeks after the first year. Tumor response is evaluated by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

[0170] Patients receive study medication until disease progression (PD), unacceptable toxicity, death, or another withdrawal criterion is met.

[0171] The study population consisted of adult patients with advanced or metastatic, unresectable colorectal or pancreatic cancer who had disease progression during or after at least one line of systemic therapy, or for whom such therapy was unavailable, intolerable, or refused. In the safety run-in, patients had to have a known mutation status and be histologically or cytologically confirmed to have colorectal or pancreatic cancer with an oncogenic B-RAF or K-RAS / N-RAS mutation for which no effective standard therapy was available or acceptable to patients. The number of pancreatic patients could not exceed one-third of the safety run-in cohort. In the dose expansion, patients had to have a known mutation status and be histologically or cytologically confirmed to have advanced or refractory solid colorectal cancer with an oncogenic K-RAS / N-RAS mutation or pancreatic cancer with a K-RAS mutation for which no effective standard therapy was available or acceptable to patients.

[0172] To be eligible for the study, patients had to: be able to provide written informed consent and be able to understand and comply with the study requirements; be ≥ 18 years of age (or the legal age of consent in the jurisdiction where the study was conducted) on the day of signing the informed consent form (ICF); and have advanced or metastatic, unresectable colorectal cancer with disease progression according to RECIST v1.1 during or after at least one line of systemic therapy, or for whom such therapy was unavailable, intolerable, or refused.

[0173] In addition, patients had to meet the following eligibility criteria for the corresponding part of the study. In the safety run-in, patients had to have a known mutation status and be histologically or cytologically confirmed to have colorectal or pancreatic cancer with an oncogenic B-RAF or K-RAS / N-RAS mutation for which no effective standard therapy was available or acceptable to patients. The number of pancreatic patients could not exceed one-third of the safety run-in cohort. In the dose expansion, patients had to have a known mutation status and be histologically or cytologically confirmed to have advanced or refractory colorectal cancer with an oncogenic K-RAS / N-RAS mutation or pancreatic cancer with a K-RAS mutation for which no effective standard therapy was available or acceptable to patients. Eligible patients had to further: have archived tumor tissue or consent to a tumor biopsy at baseline for mutation and biomarker analysis; have measurable disease as defined by RECIST1.1; have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at screening; have a life expectancy of ≥ 12 weeks at the time of signing the ICF; and have organ function within requirements without transfusion within 14 days of the first dose of IMP, as indicated by the following laboratory values: · Absolute neutrophil count (ANC) ≥ 1500 cells / μL · Platelets ≥ 100,000 / μL · Hemoglobin ≥ 9 g / dL or ≥ 5.6 mmol / L · Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or calculated creatinine clearance > 50 ml / min · Serum total bilirubin ≤ 1.5 × ULN (for patients with Gilbert's syndrome, total bilirubin must be < 3 × ULN) and · For patients with liver metastases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN.

[0174] In addition, if a female patient is infertile (i.e., physiologically unable to conceive), she is eligible to enter and participate in the study, including any of the following females: those who have had a hysterectomy; those who have had bilateral oophorectomy (ovariectomy); those who have had bilateral tubal ligation; or those who are postmenopausal (amenorrhea has ceased for ≥ 1 year). If a female patient is fertile and has a negative serum pregnancy test within 7 days of the first administration of IMP, is not breastfeeding, and uses a protocol-approved contraceptive method before entering the study and throughout the study until 90 days after the last dose of IMP is administered, then such patients are also eligible to enter and participate in the study. If a male patient has had a vasectomy or agrees to use a protocol-approved contraceptive method during the study treatment period and for at least 90 days after the last dose of IMP is administered, then such patients are eligible to enter and participate in the study.

[0175] Patients may be excluded if they have previously received any RAF or MEK inhibitor treatment; currently have or have a history of central nervous system (CNS) metastases; an ophthalmic examination shows a history or evidence of retinal pathology that is considered a risk factor for central serous retinopathy, RVO, or neovascular age-related macular degeneration; have any of the following RVO risk factors: · Intraocular pressure ≥ 21 mmHg · Serum cholesterol ≥ grade 2 · Hypertriglyceridemia ≥ grade 2 · Hyperglycemia (fasting) ≥ grade 2 or symptomatic · Hypertension ≥ grade 2.

[0176] Patients may also be excluded if they: have a history of glaucoma; have pulmonary fibrosis / interstitial lung disease (ILD); have a history of active parathyroid disorders or malignancy-related hypercalcemia; have had any of the following within 6 months (24 weeks) of signing the informed consent form: clinically significant heart disease (New York Heart Association class III or IV), myocardial infarction, severe / unstable angina, coronary / peripheral artery bypass grafting, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism; an LVEF ≤ 50% as assessed by multiple gated acquisition (MUGA) scan or ECHO; corrected QT interval abnormalities (male patients > 450 msec, female patients > 470 msec, or > 480 msec in patients with bundle branch block) after correction of electrolytes at screening; currently have severe, uncontrolled systemic diseases, including but not limited to clinically significant cardiovascular, pulmonary, renal diseases, or severe infections; have any unstable, pre-existing major medical conditions that the investigator deems contraindicated for the use of the IMP, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients who are positive for hepatitis B surface antigen (HBsAg) or HCV antibody at screening may be enrolled provided that the HBV DNA titer < 500 IU / mL or the HCV RNA polymerase chain reaction test is negative, respectively.

[0177] Patients may also be excluded if they: have had any CTCAE v5.0 grade 3 or higher major bleeding or bleeding event within 28 days of Day 1 of Cycle 1; have elevated serum calcium (> 1 × ULN) or serum phosphorus (> 1 × ULN) levels; are unable to swallow oral medications (capsules and tablets) without chewing, biting, crushing, opening, or otherwise altering the IMP formulation; have gastrointestinal diseases (e.g., malabsorption syndrome); are on concomitant systemic or ocular glucocorticoid therapy; are on concomitant vitamin D; have had major surgery or a severe traumatic injury within 4 weeks prior to the first dose of IMP treatment in Cycle 1, or are expected to require major surgery during the course of study treatment; are receiving concomitant medications that are potent CYP3A inhibitors; have a history of significant toxicity caused by another RAF, MEK, ERK, or anti-EGFR antibody inhibitor that required discontinuation of these medications; have previously received panitumumab and had a dose reduction; have underlying medical conditions, laboratory abnormalities, or alcohol or drug abuse or dependence that the investigator deems unfavorable for the administration of the study drug or affect the interpretation of drug toxicity or adverse events; have inadequate compliance during the study period according to the investigator's judgment; or are pregnant or lactating.

[0178] Patients may also be excluded if they have received any of the following treatments: Cyclic chemotherapy within a period shorter than the cycle length of the treatment before the start of the study treatment (e.g., 6 weeks for nitrosoureas, mitomycin-C); Biological therapy (e.g., antibodies, except bevacizumab or aflibercept), continuous or intermittent small molecule therapy, or any other study agent within a period of ≤5 half-lives (t1 / 2) or ≤4 weeks (whichever is shorter) before the start of the study treatment; Bevacizumab or aflibercept treatment within ≤3 weeks before the start of the study treatment; Radiotherapy to >30% of the bone marrow at any time point or within 28 days before the first dose of the study treatment.

[0179] The dose levels of panitumumab and Compound A in the safety run-in were · 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

[0180] 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 above 1000 mg should be administered over 90 minutes. Compound A is administered orally (PO), once daily. The recommended dose levels may be modified; additional dose levels (including higher doses) or dosing regimens may be considered. Any modification of the dose level or dosing regimen is reviewed and approved by the SMC.

[0181] The dose levels for dose expansion are to continuously administer Compound A orally (PO) once daily at the dose levels determined according to dose escalation in a 28-day cycle. In addition to the daily oral dose of Compound A, patients receive panitumumab IV every 2 weeks at the dose levels determined according to dose escalation in a 28-day cycle.

[0182] The SMC makes recommendations on the selection of the panitumumab dosing regimen based on the available safety, efficacy, PK, and exploratory data from the safety run-in. Example 2

[0183] Table 2 provides the general properties of the solid form (Form F) of Compound A used.

[0184] Table 2. General properties of the solid form (Form F) of Compound A used

[0185] A powder of Form F with a particle size of D90 < 200 μm after micronization. The material content (purity) is not less than 98.0%. Example 3

[0186] 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 and Panitumumab in Patients with Advanced or Metastatic RAS-Mutated Colorectal Cancer and Pancreatic Ductal Adenocarcinoma".

[0187] Objectives and Endpoints

[0188] Dose Escalation (Part 1)

[0189] The primary objective of Dose Escalation (Part 1) is to evaluate the safety and tolerability of the combination of Compound A and panitumumab in participants with advanced or metastatic CRC with a known mutation status and tumors harboring BRAF, KRAS, or NRAS oncogenic mutations and who have documented disease progression during or after at least 1 line of prior therapy, and to determine the MTD of the combination of Compound A and panitumumab and the RP2D of the combination.

[0190] The secondary objectives of Dose Escalation (Part 1) are to determine the PK characteristics of Compound A and any related metabolites after single-dose and multiple-dose administration of the combination of Compound A and panitumumab, and to evaluate the preliminary antitumor activity of the combination of Compound A and panitumumab.

[0191] The primary endpoints of Dose Escalation (Part 1) include: The safety and tolerability of the Compound A + panitumumab combination treatment are evaluated by the incidence of SAE and the incidence and severity of all TEAEs and adverse events of special interest (AESIs); the severity of all AEs is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0; additional safety outcomes include: · Laboratory values (hematology, clinical chemistry, thyroid function tests, coagulation, and urine analysis). · Vital signs. · Electrocardiogram (ECG) and echocardiogram (ECHO) / multigated acquisition (MUGA) results (if applicable). · Physical examination and ophthalmologic examination. · Eastern Cooperative Oncology Group (ECOG) performance status (PS). · Interruption and / or dose reduction of Compound A administration.

[0192] The MTD was determined according to a modified toxicity probability interval-2 (mTPI-2) design (Guo W, Wang SJ, Yang S, LynnH, 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 incidence of DLTs and the emerging safety and tolerability profile of the compound A+panitumumab combination.

[0193] The RP2D is based on safety, preliminary efficacy and other supplemental data from all dose-finding cohorts.

[0194] The sponsor makes recommendations on the selection of the Compound A + panitumumab dose to be evaluated as the RP2D. Both the MTD and the RP2D must be confirmed by the SMC.

[0195] Secondary endpoints for dose exploration (Part 1) are described here. For Compound A and any related metabolites, PK in plasma was assessed as described in the SOA (see Table 7). RECIST v1.1 was used to determine tumor response based on the following efficacy endpoints: ORR, defined as the proportion of participants with confirmed CR or PR who received Compound A and panitumumab; duration of response (DOR), defined as the time from the first confirmed response to the first documented progression or death from any cause (whichever occurred first) for those participants with confirmed response; DCR, defined as the proportion of participants with CR+PR+SD ≥ 24 weeks who received Compound A and panitumumab; PFS, defined as the time from the date of the first administration of study drug to the date of the first documented disease progression or death from any cause (whichever occurred first).

[0196] Dose Expansion (Part 2):

[0197] The primary objective of dose expansion (Part 2) was to determine the ORR as assessed by investigator's initial review of Compound A and panitumumab combination treatment at RP2D using RECIST v1.1.

[0198] The secondary objectives of dose expansion (Part 2) are to further evaluate the safety and tolerability of Compound A and panitumumab in patients with advanced or metastatic CRC with KRAS or NRAS mutations and in patients with advanced or metastatic PDAC with KRAS mutations who have documented disease progression during or after at least 1 line of prior therapy; to determine the ORR, as evaluated by central review of the combination therapy of Compound A and panitumumab at the RP2D using RECIST v1.1; to determine the preliminary activity of Compound A and panitumumab at the RP2D, as evaluated by the DCR initially reviewed by the investigator using RECIST v1.1; DOR; and PFS; and to further determine the PK characteristics of Compound A and any related metabolites.

[0199] The exploratory objectives of dose expansion (Part 2) are to identify potential predictive biomarkers of molecular remission of Compound A and panitumumab and to evaluate potential pharmacodynamic (PDx) biomarkers of target engagement, biological activity, and mechanism of action. The results of dose expansion may be reported separately from the final clinical study report (CSR).

[0200] Secondary endpoints

[0201] The secondary endpoints of dose expansion (Part 2) are the safety and tolerability of the combination therapy of Compound A and panitumumab at the RP2D, based on the incidence of SAE and the incidence and severity of all TEAEs and AESIs, where the severity of all AEs is graded according to NCI-CTCAE v5.0. Additional safety outcomes include: laboratory values (hematology, clinical chemistry, coagulation, and urine analysis); vital signs; ECG and ECHO / MUGA results (if applicable); physical and ophthalmologic examinations; ECOGPS; interruption and / or dose reduction of Compound A administration; ORR, defined as the proportion of participants receiving the combination therapy of Compound A and panitumumab at the RP2D who have a confirmed CR or PR; DCR, DOR, and PFS – as defined in the dose exploration part of Part 1; and determination of the plasma concentrations of Compound A and any related metabolites.

[0202] Exploratory endpoints

[0203] The exploratory endpoints of dose expansion (Part 2) are predictive and PDx biomarkers, including but not limited to markers of mutations, amplifications, transcriptions, and phosphorylation characteristics of MAPK pathway signaling evaluated in baseline tumor tissue and peripheral blood samples, and exploratory subgroup analyses, such as circulating tumor deoxyribonucleic acid (ctDNA) / serum (which may be performed if data permit), to investigate the resistance mechanisms of participants who receive the combination therapy of Compound A and panitumumab but do not respond or develop resistance.

[0204] Study plan

[0205] This is a multicenter, global, open-label, Phase 1b dose-escalation and dose-expansion study in participants with advanced or metastatic CRC and PDAC whose tumors harbor BRAF and KRAS / NRAS oncogenic mutations and who may respond to combination therapy with Compound A (a RAF dimer inhibitor) and panitumumab (an EGFR inhibitor).

[0206] Participants were recruited into the study after initial referral from an oncology center and receipt of at least 1 standard-of-care anti-cancer therapy. Eligible and consenting study participants sequentially entered the dose-escalation (Part 1) phase, followed by the dose-expansion (Part 2) phase. Part 1 of the study aimed to determine the MTD and RP2D by assessing the safety, tolerability, preliminary anti-tumor activity, and PK characteristics of the combination of Compound A and panitumumab. Part 2 of the study further evaluated the safety, PK, and assessed the preliminary anti-tumor activity of the Compound A + panitumumab combination at the RP2D.

[0207] An exploratory investigation of predictive and PDx biomarkers was conducted for both Part 1 and Part 2 of the study.

[0208] The study design is summarized in Figure 2 (by study part) and Figure 3 (by study phase).

[0209] Part 1 - Dose Escalation

[0210] Enrollment in the dose-escalation part of the study occurred in 4 planned sequential cohorts, with each dose level of Compound A administered in combination with panitumumab containing at least 3 and up to 6 evaluable participants. Dose-escalation cohort enrollment included participants with advanced or metastatic CRC with known mutation status and tumors harboring BRAF, KRAS, or NRAS oncogenic mutations and documented disease progression according to RECIST criteria during or after at least 1 line of prior therapy. Approximately 30 participants were enrolled to ensure a total of approximately 24 evaluable participants.

[0211] All participants underwent repeated 28-day treatment cycles of Compound A + panitumumab. The starting dose of Compound A was 5 mg, administered PO, QD. Panitumumab was administered at 6 mg / kg body weight by IV infusion, Q2W, and given within 60 minutes (+30 minutes) after the oral administration of Compound A on those days.

[0212] The following dose levels were used in Part 1 for evaluation of the combination: · 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

[0213] Dose Escalation and Cohort Progression

[0214] During the dose exploration part of Study Part 1, the regular safety evaluations were conducted by the SMC, which met during the dose exploration part to actively monitor and review all cumulative data, including safety and efficacy data, and all available PK and PDx data for the ongoing study. The SMC could make recommendations on early study termination or changes to the study implementation. The dose cohort size management and dose escalation decisions for Part 1 were made according to the mTPI-2 model-assisted design (Guo et al., 2017) and had to be confirmed by the SMC. The sponsor could decide to stop or adjust the study based on the SMC recommendations.

[0215] The target toxicity rate for the MTD was φ = 0.30, and the acceptable toxicity probability interval was (0.25, 0.33). The mTPI-2 design used a Bayesian statistical framework and a beta-binomial hierarchical model to calculate the posterior values of the dosing intervals to reflect the relative differences between the toxicity rates at each dose level. The unit probability mass (UPM) was 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), (0.97, 1).

[0216] Note that, except for the first and last intervals, the width of each interval was 0.08. The UPM of an interval was the posterior toxicity probability within the interval divided by the interval width (Ji et al., 2010).

[0217] The recommendations according to the mTPI-2 design were as follows: If the maximum UPM was in an interval below (0.25, 0.33), escalate to the next dose (or stay at the same dose if the current dose was the highest dose level); if the maximum UPM was within (0.25, 0.33), stay at the same dose; if the maximum UPM was in an interval above (0.25, 0.33), de-escalate to the previous safe dose. This study followed the following 2 additional safety rules (according to Ji et al., 2010):

[0218] Safety Rule 1 (Early Termination): Assume a participant is treated at Dose Level 1. If the posterior probability of toxicity greater than 0.30 exceeds 95%, the trial is terminated due to excessive toxicity.

[0219] Safety Rule 2 (Dose Exclusion): Assume a decision is made to escalate from the current Dose Level I to the next level (i + 1). If the posterior probability greater than 0.3 in Dose Level 1 exceeds 95%, then the participants in the next cohort are treated at Dose i, and Dose (i + 1) and higher doses are excluded from the study, i.e., these doses are no longer used in the study.

[0220] Before determining the dose level of the next dose - exploration cohort, it is necessary to evaluate a cohort of at least 3 participants who have completed 1 treatment cycle (up to Day 28 (inclusive)) at each dose level of Compound A in combination with panitumumab.

[0221] Table 3 shows various scenarios for the number of DLTs observed in "n" participants at a certain dose level, based on the mTPI - 2 decision table, to assist the SMC in making decisions. When deciding to maintain, escalate, or de - escalate a specific dose level of Compound A, the SMC also considers the integrity of safety and efficacy data as well as all available PK and PDx data.

[0222] If the highest planned dose level (Dose Level 4 - Compound A 30 mg PO QD+panitumumab 6 mg / kg Q2W) is determined by the SMC based on the mTPI - 2 of the estimated toxicity rate and all available data in the review study, the sponsor may consult with the SMC to propose escalating Compound A to 40 mg (based on the MTD of Compound A monotherapy) and / or an alternative dosing regimen. The maximum dose of Compound A in the dose - exploration part should not exceed 40 mg QD.

[0223] A cohort can accept the tested dose levels of Compound A, but cannot reconsider the doses related to the "dose de - escalation, unacceptable toxicity" decision, and no additional participants should be treated with that dose or higher doses of Compound A for the remainder of the trial.

[0224] Table 3. Decision Table for Compound A - EGFR - 001 Part 1 - Dose Exploration Using mTPI - 2 #DLT N＝3 N＝4 N＝5 N＝6 0 E E E E 1 D* S E E 2 D D D D 3 DU DU D D 4 DU DU DU 5 DU DU 6 DU E: Increase to the next higher dose; S: Maintain the same dose; D: Decrease to the previous lower dose; DU: Decrease to the previous lower dose and do not use the current dose again in the study. *For participants in dose level 1, enroll another participant for evaluation. Beta prior parameters: (1, 1), posterior toxicity probability of target toxicity (pt) = 0.30, toxicity equivalence interval = (0.25, 0.33); N = total number of participants administered at a given level; #DLT = total number of participants with dose-limiting toxicity

[0225] Dose-limiting toxicity

[0226] For the purpose of the tolerance decision in Part 1, DLT is defined as any AE or abnormal laboratory value that occurs within the first 28-day cycle of treatment and is evaluated to be unrelated to the underlying disease, disease progression, intercurrent disease, or concomitant medications / treatments. The severity of DLT is graded according to NCI-CTCAE v5.0. DLT must meet at least 1 of the following criteria:

[0227] Hematological DLT is: any hematological toxicity of grade ≥ 4; febrile neutropenia (defined as absolute neutrophil count (ANC) < 1000 / mm 3 , and single body temperature > 38.3 °C (101 °F) or body temperature ≥ 38.0 °C (100.4 °F) for > 1 hour); grade 3 neutropenia lasting > 7 days; grade 3 thrombocytopenia with clinically significant (CS) bleeding; or grade 3 anemia requiring transfusion according to local or international guidelines in the absence of bleeding.

[0228] Non-hematological DLTs are: any death not clearly attributable to underlying disease or external causes, and any toxicity requiring permanent discontinuation of the study drug; any non-hematological event of grade ≥4, unless otherwise specified (see below); grade ≥3 total bilirubin (TBIL; except for participants with Gilbert syndrome) or transaminases (ALT or AST); grade ≥3 skin and subcutaneous tissue disorders that do not begin to resolve within 28 days despite initiation of optimal medical and supportive treatment and protocol-specified dose management of compound A and panitumumab; grade ≥3 significant neurological toxicity (e.g., seizures, hallucinations, confusion, or delirium); grade ≥3 elevation of creatine phosphokinase (CPK) with symptoms or grade ≥2 rhabdomyolysis; grade ≥3 non-hematological treatment-related toxicities not listed above that do not resolve to ≤grade 1 within 3 days of initiation of optimal medical and supportive treatment; other clinically important or persistent toxicities may also be considered DLTs after review by the sponsor in consultation with the investigator or after review by the SMC; confirmation of the occurrence of Hy's Law or potential drug-induced liver injury (DILI) as defined by the US FDA and not explained by any other cause (e.g., viral hepatitis, exposure to other hepatotoxins), without evidence of cholestasis, and including the following laboratory abnormalities (this specific category of DLT is defined using ULN instead of NCI-CTCAE grades): · The baseline values of AST or ALT and TBIL in the participant are within the normal range, and subsequently, the AST or ALT value is ≥3 times the upper limit of normal (ULN), while the TBIL value is ≥2 times ULN and there is no evidence of hemolysis, and the ALP value is ≤2 times ULN or other results indicating no cholestasis. · For participants with baseline ALT or AST values above ULN, the AST or ALT value ≥2 times the baseline value should be used in the above definition.

[0229] In addition, any CS toxicity occurring after the specified DLT observation period at a given dose level can be considered in subsequent dose escalation and / or RP2D decisions. The following toxicities are not considered DLTs: isolated and asymptomatic grade ≥3 laboratory abnormalities not listed above, without clinical relevance and resolving to ≤grade 1 within 3 days with or without initiation of medical and supportive treatment; grade ≥3 panitumumab infusion reactions; grade ≥3 laboratory abnormalities that do not show clinical relevance or harm and are correctable (e.g., hypoalbuminemia and lymphopenia); grade ≥3 nausea, vomiting, or diarrhea that resolves to ≤grade 1 within 3 days; grade ≥3 fatigue that resolves to ≤grade 1 within 5 days; grade ≥3 asymptomatic elevation of lipase or amylase without pancreatitis that resolves to ≤grade 1 within 7 days.

[0230] Participants who experience DLTs are managed according to the guidelines for treatment adjustments due to TEAEs in this protocol.

[0231] To be considered DLT evaluable, participants must receive ≥ 80% of the assigned dose of Compound A in combination with two doses of panitumumab and remain in the study for 28 days from the administration of Compound A + panitumumab on Day 1 of Cycle 1. If a participant discontinues the study drug for any reason other than DLT and receives less than 80% of the assigned dose, that participant is replaced.

[0232] Early stopping rules

[0233] In the dose exploration part, participants' AEs, SAEs, and DLTs are carefully monitored. According to the recommendations of the mTPI-2 model-assisted design. If the lowest dose is being studied and the UPM is in the interval above (0.25, 0.33), the trial is terminated due to excessive toxicity. In addition, if the posterior toxicity probability greater than 0.30 at the lowest dose is proven to exceed 95%, the study is terminated due to excessive toxicity using Safety Rule 1. Otherwise, the study continues based on the mTPI-2 recommendations.

[0234] Maximum tolerated dose (MTD)

[0235] The MTD is determined according to the mTPI-2 model-assisted design and is based on the incidence of DLT and the emerging safety and tolerability characteristics of the Compound A + panitumumab combination. Using the mTPI-2 model, the target toxicity rate for the MTD is φ = 0.30, and the acceptable toxicity probability interval is (0.25, 0.33).

[0236] Recommended Phase 2 dose (RP2D)

[0237] The RP2D is the dose level and dosing regimen of the Compound A + panitumumab combination selected for further study in the dose expansion part of the study. The sponsor provides recommendations on the selection of the dose of Compound A + panitumumab to be evaluated. The RP2D must be confirmed by the SMC based on the safety, preliminary efficacy, and other supplementary data of all dose exploration cohorts.

[0238] Part 2 - Dose expansion

[0239] The dose expansion part of the second part of the study can only be initiated after the RP2D and dosing regimen of the dose exploration part of the first part of the study are confirmed. Participants who were enrolled in the dose exploration cohort may not be enrolled again in the dose expansion part of the study. The dose expansion part of the study evaluates the RP2D in the following groups:

[0240] Group 1: Participants with advanced or metastatic CRC with KRAS or NRAS mutations who have received prior treatment and have documented disease progression during or after at least 1 line of prior treatment according to RECIST criteria.

[0241] Group 2: Participants with advanced or metastatic PDAC with KRAS mutations who have received treatment and had documented disease progression according to RECIST criteria during or after at least 1 line of prior treatment.

[0242] Approximately 25 participants were enrolled in each expansion cohort to achieve 20 evaluable participants for efficacy in each group. All participants underwent repeated 28-day treatment cycles of Compound A + panitumumab.

[0243] Study Phases

[0244] Each study part included screening, treatment, and safety follow-up periods ( Figure 3 ). The screening, treatment, and follow-up schedules for Study Parts 1 and 2 were the same, as shown in Table 7.

[0245] Screening Period

[0246] Study screening occurred within 28 days prior to the first administration of the study drug on Day 1 of Cycle 1 of study enrollment and treatment. Informed consent (from the participant or their legally authorized representative) had to be documented before any study-specific procedures (including those for screening) were conducted.

[0247] Consenting participants who met all eligibility criteria at screening were enrolled after eligibility confirmation.

[0248] As defined in the study eligibility criteria, there was at least a washout / recovery period for prior anticancer treatments (e.g., systemic chemotherapy, radiotherapy, biotherapy, continuous or intermittent small molecule therapy, or any other study agent) and major surgery before the start of study treatment.

[0249] Baseline assessments were conducted in all participants before the first dose of the study drug. Tumor tissue had to be collected from archived tumor tissue or fresh tumor biopsies at the screening visit to determine the baseline retrospective mutation status.

[0250] For participants with easily accessible tumor lesions, it was strongly recommended to collect fresh baseline tumor biopsies for analysis at screening. Participants were selected for screening and eligibility confirmation based on the known mutation status obtained from local molecular testing results of tumor tissue samples collected at any time before screening. Blood samples were collected from all participants at baseline for biomarker analysis.

[0251] All screening and baseline assessments are outlined in Table 7.

[0252] Treatment Period

[0253] The treatment periods for the dose-escalation in Study Part 1 and dose-expansion in Study Part 2 were as follows.

[0254] Participants undergo repeated 28-day treatment cycles of compound A + panitumumab combination. Participants receive the study drug until: clinical or radiological disease progression; participants with clinical or radiological disease progression (PD) as determined by RECIST v1.1 withdraw from the study; study treatment is discontinued due to death, intolerance, or withdrawal of informed consent; 2 years of treatment are completed (unless the investigator's benefit-risk assessment supports continued treatment); at the investigator's discretion; or the sponsor discontinues the study for any reason.

[0255] All participants who discontinue study participation prematurely are to complete all required assessments, optimally at the end-of-treatment (EoT) visit. The EoT visit is preferably conducted within 7 days after the investigator determines that the study drug is no longer being used.

[0256] Participants who discontinue study treatment prematurely for reasons other than disease progression (e.g., toxicity) continue to receive tumor assessments according to the protocol's tumor response assessment schedule until the participant initiates subsequent anti-cancer treatment, experiences disease progression, withdraws consent, dies, or until the study is terminated (whichever occurs first).

[0257] Safety follow-up period

[0258] The safety follow-up period includes an in-person visit 30 (+7) days after the last dose of the study drug and another in-person visit 60 (+7) days after the last dose of panitumumab.

[0259] After the defined safety follow-up period, the investigator shall continue to report any SAEs and deaths considered related to the study drug, regardless of cause (if the investigator becomes aware of these events). Study participants who discontinued the study drug due to ≥ grade 3 drug-related AEs are followed up until the AE resolves (to ≤ grade 1, baseline, or stable) or a new anti-cancer treatment is initiated (whichever occurs first).

[0260] At the investigator's discretion, additional unplanned assessments and visits may occur if considered necessary for clinical safety reasons.

[0261] Population

[0262] Definition

[0263] Participants are formally screened under informed consent.

[0264] Screening failure is defined as a participant who consents to participate in the clinical study but does not subsequently enroll in the study intervention. To ensure transparency in reporting screening failures, meet the publication requirements of the Consolidated Standards of Reporting Trials (CONSORT), and respond to regulatory inquiries, a minimum set of screening failure information is required. The minimum information includes demographics, detailed screening failure information, eligibility criteria, and any SAEs.

[0265] Individuals who do not meet the criteria for participation in this study (screening failure) due to administrative reasons or have borderline test results may be screened again. Re-screened participants should repeat all abnormal screening tests and procedures.

[0266] Eligible consenting participants are enrolled in the study. Before enrolling participants, the following must occur:

[0267] Confirm that the participant (or LAR) has voluntarily signed the ICF.

[0268] Participants may only be enrolled if they meet all study eligibility criteria and are evaluated by the investigator as suitable candidates for participation in the study.

[0269] Prospective approval of protocol deviations from the enrollment and inclusion criteria, also known as protocol waivers or exemptions, is not permitted.

[0270] To assess any potential impact on participant eligibility in terms of safety, the investigator must refer to Compound AIB for detailed information on warnings, precautions, contraindications, AEs, and other important data related to the investigational drug used in this study.

[0271] Inclusion Criteria

[0272] Participants who meet all of the following inclusion criteria at the time of screening (and on the day of the first dose, if applicable) are eligible to participate in the study:

[0273] The participant (or LAR) has voluntarily consented to participate in the study by providing written informed consent and must be ≥ 18 years old on the day of signing the ICF.

[0274] Participants with histologically confirmed advanced or metastatic solid tumors who have documented disease progression during or after at least 1 line of prior systemic anti-cancer therapy in the representative population according to RECIST criteria, or who are unable to receive standard of care treatment as described in local guidelines.

[0275] Participants must meet the following eligibility criteria for the corresponding part of the study:

[0276] Dose Escalation: Participants with CRC with a known mutation status from local testing and whose tumors carry BRAF, KRAS, or NRAS oncogenic mutations in the archived tumor sample or fresh tumor biopsy.

[0277] Dose Expansion: Participants must have a known mutation status from local testing and meet one of the following criteria according to the cohort in which they are enrolled:

[0278] Cohort 1: Participants with CRC who carry KRAS or NRAS mutations in the archived tumor sample or fresh tumor biopsy.

[0279] Group 2: PDAC participants with KRAS mutations in archived tumor samples or fresh tumor biopsies.

[0280] Participants must provide archived tumor tissue or fresh tumor biopsies for retrospective mutation status analysis by next-generation sequencing (NGS) analysis certified by the Clinical Laboratory Improvement Amendments (CLIA) and for biomarker analysis. For participants with easily accessible tumor lesions, fresh tumor biopsies are strongly recommended at screening.

[0281] Participants must: have radiologically measurable disease as defined by RECIST v1.1 at screening; have an ECOG PS ≤ 1 at screening; have a life expectancy ≥ 12 weeks at screening according to the investigator's best judgment; baseline serum electrolytes must be within the normal range of the local laboratory, and if baseline serum electrolytes are out of range, these can be corrected and potential participants can be re-screened; adequate renal function, determined by estimated creatinine clearance; Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) ≥ 50 mL / min; TBIL ≤ 1.5 x ULN (≤ 3 x ULN for participants with Gilbert syndrome); for participants with liver metastases, AST and ALT ≤ 3 x ULN or ≤ 5 x ULN; adequate cardiac function, as determined by: · Systolic blood pressure < 160 mmHg and diastolic blood pressure < 100 mmHg, · (≤ Grade 2) despite optimal antihypertensive management, · Left ventricular ejection fraction (LVEF) ≥ 50% according to ECHO or MUGA, · No CS ECG waveform abnormalities, · QTcF ≤ 470 msec, as determined by the mean QTcF value evaluated according to ECG (three repeats) at screening,

[0282] and adequate hematological and organ function, as indicated by the following laboratory values before Day 1 of Cycle 1: ANC ≥ 1500 / mm 3 , or 1.5 x 10 9 / L; platelet count ≥ 100,000 / mm 3 , or 1.0 x 10 9 / L; hemoglobin ≥ 8 g / dL, and for hematologic function, participants must not have received blood transfusions or growth factor support ≤ 14 days prior to sample collection. Female participants are eligible to enter and participate in the study if they: are infertile; have a negative serum pregnancy test at screening (within 7 days prior to the first dose of study drug) and agree to use contraception before entering the study and throughout the study until 180 days after the last dose of study drug is administered. Male participants are eligible to enter and participate in the study if they have had a vasectomy or agree to use contraception during the study treatment and for at least 180 days after the last dose of study drug is administered.

[0283] Participants who meet any of the following exclusion criteria at screening and on the day of the first dose are not eligible for the study: female participants who are pregnant or breastfeeding; any major surgery within 4 weeks prior to Day 1 of Cycle 1; active infection requiring systemic treatment at the start of study treatment; participants who are receiving cancer treatment (chemotherapy or other systemic anti-cancer treatment, immunotherapy, radiotherapy, or surgery) on Day 1 of Cycle 1. Examples of such cancer treatments are: systemic chemotherapy within 4 weeks prior to Day 1 of Cycle 1, or nitrosourea and mitomycin C treatment within 6 weeks prior; biologic therapy (i.e., antibody), continuous or intermittent small molecule therapy, or any other study agent within 5 times the agent's half-life or within 4 weeks (whichever is shorter) prior to Day 1 of Cycle 1; and curative radiotherapy within 2 weeks prior to Day 1 of Cycle 1.

[0284] Participants who meet any of the following exclusion criteria at screening and on the day of the first dose are also not eligible for the study: any of the following cardiovascular criteria: current evidence of unstable angina or another form of symptomatic myocardial ischemia; onset of symptomatic pulmonary embolism or other CS thromboembolic disease ≤ 6 months prior to Day 1 of Cycle 1; acute myocardial infarction ≤ 6 months prior to Day 1 of Cycle 1; New York Heart Association class III or IV heart failure ≤ 6 months prior to Day 1 of Cycle 1; ≥ grade 2 ventricular arrhythmia ≤ 6 months prior to Day 1 of Cycle 1; cerebrovascular event (CVA) or ≥ grade 2 transient ischemic attack (TIA) ≤ 6 months prior to Day 1 of Cycle 1; ≥ grade 2 hypertension that cannot be managed with standard antihypertensive medications prior to Day 1 of Cycle 1.

[0285] Participants who meet any of the following exclusion criteria at the time of screening and on the day of the first dose are also ineligible for the study: syncope or seizure ≤ 6 months prior to Day 1 of Cycle 1; any major surgery within 28 days prior to Day 1 of Cycle 1; participants with toxicity that has not recovered to ≤ Grade 1 or is not stable and Grade 2 toxicity listed as allowed in other eligibility criteria; 2 - grade neuropathy without clinical relevance or isolated asymptomatic 2 - grade laboratory abnormalities may be acceptable at the discretion of the investigator in consultation with the medical monitor; participants with a history of pneumonia or interstitial lung disease; participants with immune - related toxicities (including myositis, cutaneous toxicity, colitis, and myocarditis) that have not resolved after appropriate management (i.e., thyroid replacement or diabetes management) after discontinuation of checkpoint inhibitors; a history of gastrointestinal diseases or other conditions known to interfere with drug absorption or the presence of gastrointestinal diseases or other conditions that interfere with drug absorption; a history of ulcerative colitis or Crohn's disease, or persistent immune - mediated diarrhea after long - term use of prior checkpoint inhibitors; a history of corneal perforation, keratitis, or severe dry eye; current evidence of symptomatic CNS metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Asymptomatic brain metastases, treated or untreated, are permitted if the investigator determines that the participant is clinically stable; any active malignancy ≤ 3 years prior to Day 1 of Cycle 1, except for the specific cancer being studied in this trial and any local or non - invasive cancer that has been cured by definitive treatment (e.g., resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast); any unstable, pre - existing major medical condition that the investigator deems contraindication to the study drug, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; participants who are positive for hepatitis B surface antigen (HBsAg) or HCV antibody at screening may be enrolled provided that the HBV deoxyribonucleic acid (DNA) titer < 500 IU / mL or the HCV ribonucleic acid (RNA) polymerase chain reaction test is negative; participants with HIV infection at screening may be enrolled provided that the CD4+ T - cell (CD4+) count ≥ 350 cells / μL; known hypersensitivity to RAF inhibitors, anti - EGFR monoclonal antibodies, or their excipients; a history of ≥ Grade 3 toxicity lasting > 14 days caused by any known other RAF, MEK, ERK, or anti - EGFR antibody inhibitor that required discontinuation of these drugs; a history of solid organ transplantation requiring anti - rejection medications; psychological, familial, social, or geographical conditions that may interfere with protocol compliance; deemed unfit for the study by the investigator after medical interview, physical examination, and / or screening study; receipt of any prohibited drugs listed in the protocol or anticipation of the need for any of these drugs; concurrent participation in another therapeutic clinical trial; receipt of any potent CYP3A4 inhibitor or inducer treatment ≤ 14 days (or 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.

[0286] Study Limitations

[0287] Contraception Requirements

[0288] Any participant who becomes pregnant during the study must immediately discontinue further study drug treatment.

[0289] Fasting and Dietary Restrictions

[0290] Participants do not need to fast before blood samples are collected for safety laboratory tests.

[0291] For Part 1 and Part 2, Compound A is orally administered 1 hour before a meal or 2 hours after a meal every dosing day during treatment.

[0292] Grapefruit and grapefruit juice, limes, pomelos, exotic citrus fruits, or grapefruit hybrids are not permitted within 14 days before the start of study treatment, during treatment, and until the EoT visit. There are no other dietary restrictions.

[0293] Other Lifestyle Restrictions

[0294] Exposure to sunlight can exacerbate skin toxicities associated with Compound A and panitumumab treatment. Participants are advised to apply sunscreen, wear a hat, and limit sun exposure while receiving study drug treatment.

[0295] Prior and Concomitant Treatments

[0296] Cancer treatments or procedures (chemotherapy or other systemic anticancer treatments, immunotherapy, radiotherapy, or surgery) are prohibited or restricted during the study from Cycle 1 Day 1 and until the completion of the study treatment period as follows: systemic chemotherapy within 4 weeks before Cycle 1 Day 1 and until the completion of the treatment period, or nitrosourea and mitomycin C treatments within 6 weeks before; biologic therapies (i.e., antibodies), continuous or intermittent small molecule therapies, or any other study agent within 5 times the agent's half-life or 4 weeks (whichever is shorter) before Cycle 1 Day 1 and until the completion of the treatment period; any major surgery within 4 weeks before Cycle 1 Day 1 and until the completion of the treatment period.

[0297] The following treatments are prohibited or restricted during the study: any major surgery within 4 weeks prior to Day 1 of Cycle 1 up to the completion of the treatment period; long-term systemic or ocular glucocorticoid therapy within 14 days prior to the start of study treatment and up to the completion of the treatment period, except for the following: physiological or stress doses of steroids (when indicated for participants with endocrine deficiencies); corticosteroids as premedication for blood product infusions; corticosteroids as pulse therapy for acute allergic reactions or bronchospasm; inhaled corticosteroids for asthma and reactive airway disease; oral or IV corticosteroids for up to 6 consecutive days after consultation with the medical monitor and / or ophthalmologist when used to manage AEs (e.g., ≥ Grade 3 thrombocytopenia).

[0298] The following treatments are prohibited or restricted during the study: platelet or blood transfusions for the treatment of thrombocytopenia within 14 days prior to the start of study treatment and during the DLT period (Cycle 1), provided that after the specific thrombocytopenia event has been determined to be a DLT, the investigator may, at their discretion, permit platelet or blood transfusions for the treatment of thrombocytopenia; red blood cell (RBC) or blood transfusions or erythropoietin (EPO) for the treatment of anemia within 14 days prior to the start of study treatment and during the DLT assessment period (Cycle 1), provided that if chronic anemia has persisted within 28 days prior to the start of study treatment, the investigator may, at their discretion, permit RBC or blood transfusions for the treatment of anemia; 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 assessment period (Cycle 1); potent CYP3A4 inhibitors and inducers within 14 days prior to the start of study treatment and during the treatment period up to the completion of the treatment period (see Table 4); CYP2C8 or CYP2C9 substrates with a narrow therapeutic range during the treatment period up to completion (see Table 5).

[0299] If the EPO dose has been stable within 28 days prior to the start of study treatment, the investigator may, at their discretion, permit EPO for the treatment of anemia.

[0300] The following treatments are also prohibited or restricted during the study: Herbal medicines known to potentially interfere with liver or other vital organ functions (i.e., hypericin) or those that are potent CYP3A4 inhibitors from 14 days before the start of study treatment until the completion of the treatment period; Live and live attenuated vaccines are prohibited (within 4 weeks before the start of study treatment), including intranasal influenza vaccine and monkeypox vaccine; And the COVID-19 vaccination schedule must be completed at least 2 weeks before the start of study treatment. COVID-19 vaccination is prohibited during DLT (Cycle 1), but is allowed from Day 1 of Cycle 2 until the end of the study. However, the investigator may decide at their discretion to temporarily suspend treatment (1 - 2 days before and / or after each dose of vaccine). Note: Influenza vaccine is allowed at any time before and during the trial.

[0301] COVID-19 treatment with PAXLOVID (nirmatrelvir + ritonavir) is contraindicated for use with drugs that are highly dependent on CYP3A clearance; as shown by in vitro data, Compound A is primarily metabolized via the CYP3A pathway.

[0302] The following radiotherapy is prohibited or restricted during the study: Prior curative radiotherapy is prohibited within 2 weeks before Day 1 of Cycle 1; Concomitant radiotherapy for tumor lesions selected as target lesions is prohibited from the start of study treatment and until the completion of the treatment period. At any time before the start of study treatment and during treatment, the investigator may, at their discretion, allow prior and concomitant palliative radiotherapy for non-target tumor lesions.

[0303] Table 4. Potent CYP3A4 Inhibitors and Inducers

[0304] Abbreviation: CYP3A4 = Cytochrome P450, family 3, subfamily A, member 4.

[0305] The presented list of drugs is not exhaustive. Please refer to the prescribing information of concomitant medications to view CYP3A4 inhibition / induction risk or contact the study medical monitor.

[0306] Table 5. CYP2C8 and CYP2C9 Substrates

[0307] Abbreviations: CYP2C8 = Cytochrome P450, family 2, subfamily C8; CYP2C9 = Cytochrome P450, family 2, subfamily C94; NSAID = Nonsteroidal anti-inflammatory drug. * CYP2C8 substrate with a narrow therapeutic range. ** CYP2C9 substrate with a narrow therapeutic range.

[0308] The presented list of medications is not exhaustive. Refer to the prescribing information accompanying the medications to view CYP2C8 or CYP2C9 substrates or contact the study medical monitor.

[0309] Study duration and length of participation

[0310] Each study part includes a screening, treatment, and safety follow-up period. The screening, treatment, and follow-up schedules are the same for both study parts, as shown in the SOA (Table 1). The screening period is the time between signing the informed consent and the first administration of the study medication (up to 28 days). The treatment periods for the dose exploration and dose expansion parts of the study are as follows: · Participants undergo repeated 28-day treatment cycles of Compound A + panitumumab combination. · Participants receive the study medication until: · Clinical or radiological disease progression. · Participants who have clinical or radiological disease progression (PD) according to RECIST v1.1 withdraw from the study. · Study treatment is stopped due to death, intolerance, or withdrawal of study consent. · 2 years of treatment are completed (unless the investigator's benefit-risk assessment supports continued treatment). · The investigator's decision; or · The sponsor stops the study for any reason.

[0311] All participants who stop their study participation early complete all required assessments at the end-of-treatment (EoT) visit, if possible. Optimally, the EoT visit is conducted within 7 days after the investigator determines that no further study medication will be used.

[0312] Participants who stop study treatment early for reasons other than disease progression (e.g., toxicity) continue to receive tumor assessments according to the protocol's tumor response assessment schedule until the participant starts subsequent anti-cancer treatment, experiences disease progression, withdraws consent, dies, or until the study is terminated (whichever occurs first).

[0313] The safety follow-up period includes a follow-up site visit 30 (+7) days after the last dose of the study medication and another visit 60 (+7) days after the last dose of panitumumab.

[0314] Note: After the defined safety follow-up period, the investigator should continue to report any SAEs and deaths considered related to the study medication, regardless of the cause (if the investigator becomes aware of these events). Study participants who discontinue the study medication due to ≥ Grade 3 drug-related AEs are followed up until the AE resolves (to ≤ Grade 1, baseline, or stable) or a new anti-cancer treatment is started (whichever occurs first).

[0315] At the discretion of the investigator, additional unplanned assessments and visits may occur if deemed necessary for clinical safety reasons.

[0316] Study Product, Dosage, and Administration

[0317] The study drugs include Compound A and panitumumab.

[0318] All participants will undergo repeated 28-day treatment cycles of Compound A + panitumumab.

[0319] Two (2) weeks prior to the start of study treatment, during the screening period, prophylactic management should be initiated, including moisturization, sun protection, oral antibiotics, and topical steroids.

[0320] Compound A

[0321] Compound A is provided in the form of an oral, solid immediate-release capsule formulation in strengths of 5 mg and 10 mg.

[0322] Compound A capsules are packaged in high-density polyethylene (HDPE) bottles and should be stored under the conditions specified on the label. The storage conditions of Compound A are supported by drug product stability data. In the dose-escalation part of the study, the starting dose of Compound A is 5 mg, administered orally, QD. The maximum dose of Compound A should not exceed 40 mg QD. Compound A is administered orally 1 hour before breakfast or 2 hours after a meal every day during treatment.

[0323] Panitumumab

[0324] Panitumumab (Vectibix - Amgen) is provided in sterile, single-use vials and is administered by IV infusion via an infusion pump at 6 mg / kg body weight, Q2W. Prior to infusion, panitumumab should be diluted in 9 mg / mL (0.9%) sodium chloride injection to a final concentration not exceeding 10 mg / mL. Panitumumab must be administered via a peripheral line or an 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. If the first infusion is tolerated, subsequent infusions can be administered within 30 to 60 minutes. Doses above 1000 mg should be infused over approximately 90 minutes. If an infusion-related reaction occurs, it may be necessary to reduce the infusion rate.

[0325] The panitumumab infusion should be initiated within 60 minutes (+30 minutes) after the oral administration of the Compound A capsule. Refer to the Summary of Product Characteristics (SmPC) and the United States (US) Prescribing Information (PI) for panitumumab for all preparation and administration instructions.

[0326] Safety Assessments

[0327] Physical Examinations

[0328] A complete and abbreviated symptomatic physical examination is performed by a licensed physician at the time points specified in the SOA (Table 7). The complete physical examination includes an assessment of 1) head, eyes, ears, nose, and throat, 2) cardiovascular, 3) skin, 4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) nervous systems. The limited symptomatic examination is performed at the specified time points or when there are clinical indications. Abnormalities observed at baseline are recorded on the history and baseline condition eCRF. At subsequent visits, new or worsening CS abnormalities are recorded on the AE eCRF.

[0329] Potential skin toxicity is evaluated as part of the physical examination and the characteristics and grading of the rash are attached. Any abnormalities found at baseline are recorded on the history eCRF with the appropriate disease / condition term attached. New or worsening CS abnormalities must be recorded as an AE in the eCRF.

[0330] If the investigator deems it necessary, physical examinations can be performed at multiple unscheduled time points.

[0331] Vital signs

[0332] Vital signs include measurements of body temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) after the participant has been sitting quietly for at least 5 minutes. Pulse oximetry should also be performed and recorded. Blood pressure and heart rate measurements are evaluated using a fully automated device. Manual techniques are used only when the automated device is unavailable. Body temperature is measured using a tympanic thermometer.

[0333] Electrocardiogram monitoring

[0334] A 12-lead ECG is performed at screening and during treatment on Day 1 of Cycle 1, Day 8 of Cycle 1, and within 60 minutes before dosing on Day 1 of Cycle 2 and 2 to 4 hours after Compound A administration (see Table 7). Multiple time points of ECG are not required after Day 1 of Cycle 2, but can be obtained if there are clinical indications. ECG is required at EoT and during safety follow-up. To reduce false readings, every effort should be made to perform three repeated ECGs with a 1- to 2-minute interval between ECG readings; however, a single ECG is permitted if necessary, i.e., due to a public health emergency. When performing an ECG, the participant assumes a supine or semi-recumbent position for at least 5 minutes before the reading is taken. Heart rate, PR, QRS, QTcF, RR, and the result interpretation are recorded. If the investigator deems it necessary, additional ECG monitoring can be performed at other times. When ECG assessment is performed simultaneously with any other study procedure at the same time point, ECG must be performed first, followed by vital signs, and then blood sample collection, and the blood sample is collected at the nominal time.

[0335] For safety monitoring purposes, the investigator or designated person must review all ECG tracings and sign and date them. The investigator or designated person will classify the overall ECG results as normal, or as abnormal with no clinical significance (NCS) or as CS abnormal. All CS abnormal ECG results must be reported as an AE or SAE. The paper or electronic copies of the ECG tracings are kept at the study center as part of the participant's permanent study file.

[0336] Central review

[0337] This study uses a central ECG laboratory. Calibrated ECG machines are provided to the study centers, and ECG tracings are collected from the study centers for centralized review and data recording.

[0338] Assessment of left ventricular ejection fraction

[0339] Left ventricular ejection fraction should be assessed at screening using ECHO or MUGA scan, which constitutes the baseline assessment. During the study, follow-up assessments should be performed whenever a participant shows signs or symptoms that may be related to heart failure (such as shortness of breath, exercise intolerance, and peripheral edema). The left ventricular ejection fraction assessments planned during safety follow-up should use the same modality as the baseline assessment performed at screening.

[0340] Ophthalmic examination

[0341] Real-world data show that BRAF inhibitors can cause ocular adverse 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 that RAF dimer inhibitors as a class of treatments or specifically the treatment with compound A (i.e., based on emerging data from ongoing clinical studies of compound A) may lead to an increased incidence of ocular AEs, a complete ophthalmic evaluation including visual acuity, intraocular pressure (provided numerically), slit lamp examination, cup-to-disc ratio, dilated fundus examination, and optical coherence tomography (OCT) is recommended as per the instructions of this study. Other methods (e.g., fluorescein angiography, etc.) can also be performed if indicated by the investigator, optometrist, or ophthalmologist. A complete ophthalmic examination should be performed at screening and approximately every 8 (±1) weeks within the first 12 months from the first dose of the study drug during the study period and approximately every 12 (±1) weeks in the second year. If a participant remains in the study for more than 2 years, the examination can be performed approximately every 16 (±2) weeks. If a participant reports new visual disturbances such as decreased central vision, blurred vision, or loss of vision, an immediate ophthalmic evaluation and follow-up as needed are required. Participants wearing contact lenses should be evaluated for any signs or symptoms of keratitis. Any CS findings and symptoms, including those confirmed by an ophthalmologist, must be reported as AEs.

[0342] During the entire study period, ECOG PS assessment is required at the time points shown in the SOA (see Table 7). Clinical laboratory safety assessments can be performed locally, and the results and local laboratory normal values should be entered into the eCRF. Blood samples for laboratory evaluations (serum chemistry, hematology, coagulation, and thyroid function) and urine analysis are collected at the time points specified in the SOA (see Table 7) and analyzed by the local laboratory at the study center. If safety laboratory screening tests are performed >96 hours before the first administration of the study drug on Day 1 of Cycle 1, these tests should be repeated and reviewed within 48 hours before the first administration of the study drug.

[0343] Blood samples for monitoring CPK are collected at screening; on Days 1, 8, and 15 of Cycle 1; on the first day of each subsequent treatment cycle starting from Cycle 2; and at the EoT visit and safety follow-up visits.

[0344] All participants should be monitored for electrolytes (for hypomagnesemia and hypocalcemia) during panitumumab treatment and for 8 weeks after completion of panitumumab treatment.

[0345] Blood samples for assessing coagulation parameters are taken at screening; on Day 1 of Cycle 1; then on Day 1 of each cycle (only if the participant is receiving anticoagulants) and when there are clinical indications.

[0346] Blood samples for assessing thyroid function are taken at screening and on Day 1 of every 3rd cycle starting from Cycle 4 after baseline (Cycle 4, Cycle 7, Cycle 10, etc.). The local laboratory checks thyroid function based on the analysis of thyroid-stimulating hormone (TSH), free T3, and free T4.

[0347] If the investigator deems it necessary, additional blood collections can be performed at other times in collaboration with the sponsor for safety laboratory tests, i.e., for repeat laboratory or safety evaluations, including follow-up of AEs.

[0348] Participants do not need to fast before blood sampling for safety laboratory tests. Detailed instructions on specimen handling and processing are provided in the study laboratory manual.

[0349] Serology

[0350] Hepatitis B surface antigen (HBsAg), anti-HBsAg antibody, hepatitis core antibody (HBcAb), and HCV serology are detected at screening. In addition, for participants who are HBsAg positive or HCV antibody positive at screening, viral load assessments (HBV DNA or HCV RNA) are performed respectively.

[0351] In participants known to have HIV, CD4+ T cell counts should be performed at screening.

[0352] Human chorionic gonadotropin (HCG) pregnancy test

[0353] A serum pregnancy test must be performed and recorded as negative within 7 days before the first administration of the study drug. A negative pregnancy test (serum or urine test) must be recorded within 2 days before starting treatment on Day 1 of each subsequent cycle. Serum pregnancy tests are performed at the EoT visit (and in case of early discontinuation of study participation) and at the planned safety follow-up visit 30 + 7 days after the last dose of the study drug. If the urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. For amenorrheic female participants, postmenopausal status is confirmed and recorded by verifying FSH levels at screening (if applicable).

[0354] Tumor response assessment

[0355] Tumor remission (anti-tumor efficacy) is evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), with CT being the preferred modality (chest with or without contrast, abdomen and pelvis with oral contrast unless contraindicated). Positron emission tomography / CT (PET / CT) is permitted as an additional assessment if so directed by the investigator. Throughout the study, the same imaging modality and imaging procedures used at screening to evaluate the disease site are required (i.e., the same contrast agent protocol is used for scanning).

[0356] Tumor imaging is performed approximately every 8 (±1) weeks within 28 days prior to the first administration of the study drug and during the study within the first 12 months from the first dose of the study drug, and approximately every 12 (±1) weeks in the second year. If a participant remains in the study for more than 2 years, scans may be performed approximately every 16 (±2) weeks. In addition, participants must undergo a brain CT / MRI scan at screening to confirm the presence of CNS metastases. Participants with CNS metastases at baseline should have brain CT / MRI follow-up according to the scan schedule.

[0357] Tumor remission and progression of the cancer under study are evaluated using RECIST v1.1. RECIST criteria are preferred when making decisions regarding participant treatment and discontinuation. Participants found to have clinical or radiological PD according to RECIST v1.1 criteria will discontinue study treatment.

[0358] Participants who discontinue study treatment prematurely for reasons other than disease progression as defined by RECIST (e.g., toxicity) continue to undergo tumor assessments according to the tumor remission assessment schedule (see Table 7) until the participant initiates subsequent anti-cancer treatment, experiences disease progression, revokes consent, dies, or until the study is terminated (whichever occurs first).

[0359] Central review

[0360] Study imaging (including CT and / or MRI) should be performed at a qualified imaging facility according to the schedule in the SOA (see Table 7). For all participants in the dose expansion part, the study site will submit all CT and / or MRI scans to the central imaging core laboratory for central imaging review. The purpose of the central imaging review is to conduct an independent, unbiased, and objective review of the CT and MRI data. The study site will receive an imaging acquisition manual and an imaging submission manual, which describe the imaging methods and submission procedures that must be followed. All image data submitted to the central imaging core laboratory must be de-identified prior to submission. Throughout the study, the participant identification information on the imaging data must be consistent with all study-related documents. The investigator can obtain detailed information on de-identification requirements from the provided imaging manual at any time.

[0361] Pharmacokinetic assessment

[0362] Blood samples were obtained and processed at the time points shown in the PK sampling schedule (see Table 7) according to the instructions provided in the study laboratory manual for plasma PK analysis of Compound A and any relevant metabolites (if applicable). The PK of panitumumab can be evaluated in this study.

[0363] PK samples for quantification of Compound A and any relevant metabolites (if applicable) were collected on Day 1 of Cycle 1 and Day 1 of Cycle 2. On Day 1 of Cycle 1 and Cycle 2, blood samples for PK analysis were collected before dosing of Compound A and 2 to 4 hours after dosing of Compound A. Starting from Cycle 3, blood samples for PK analysis were collected before dosing of Compound A on Day 1 of each treatment cycle to determine steady-state Ctrough.

[0364] The PK sample collection times may be changed and / or PK samples may be collected at additional time points to ensure appropriate PK monitoring. The actual collection time of each sample must be recorded in the source data, on the collection tube, and in the eCRF and provided to the bioanalytical laboratory.

[0365] The concentrations of Compound A and any relevant metabolites (if applicable) in plasma were determined by an accredited laboratory using appropriately identified and validated chromatographic methods.

[0366] The bioanalytical laboratory managed the transportation, storage, and handling of samples for PK analysis. An instruction manual and supply kit were provided for all PK assessments.

[0367] Pharmacodynamic assessment

[0368] Mutation status for study eligibility

[0369] Tumor tissue must be collected from archived tumor tissue or fresh tumor biopsies at the screening visit to determine the baseline retrospective mutation status. Participants were selected for screening and eligibility confirmation based on the known mutation status obtained from local molecular testing of tumor tissue samples collected at any time prior to screening. CRC participants with known mutation status and tumors carrying BRAF, KRAS, or NRAS oncogenic mutations were enrolled in Part 1 of the study. CRC participants with KRAS or NRAS mutations and PDAC participants with KRAS mutations were enrolled in Part 2 of the study.

[0370] For participants with easily accessible tumor lesions, it is strongly recommended to collect fresh baseline tumor biopsies for analysis at screening. The mutation status of all study participants was determined locally using fresh or archived tissue at any time prior to screening.

[0371] Retrospective confirmatory mutation analysis

[0372] Mutation results from local molecular testing and analysis must be confirmed by central testing and analysis. Confirmatory mutation testing should be performed at the central laboratory at any time during the study to support the analysis of study data. Whenever possible, the tumor samples tested locally should be the same as those tested centrally.

[0373] Definitive central laboratory mutation results (positive or negative) cannot be repeated. If it is determined that the sample is insufficient or the central test result is inconclusive, an additional sample can be submitted to the central laboratory for retesting. If the local and central laboratory results are inconsistent, or the local results cannot be confirmed by the central laboratory (e.g., insufficient sample or poor sample quality), as determined by the investigator in consultation with the sponsor's medical monitor, participants can continue to receive study treatment as long as there is no clinical deterioration or disease progression and the participants are benefiting from the study treatment. In such cases, the participants will be informed as soon as possible that their mutation status has not been confirmed and will be provided with information on follow-up procedures and alternative treatment options.

[0374] Based on the total and viable tumor content, the tumor tissue should be of good quality. Fine needle aspiration, brushing, pleural effusion cytospin, and lavage samples are not acceptable.

[0375] 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 accessed under CT guidance). Acceptable fresh biopsy samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or biopsy forceps biopsies for skin, subcutaneous, or mucosal lesions. If a biopsy is performed, 3 - 5 appropriately sized tissue cylinders should be obtained for histological examination and biomarker analysis. At least 3 cores are required for each biopsy.

[0376] Send freshly collected tumor biopsies (if any) and archived tumor tissue (the tissue should be formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides) to the central laboratory for mutation analysis. The gene panel evaluated by the central laboratory for baseline mutation testing for retrospective confirmatory analysis is described in the laboratory manual.

[0377] Blood sampling for biomarker analysis

[0378] Collect peripheral whole blood samples at the time points shown in Table 7 for the analysis of PDx biomarkers, including but not limited to mutations, amplifications, transcriptions, and / or phosphorylation alterations in the MAPK pathway signaling. The central laboratory manages the transportation, storage, and handling of tumor tissue and blood samples used for biomarker assessment. The methods for sample processing and testing can be readily obtained from common knowledge in the art.

[0379] Blood samples were also collected for the analysis of the following tumor prognostic biomarkers in the serum samples of the participants: carcinoembryonic antigen (CEA) in all Part 1 dose-escalation cohorts and Part 2 dose-expansion Group 1 (CRC participants with KRAS or NRAS mutations); and carbohydrate antigen 19-9 (CA19-9) only in Part 2 dose-expansion Group 2 (PDAC participants with KRAS mutations).

[0380] All blood samples for the analysis of tumor prognostic biomarkers were collected before the administration of the study drug during the treatment period and at other time points shown in Table 7. These blood samples were analyzed locally.

[0381] Statistical Methods and Sample Size Determination

[0382] The statistical methods are outlined in the Statistical Analysis Plan (SAP), which was finalized before the final database lock. The study results are presented by study part and dose-level cohort / group (where applicable). The study results can be listed by participant (where applicable). Generally, for the summary of continuous data, descriptive statistics (mean, standard deviation, median, minimum, and maximum) are calculated, and for the summary of discrete / categorical data, frequency counts and percentages (where applicable) are calculated. If a participant has missing or unexplained safety, efficacy, PK, or PDx data, or the participant withdraws from the study for reasons other than toxicity during the DLT period, the investigator, after consultation with the sponsor, may enroll an additional participant to replace the missing information and maintain the planned analysis sample size. Baseline is defined as the last non-missing evaluable measurement obtained before the administration of the study drug on Day 1 of Cycle 1. No formal evaluation of statistical hypotheses was conducted in this study.

[0383] Population

[0384] Sample size selection based on dose escalation (Part 1):

[0385] The sample size for Part 1 consisted of approximately 24 evaluable participants. Under the guidance of the mTPI-2 model-assisted design, the actual sample size depends on the number of dose-escalation cohorts.

[0386] Dose expansion (Part 2):

[0387] The cumulative initial goal for the study dose-expansion part was to have 20 evaluable participants in each of Group 1 (CRC patients who had received treatment, had documented disease progression according to RECIST criteria during or after at least 1 line of prior treatment, and had KRAS or NRAS mutations) and Group 2 (PDAC patients who had received treatment, had documented disease progression according to RECIST criteria during or after at least 1 line of prior treatment, and had KRAS mutations).

[0388] Dose expansion cohorts 1 and 2 are evaluated separately. If promising preliminary efficacy results (e.g., based on higher ORR or longer PFS) are observed in one of the cohorts after treatment of all planned participants, additional participants may be added to the relevant cohort for further evaluation of efficacy prior to entry into Phase 2 / 3 clinical development.

[0389] Analysis population

[0390] The study-defined analysis populations are presented in Table 6.

[0391] After database lock and prior to unblinding of the final analysis, it is determined whether participants are included in each analysis population.

[0392] Table 6. Analysis populations

[0393] Statistical analysis

[0394] Safety analysis

[0395] Safety in Parts 1 and 2 is determined by AE reports and safety laboratory values (hematology, clinical chemistry, thyroid function tests, coagulation, and urine analysis). Vital signs, ECG and ECHO / MUGA scan (if applicable) results, physical examinations, and ophthalmological examinations, as well as ECOGPS, are also used to determine the safety profile of the combination of Compound A + panitumumab. The safety population is used to summarize safety endpoints.

[0396] The incidence of AEs is presented as the number (percentage) of participants with treatment-emergent AEs (TEAEs), where TEAEs are listed by System Organ Class (SOC) and Preferred Term (PT) using the most recent regulatory activity medical dictionary (MedDRA) available at the start of the study. In addition, the proportion of subjects with treatment interruption or dose reduction of Compound A or panitumumab due to TEAEs is summarized. For laboratory parameters, ECG, ECHO / MUGA scan (if applicable), and vital signs, descriptive summary statistics are determined (i.e., for continuous variables, n, mean, standard deviation, median, minimum, maximum; for categorical variables, n [%]) and changes relative to baseline.

[0397] For shifts in ECOGPS relative to baseline, frequency counts and percentages are used to summarize descriptively at the planned time points in the protocol. Newly occurring or worsening CS abnormalities found on physical examination are recorded as AEs and are not summarized or listed separately. For ophthalmological examinations, the overall assessment by the ophthalmologist (normal, no clinically significant (NCS) abnormalities, CS abnormalities) is summarized. If the ophthalmologist's findings are abnormal in only one eye, the results of the overall eye examination are summarized as abnormal. For each examination method, the results of the ophthalmological examination are listed by participant and eye.

[0398] In addition, for Part 1, the MTD was determined according to the mTPI-2 design and based on the DLT incidence in the first 28 days before Cycle 1. This analysis was conducted for the DLT-evaluable population. At the end of Part 1, the dose with the smallest difference between the posterior mean of the ordered-transformed toxicity probability and the target toxicity rate among the doses with a posterior toxicity probability greater than 0.30 was selected as the MTD.

[0399] In the dose-escalation part, the AEs / SAEs of the participants were carefully monitored. The recommendations according to the mTPI-2 design were followed, and if the lowest dose was being studied and the maximum UPM was in the interval above (0.25, 0.33), the trial was terminated due to excessive toxicity. In addition, Safety Rule 1 was used to terminate the study, where if the posterior toxicity probability greater than 0.30 at the lowest dose exceeded 95%, the trial was terminated due to excessive toxicity. Otherwise, the study was continued using the mTPI-2 recommendations and Safety Rule 2.

[0400] Efficacy Analysis

[0401] The efficacy analyses for Part 1 and Part 2 were conducted for the mITT population. The efficacy endpoints based on the response assessments using RECIST v1.1 (i.e., ORR, DOR, DCR, and PFS) were summarized to evaluate the anti-tumor activity of the combination of Compound A + panitumumab.

[0402] ORR was defined as the proportion of participants with a confirmed CR or PR. DOR was defined as the time from the first determination of response to the first record of progression or death due to any cause (whichever occurred first) among those participants with a confirmed response. DCR was defined as the proportion of participants with a best overall response (BOR) of confirmed CR, PR, or SD ≥ 24 weeks. PFS was defined as the time from the first administration of the study drug to the first record of disease progression or death due to any cause (whichever occurred first).

[0403] ORR and DCR were summarized using two-sided exact (Clopper-Pearson) 95% CIs. The time-to-event endpoints, including PFS and DOR, were analyzed by the Kaplan-Meier method. The statistical methods for the efficacy analysis were described in detail in the SAP.

[0404] The efficacy-evaluable population included all treated patients with radiologically confirmed evaluable disease at baseline and at least 1 evaluable post-baseline radiological tumor response assessment.

[0405] Pharmacokinetic Analysis

[0406] Collect PK blood samples for the quantification of Compound A and any relevant metabolites (if applicable) in plasma. Plasma concentration data for Compound A (and any relevant metabolites) may not be summarized but provided as a list. Additional PK analyses, including population PK (PopPK) analysis, may be conducted as appropriate. These analyses may be reported separately from the CSR.

[0407] If supported by data, exposure-response (efficacy or safety endpoint) analyses may be conducted. The correlation between PK and biomarker endpoints may be explored as appropriate. The results of such analyses may be reported separately from the CSR.

[0408] Pharmacodynamics and other exploratory analyses

[0409] Provide summary statistics for predictive and PDx biomarkers, including but not limited to assessing the mutation, amplification, transcription, and / or phosphorylation status of the MAPK pathway in baseline tumor tissue and peripheral blood samples. Based on the data provided, the analysis of biomarkers may be descriptive in nature.

[0410] The results of exploratory analyses may be reported separately from the CSR.

[0411] Numerous references have been cited, and the disclosures of these references are incorporated herein by reference in their entirety.

[0413] Abbreviations: AE = adverse event; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; CPK = creatine phosphokinase; CRC = colorectal cancer; CT = computed tomography; D / d = day; DLT = dose-limiting toxicity; ECG = electrocardiogram; ECHO = echocardiogram; ECOGPS = Eastern Cooperative Oncology Group performance status; EoT = end of treatment; FSH = follicle-stimulating hormone; IV = intravenous; MRI = magnetic resonance imaging; MUGA = multigated acquisition; PDx = pharmacodynamics; PDAC = pancreatic ductal adenocarcinoma; PK = pharmacokinetics; PO = oral; Q2W = 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.

[0414] Screening: Individuals who do not meet the criteria for participation in this study (screening failure) due to administrative reasons or have borderline test results may be screened again. Re-screened participants should repeat all abnormal screening tests and procedures.

[0415] Informed consent must be documented before any study-specific procedures are conducted, including procedures for screening.

[0416] Demographics: As part of the screening procedure, year of birth, age (calculated), sex, and self-reported ethnicity / race are recorded. Female participants are evaluated as WOCBP or non-fertile women.

[0417] Medical history: Includes any history of clinically significant (CS) diseases, surgical history, and cancer history.

[0418] Eligibility criteria, medical history, and prior / current medications: Reviewed before the first administration of the study drug on Day 1 of Cycle 1, and any changes since screening are documented.

[0419] Pregnancy or FSH test: A serum pregnancy test (for fertile women (WOCBP)) must be performed within 7 days before the first administration of the study drug and documented as negative. A negative pregnancy test (serum or urine test) must be documented within 2 days before starting treatment on Day 1 of each subsequent cycle. Serum pregnancy tests are performed at the end-of-treatment (EoT) visit (and in the case of early discontinuation of study participation) and at the safety follow-up visit (30 + 7 days after the last dose of the study drug). If the urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. For amenorrheic female participants, postmenopausal status is confirmed by measuring follicle-stimulating hormone (FSH) levels (> 30 IU / L) at screening.

[0420] Physical examination: A complete and limited symptomatic physical examination is performed by a licensed physician. The complete physical examination includes an assessment of 1) head, eyes, ears, nose, throat, 2) cardiovascular, 3) skin, 4) musculoskeletal, 5) respiratory, 6) gastrointestinal, and 7) nervous systems. Potential skin toxicity is evaluated as part of the physical examination, and the characteristics and grading of the rash are noted. The limited symptomatic examination is performed at specified time points or when there are clinical indications. The physical examination may be performed at multiple unscheduled time points if the investigator deems it necessary.

[0421] Ophthalmological examinations: A complete ophthalmological assessment, including visual acuity, intraocular pressure (provided as a numerical value), slit lamp examination, cup-to-disc ratio, dilated fundus examination, and optical coherence tomography (OCT), should be performed at screening and approximately every 8 (±1) weeks within the first 12 months from the first dose of the study drug during the study period and approximately every 12 (±1) weeks in the second year. If the participant remains in the study for more than 2 years, the examinations can be performed approximately every 16 (±2) weeks. Other methods (e.g., fluorescein angiography, etc.) can also be performed if indicated by the investigator, optometrist, or ophthalmologist. If the participant reports new visual disturbances, such as decreased central vision, blurred vision, or vision loss, an ophthalmological assessment should be performed at any time and follow-up as needed. For participants using contact lenses, ensure that the evaluation includes a careful examination for keratitis. Any CS findings and symptoms, including those confirmed by an ophthalmologist, must be reported as AEs.

[0422] Height and weight: Height should be measured only at screening. Weight should be monitored throughout the study period and recorded at each time point using the same scale if possible.

[0423] Vital signs include measurements of body temperature (tympanic), heart rate, respiratory rate, and blood pressure (systolic and diastolic) after the participant has been sitting quietly for at least 5 minutes. Pulse oximetry should also be performed and recorded. At the scheduled visits, vital signs should be collected within 15 minutes before and 15 minutes after each study drug administration.

[0424] ECG: A 12-lead ECG should be performed at screening and within 60 minutes before dosing on Day 1 of Cycle 1, Day 8 of Cycle 1, and Day 1 of Cycle 2 during treatment, and within 2 to 4 hours after Compound A administration. An ECG is required at EoT and during safety follow-up. An ECG is not required after Day 1 of Cycle 2, but can be obtained if there are clinical indications. To reduce false readings, every effort should be made to perform three repeated ECGs with an interval of 1 to 2 minutes between the ECG readings; however, a single ECG is allowed if necessary, i.e., due to a public health emergency. When performing an ECG, the participant should assume a supine or semi-recumbent position for at least 5 minutes before the reading is taken. All ECG tracings should be reviewed by the investigator or a qualified designated person. Record the heart rate, PR, QRS, QTcF, RR, and the result interpretation. Additional ECG monitoring can be performed at other times if the investigator deems it necessary.

[0425] ECHO / MUGA: The same method should be used throughout the study period, always using ECHO or MUGA.

[0426] Viral serology: HBV and HCV testing includes HBV and HCV serology (hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and HCV antibody). In addition, for participants who are HBsAg positive or HCV antibody positive at screening, viral load assessments (HBV deoxyribonucleic acid (DNA) or HCV ribonucleic acid (RNA)) are performed, respectively. In participants known to have HIV, CD4+ T cell counts should be performed at screening.

[0427] Hematology, chemistry, and coagulation: Hematology, serum chemistry, and coagulation parameters are evaluated by the local laboratory. If the screening examination is performed more than 96 hours before the first administration of the study drug on Day 1 of Cycle 1, these examinations should be repeated and reviewed within 48 hours before the first administration of the study drug. The local laboratory evaluation can be performed up to 2 days (-2) before Day 1.

[0428] In addition: · Blood samples for monitoring creatine phosphokinase (CPK) are collected at screening; on Days 1, 8, and 15 of Cycle 1; starting from Cycle 2, on the first day of each subsequent treatment cycle; and at the EoT visit (if applicable) and safety follow-up visits. · All participants should be monitored for electrolytes (for hypomagnesemia and hypocalcemia) during panitumumab treatment and within 8 weeks after completion of panitumumab treatment. · Participants do not need to fast before collecting blood samples for safety laboratory tests.

[0429] Thyroid function tests: Local laboratory thyroid function tests are performed for thyroid-stimulating hormone (TSH), free T3, and free T4.

[0430] Urinalysis: Local laboratory evaluation of urinalysis parameters is performed.

[0431] Eastern Cooperative Oncology Group.

[0432] Tumor Imaging - Computed tomography (CT) or magnetic resonance imaging (MRI) should be performed approximately every 8 (±1) weeks during the first 28 days before the first administration of the study drug and within the first 12 months from the first dose of the study drug during the study period, and approximately every 12 (±1) weeks in the second year. CT is preferred (with or without contrast agent for the chest, and oral contrast agent for the abdomen and pelvis). If indicated by the investigator, positron emission tomography / CT (PET / CT) is allowed as an additional assessment. Scans completed within the time window but before signing the ICF can be used for baseline scans. If a participant remains in the study for more than 2 years, scans can be performed approximately every 16 (±2) weeks. The same imaging technique should be used in participants throughout the study period. In addition, participants must undergo a brain CT / MRI scan at screening to confirm the presence of CNS metastases. Participants with CNS metastases at baseline should undergo brain CT / MRI follow-up according to the scan schedule.

[0433] Tumor Tissue Biopsy: Tumor tissue must be collected from archived tumor tissue or fresh tumor biopsies at the screening visit to determine the baseline retrospective mutation status. For participants with easily accessible tumor lesions, it is strongly recommended to collect fresh baseline tumor biopsies for analysis at screening. Based on the known mutation status obtained from local molecular testing results of tumor tissue samples collected at any time before screening, participants are selected for screening and eligibility confirmation. The mutation results from local molecular testing are confirmed by testing performed at the central laboratory. Central testing is retrospective and can be performed at any time during the study. Tumor samples should be submitted in the form of formalin-fixed paraffin-embedded blocks or approximately 15 unstained slides. Whenever possible, the tumor samples for central testing should be the same as those for local testing.

[0434] Blood Samples for Monitoring Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA19-9): Blood samples for the analysis of CEA are collected in the dose exploration cohort and dose expansion group 1 (participants with colorectal cancer (CRC) carrying KRAS or NRAS mutations). Blood samples for the analysis of CA19-9 are collected only in dose expansion group 2 (participants with pancreatic ductal adenocarcinoma (PDAC) carrying KRAS mutations). All blood samples for the analysis of tumor biomarkers are collected before the administration of the study drug during treatment, and these blood samples are analyzed locally.

[0435] Study drug administration: Compound A is administered orally (PO), once daily (QD). Panitumumab is administered by intravenous (IV) infusion, once every 2 weeks (Q2W; on Days 1 and 15 of each treatment cycle), and is given within 60 minutes (+30 minutes) after oral administration of Compound A. All participants undergo repeated 28-day treatment cycles of Compound A + panitumumab. At the study visits conducted on Days 1 and 15 of each treatment cycle, the study drugs (Compound A, then panitumumab) are administered to the participants on-site. Participants are instructed to self-administer the daily dose of Compound A on all other study days during the treatment period (i.e., Days 2 - 14 and Days 16 - 28 of each treatment cycle).

[0436] PK: Blood samples for analysis of Compound A and any relevant metabolites (if applicable) in plasma are collected on Day 1 of Cycle 1 and Day 1 of Cycle 2 (before dosing and 2 to 4 hours after administration of Compound A) and on Day 1 only of each subsequent cycle (before administration of Compound A on these days).

[0437] AE and concomitant medication review: All AEs and the use of concomitant medications are queried at every interaction with the participants starting from informed consent. Participants are also instructed to inform the investigator or clinical staff of any AEs or intercurrent illnesses that occur during the trial. For the purpose of tolerance decisions in Part 1, the DLT in this study is defined as any AE or abnormal laboratory value that occurs within the first 28-day cycle of study drug treatment, is evaluated to be unrelated to the underlying disease, disease progression, intercurrent illness, or concomitant medications / treatments, and meets at least 1 criterion

[0438] DLT period: The incidence of DLT is evaluated within the first 28 days of Cycle 1 treatment with the Compound A + panitumumab combination in Part 1 (dose exploration part).

[0439] Day 22 telephone contact in Cycle 1: On Day 22 of the first treatment cycle, the AEs and the use of concomitant medications are monitored by a follow-up telephone contact (TC) between the study center staff and the study participants. If needed, after the TC, the investigator decides to schedule an on-site visit.

[0440] End of Treatment: All participants received the study drug until clinical or radiological disease progression; discontinuation of study treatment due to death, intolerance, or withdrawal of informed consent; completion of 2 years of treatment (unless the investigator's benefit-risk assessment supported continued treatment); investigator's decision; or discontinuation of the study by the sponsor for any reason. All participants who discontinued study participation prematurely completed all required assessments, to the extent possible, at the EoT visit. Optimally, the EoT visit was conducted within 7 days after the investigator determined that the study drug was no longer being used. Participants who discontinued study treatment prematurely for reasons other than disease progression (e.g., toxicity) continued to receive tumor assessments according to the protocol's tumor response assessment schedule until the participant initiated subsequent anticancer treatment, experienced disease progression, withdrew consent, died, or until the study was terminated (whichever occurred first).

[0441] Note: · The investigator or participant could request additional, unscheduled site visits at any time during the entire study. Assessments were conducted at unscheduled visits when clinically indicated. When vital signs, 12-lead ECG, and PK / PDx biomarker blood draws were scheduled at the same nominal time, the assessments should be performed in the following order: 12-lead ECG, vital signs, PK / PDx biomarker blood draw; so that the time allowed for the blood draw was at the exact nominal time. · Participants who discontinued study drug treatment prematurely for reasons other than disease progression (e.g., toxicity) continued to receive tumor assessments according to the protocol's tumor response assessment schedule until the participant initiated subsequent anticancer treatment, experienced disease progression, withdrew consent, died, or until the study was terminated (whichever occurred first).

[0442] Numerous references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. A combination, the combination comprising (i) 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 a compound A having the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof; and (ii) an anti-EGFR antibody or an antigen-binding fragment thereof.

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

3. The combination according to claim 2, wherein the anti-EGFR antibody is (a) panitumumab; or (b) an isolated human antibody, the isolated human antibody comprising a heavy chain immunoglobulin molecule and a light chain immunoglobulin molecule, the heavy chain immunoglobulin molecule comprising: 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 the light 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.

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

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

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

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

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

9. A method of treating cancer in a subject in need thereof, the method comprising simultaneously administering to the subject: (i) 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 a compound A having the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof; and (ii) an anti-EGFR antibody.

10. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject Title: 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 Compound A with the Structure of Formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof, wherein the subject has received an anti-EGFR antibody.

11. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an anti-EGFR antibody, wherein the subject has received 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 Compound A having the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof.

12. The combination or combination kit according to any one of claims 1-7, for use in treating cancer in a subject in need thereof.

13. 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 Compound A with the structure of formula (I): Use of or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is adapted to be administered together with panitumumab.

14. Use of panitumumab in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the medicament is adapted to be administered together with 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 Compound A having the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof.

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

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

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

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

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

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

21. The method, combination, combination pharmaceutical kit or use according to any one of claims 8 - 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. The method, combination, combination pharmaceutical kit or use according to 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. The method, combination, combination pharmaceutical kit or use according to claim 22, wherein the cancer is characterized by a mutation in a gene selected from NRAS, KRAS, BRAF and any combination thereof.

24. The method, combination, combination pharmaceutical kit or use according to any one of claims 8 - 15, wherein the cancer is characterized by: (i) a mutation in a gene selected from ARAF, BRAF, RAF1, KRAS, HRAS, NF1, MAP2K1, MAP2K2, MAPK1 and any combination thereof; (ii) selected from 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, BRAFS151A, 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, BRAFT241M, BRAF L245F, BRAF A246P, BRAF F247L, BRAF Q257R, BRAF Q257H, BRAF G258V, BRAFF259L, BRAF Q262R, BRAF H269Y, BRAF R271H, BRAF E275K, BRAF D287H, BRAF F294L, BRAFT310I, BRAF A320T, BRAF I326V, BRAF P341S, BRAF R347*, BRAF P348T, BRAF S363F, BRAFS364L, BRAF P367S, BRAF P367R, BRAF P367L, BRAF D380H, BRAF R389C, BRAF T401I, BRAFA404Cfs*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, BRAF G466A, BRAFG466V, 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, BRAF N581K, BRAF I582M, BRAFF583C, 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, BRAF S605A, BRAF S605F, BRAF S605E, BRAF S605G, BRAFMutations of 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) mutations selected from 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 - BRAF fusion, AKAP9 - BRAF fusion, ARMC10 - BRAF fusion, CUL1 - BRAF fusion, GTF2I - BRAF fusion, PAPSS1 - BRAF fusion, PCBP2 - BRAF fusion, PPFIBP2 - BRAF fusion, SND1 - BRAF fusion, TRIM24 - BRAF fusion, ZKSCAN1 - BRAF fusion, SEPT3 - BRAF fusion and any combination thereof; or (iv) mutations selected from 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 E132K, NRAS K135N, NRAS A146P, NRAS A146T, NRAS A146V, NRAS E162* and any combination thereof.

25. The method, combination, combination kit or use according to any one of claims 8 - 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 fusion and any combination thereof.

26. The method, combination, combination kit or use according to 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. The method, combination, combination kit or use according to 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 according to any one of claims 8 - 11, wherein the cancer is characterized by genomic aberrations in the MAPK pathway.

29. The method according to any one of claims 8 - 11, wherein compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof is administered one to three times a day.

30. The method according to any one of claims 8 - 11, wherein compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, solvate or prodrug thereof is administered once a day.

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

32. The method according to claim 31, wherein compound A or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopomer, 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 according to any one of claims 8 - 11, wherein the method provides in a subject a plasma compound AAUC 8h between about 2,128 ng*h / ml and about 45,000 ng*h / ml.

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

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

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

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

38. The method according to any one of claims 8 - 11, wherein the subject achieves disease stabilization, partial remission or complete remission.

39. The method, combination, combination kit or use according to any one of claims 8 - 38, wherein panitumumab is administered intravenously once every 14 days as an intravenous infusion at a dose of about 6 mg / kg, administered within about 60 minutes when the amount of panitumumab administered within 14 days does not exceed about 1000 mg, or administered within about 90 minutes when the amount of panitumumab administered within 14 days exceeds about 1000 mg; and compound A is administered orally once a day at a dose of 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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