Tablet formulations and uses thereof

Abstract

Provided are formulations comprising (5R,6S)-10,11-difhioro-12-((2-fhioro-4-iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-1H-spiro[benzo[b][l,5,4]oxathiazecine-3,1'-cyclopropane] 2,2-dioxide or a pharmaceutically acceptable salt or solid form thereof, methods for treating, preventing and managing diseases or disorders, such as cancer, using the same.

Description

Attorney Docket No. 14763-026-228TABLET FORMULATIONS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of International Application No.PCT / CN2024 / 133928, filed November 22, 2024; U.S. Provisional Application No. 63 / 744,073, filed January 10, 2025; U.S. Provisional Application No. 63 / 815,358, filed May 30, 2025; and U.S. Provisional Application No. 63 / 854,343, filed July 30, 2025, the disclosure of each of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are pharmaceutical formulations comprising (5R,6S)-10,l 1 -difluoro- 12- ((2-fluoro-4-iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-lH- spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide or a pharmaceutically acceptable salt or solid form thereof, and methods for preparing and using the formulations. In certain embodiments, the pharmaceutical formulations provided herein are used for treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies. In certain embodiments, provided herein are the pharmaceutical formulations provided herein for use in methods of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies.SUMMARY

[0003] In certain embodiments, provided herein are pharmaceutical compositions comprising tablets, wherein each tablet comprises (5R, 6 S)-l 0,11 -difluoro- 12-((2-fluoro-4-iodophenyl)amino)- 5,6-dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2- dioxide or a pharmaceutically acceptable salt or solid form thereof, and one or more excipients selected from a diluent, a disintegrant, a glidant, and a lubricant.

[0004] Also provided herein are methods of preparing the pharmaceutical compositions provided herein.

[0005] Further provided herein are methods of treating and managing various diseases or disorders comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition provided herein.

[0006] In certain embodiments, provided herein are methods of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, comprising administering a pharmaceutical composition provided herein.1NAI-5006806042vlAttorney Docket No. 14763-026-228

[0007] In certain embodiments, provided herein is a pharmaceutical composition for use in the methods of treating and managing diseases or disorders provided herein.

[0008] In certain embodiments, the pharmaceutical composition provided herein is used for oral administration in a subject for treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies.

[0009] Further provided herein are methods of preparing a tablet comprising: i) screening the excipients (except lubricant); ii) blending intra-granular components to obtain an intragranular blend, ii) roller compacting the intra-granular blend to obtain roller compacted granules, iii) blending extra-granular components to obtain an extra-granular blend, iv) blending the roller compacted granules with the extra-granular blend to obtain a final blend, and v) compressing the final blend to obtain the tablet, wherein the intragranular blend comprises 5R,6S)-10,l l-difluoro- 12-((2-fluoro-4-iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-lH- spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide or a solid form thereof (Compound 1), a diluent, a disintegrant, a glidant, and a lubricant, and the extra-granular blend comprises a glidant, and a lubricant.

[0010] Further provided herein are methods of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, comprising administering to a subject having the disease or disorder, the tablet of according to any embodiment disclosed herein. In certain embodiments, the disease or disorder is a neurofibromatosis (NF) related disorder. In certain embodiments, the NF related disorder is a neurofibromatosis 1 (NF1) related disorder. In certain embodiments, the NF 1 related disorder is a cutaneous or plexiform neurofibroma. In certain embodiments, the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.[OH] In certain embodiments, provided herein is a method of treating a disease or disorder in which the RAS pathway is upregulated comprising administering (5R,6S)-10,l l-difluoro-12-((2- fluoro-4-iodophenyl)amino)-5, 6-dihydroxy -4,5,6, 7-tetrahydro-lH- spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide (Compound 1) to a subject having the disease or disorder. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is gastroesophageal cancer, colorectal cancer, melanoma, non-small cell lung cancer, pancreatic cancer, or ovarian cancer. In certain embodiments, the disease or disorder is a neurofibromatosis (NF) related disorder. In certain embodiments, the NF-related disorder is a neurofibromatosis 1 (NF1) related disorder. In certain embodiments, the NF1 related disorder is a cutaneous or plexiform neurofibroma. In certain embodiments, the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent. In certain embodiments,2NAI-5006806042vlAttorney Docket No. 14763-026-228Compound 1 is administered in an amount of about 2 mg to about 45 mg per day to the subject. In certain embodiments, subject has been previously treated with one or more lines of therapy prior to being administered Compound 1. In certain embodiments, the one or more lines of therapy comprises a MEK inhibitor, BRAF inhibitor, or a combination thereof.BRIEF DESCRIPTION OF DRAWINGS

[0012] FIG. 1 shows a flow chart of the process for the formulation 1 mg and 4 mg tablets of Compound according to Example 2.

[0013] FIG. 2 shows a dissolution plot for 1 mg and 4 mg tablets under the condition of pH 6.8 NaH2PO4 buffer with 0.5% SDS, 50 rpm.

[0014] FIG. 3 shows a flow chart of the process for the formulation of 10 mg tablets of Compound 1 according to Example 3.

[0015] FIG. 4 shows a dissolution plot for 1 mg, 4 mg, and 10 mg tablets under the condition of pH 6.8 NaH2PC>4 buffer with 0.5% SDS, 50 rpm.

[0016] FIG. 5 shows dissolution plots for 1 mg, 4 mg, and 10 mg tablets and 1 mg, 4 mg, and 10 mg capsules under conditions of pH 6.8 NaH2PC>4 buffer with 0.5% SDS, 50 rpm.

[0017] FIG. 6 shows interim PK results at Day 22 (steady state) from a Phase I study of Compound 1. The plot depicts the mean concentration versus time for a 2 mg (bottom trace), 4 mg (second trace from bottom), 8 mg (middle trace), and 15 mg capsule (top trace) versus 4 mg tablet (second trace from top) of Compound 1.

[0018] FIG. 7 shows interim PK results steady state from a Phase I study of Compound 1. The plot depicts the mean concentration versus time for a 2 mg (bottom trace), 4 mg (second trace from bottom), 8 mg (third trace from bottom), 15 mg (top trace at t=0), and 22 mg capsule (second trace from top at t=0), and a 4 mg tablet (third trace from top) of Compound 1.

[0019] FIG. 8 shows a Swimmer Plot from a Phase I study of Compound 1 depicting duration on treatment of Compound 1 and time to response. The top four sets of data, having three bars each represent, from top to bottom, Cohorts 1, 2, 3, and 4A, respectively. The set of data having 5 bars represents cohort 4B, and the bottom-most set of data represents Cohort 5.

[0020] FIG. 9 shows a Spider Plot from a Phase I study of Compound 1 depicting percent change of lesion size over time on treatment of Compound 1.

[0021] FIG. 10 shows a Waterfall Plot depicting the overall response of lesions to treatment to Compound 1.

[0022] FIG. HA shows the concentration versus time curve of Compound 1 (flat line) once a day dosing (QD) as compared to Mirdametinib (line with peaks) twice a day (BID) dosing.3NAI-5006806042vlAttorney Docket No. 14763-026-228

[0023] FIG. 11B shows the concentration versus time curve of Compound 1 (flatter once a day dosing (QD) as compared to Selumetinib (line with peaks) twice a day (BID) dosing.

[0024] FIG. 12A shows percent inhibition in three neurofibroma-derived NF 1 mutant cell lines (NFl' / _) and wild-type cell lines (NFL'1"1) versus concentration of Compound 1.

[0025] FIG. 12B shows percent inhibition in three neurofibroma-derived NF 1 mutant cell lines (NFFA) and wild-type cell lines (NFL'1"1) versus concentration of Selumetinib (AZD6244).

[0026] FIG. 13A shows Compound 1 effect on tumor volume in NF1 mouse model by measuring the dorsal root ganglion (DRG) volume compared to vehicle-treated mice and Selumetinib (AZD6244). Statistical Analysis was performed using the Fishers LSD. *p < 0.05 **p < 0.01 ***p < 0.0014. Abbreviations: ns = statistically non-significant.

[0027] FIG. 13B shows Compound 1 effect on tumor number in NF1 mouse model compared to vehicle-treated mice and Selumetinib (AZD6244). Statistical Analysis was performed using the Fishers LSD. *p < 0.05 **p < 0.01 ***p < 0.0014. Abbreviations: ns = statistically nonsignificant.

[0028] FIG. 14 shows dose normalized exposures following administration of Compound 1 tablets for the 8 mg tablet (top trace) and the 22 mg capsule (bottom trace).DETAILED DESCRIPTION

[0029] The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are intended to describe non-limiting embodiments.Other embodiments and different ways to practice the invention are expressly included. Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having,” “containing”, “involving”, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0030] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

[0031] The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term4NAI-5006806042vlAttorney Docket No. 14763-026-228"consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0032] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps, or acts are in some way inherently mutually exclusive.1. Definitions

[0033] As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0034] As used in this application, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an intragranular excipient” includes one or more intragranular excipients.

[0035] As used herein, the term “minitablet” refers to compressed tablets with diameter and height between one to four millimeters (mm).

[0036] “Compound 1” i s meant to refer to (5R, 6 S)- 10, 11 -difluoro- 12-((2-fluoro-4- iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'- cyclopropane] 2,2-dioxide or a pharmaceutically acceptable salt thereof, including solid forms of the free base and salts thereof. The compound chemically named 10,l l-difluoro-12-((2-fluoro-4- iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'- cyclopropane] 2,2-dioxide belongs to a novel class of MEK1 / 2 inhibitors having a macrocyclic scaffold, which has been disclosed in US 9,034,861, which is herein incorporated by reference in its entirety. Solid forms of (5R,6S)-10,l l-difluoro-12-((2-fluoro-4-iodophenyl)amino)-5,6- dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2- dioxide have been described in Chinese priority application No. PCT / CN2024 / 070736 (filed January 5, 2024) and US provisional application No. 63 / 722,522 (filed November 19, 2024). (5R,6S)-10,l l-difluoro-12-((2-fluoro-4-iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-lH- spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide, its corresponding diastereoisomers, and its solid forms have also been disclosed in US provisional application Nos. 63 / 618,167 and 63 / 722,523 (filed January 5, 2024 and November 19, 2024 respectively). All of the abovementioned applications are herein incorporated by reference in their entirety.

[0037] The term “solid form” refers to a crystal form or an amorphous form or a mixture thereof of (5R,6S)-10,l l-difluoro-12-((2-fluoro-4-iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-5NAI-5006806042vlAttorney Docket No. 14763-026-228 lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide or a pharmaceutically acceptable salt thereof.

[0038] As used herein, and unless otherwise specified, a crystalline or amorphous form that is “pure,” z.e., substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of one or more other crystalline or amorphous forms, less than about 5% by weight of one or more other crystalline or amorphous forms, less than about 3% by weight of one or more other crystalline or amorphous forms, or less than about 1% by weight of one or more other crystalline or amorphous forms.

[0039] As used herein, API refers to “active pharmaceutical ingredient”. In one embodiment, the API is Compound 1. The API may be present in an amorphous state or crystalline form. In some embodiments, the API is in crystalline form.

[0040] The term “treat” means decrease, suppress, attenuate, alleviate, diminish, arrest, or stabilize the development or progression of a disease / disorder (z.e., a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and / or laminopathies).

[0041] The term “treat” also encompasses reducing symptoms of the disease / disorder. Evidence of “treating” may be, for example, a reduction of tumor volume, improve the appearance of tumors, and / or reduce symptoms associated with the presence of tumors. In the methods disclosed herein, such tumors may be plexiform and / or cutaneous neurofibroma tumors.

[0042] As used herein, and unless otherwise specified, the terms “prevent,” “preventing” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. The terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder or symptoms thereof, which inhibits or reduces the severity of the disease or disorder.

[0043] As used herein, and unless otherwise indicated, the terms “manage,” “managing” and “management” encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development or duration of the disease or disorder, or changing the way that a patient responds to the disease or disorder.

[0044] The treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see, Thereasse P., et al. J. of the National Cancer Institute, 2000; (92) 205- 216 and Eisenhauer et al. European J. Cancer; 2009; (45) 228-247).

[0045] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management6NAI-5006806042vlAttorney Docket No. 14763-026-228 of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the disease or disorder. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0046] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease or disorder, or one or more symptoms thereof, or prevent the recurrence of the disease or disorder, or one or more symptoms thereof. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease or disorder. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0047] Unless otherwise specified, the term “composition” as used herein is intended to encompass a product comprising the specified ingredient(s) (and in the specified amount(s), if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredient(s) in the specified amount(s).

[0048] A “pharmaceutically acceptable excipient, diluent or carrier,” refers to a substance that aids the administration of an active agent to a subject by for example by modifying the stability of an active agent or modifying the absorption by a subject upon administration. A pharmaceutically acceptable excipient typically has no significant adverse toxicological effect on the patient.Examples of pharmaceutically acceptable excipients include, for example bulking agents, buffers, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidine, and colors, and the like. One of skill in the art will recognize that other pharmaceutical excipients known in the art are useful in the present invention and include those listed in for example the Handbook of Pharmaceutical Excipients, Rowe R.C., Shesky P.J., and Quinn M.E., 6thEd., The Pharmaceutical Press, RPS Publishing (2009). The terms “bulking agent”, and “buffer” are used in accordance with the plain and ordinary meaning within the art.

[0049] As used herein, “administer” or “administration” refers to the act of physically delivering a substance as it exists outside the body into a subject. Administration includes all forms known in the art for delivering therapeutic agents, including but not limited to oral, topical, mucosal, injections, intradermal, intravenous, intramuscular delivery or other method of physical delivery described herein or known in the art (e.g., implantation of a slow-release device, such as a mini-7NAI-5006806042vlAttorney Docket No. 14763-026-228 osmotic pump to a subject; liposomal formulations; buccal; sublingual; palatal; gingival; nasal; vaginal; rectal; intra-arteriole; intraperitoneal; intraventricular; intracranial; or transdermal).

[0050] As used herein, “subject” or “patient” is an animal, typically a mammal, including a human, such as a human patient. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. The term “pediatric” refers to a human subject under the age of 21 years at the time of treatment. The term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). See, e.g., Berhman R E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W. B. Saunders Company, 1996; Rudolph A M, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery M D, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0051] In the context of a cancer, inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from treatment onset until death from any cause. TTP, as used herein, means the time from treatment onset until tumor progression; TTP does not include deaths. In one embodiment, PFS means the time from treatment onset until tumor progression or death. In one embodiment, PFS means the time from the first dose of compound to the first occurrence of disease progression or death from any cause. In one embodiment, PFS rates are computed using the Kaplan-Meier estimates. Event-free survival (EFS) means the time from treatment onset until any treatment failure, including disease progression, treatment discontinuation for any reason, or death. In one embodiment, overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment, ORR means the sum of the percentage of patients who achieve complete and partial responses. In one embodiment, ORR means the percentage of patients whose best response > partial response (PR), according to the IMWG Uniform Response Criteria. In one embodiment, duration of response (DoR) is the time from achieving a response until relapse or disease progression. In one embodiment, DoR is the time from achieving a response > partial8NAI-5006806042vlAttorney Docket No. 14763-026-228 response (PR) until relapse or disease progression. In one embodiment, DoR is the time from the first documentation of a response until to the first documentation of progressive disease or death. In one embodiment, DoR is the time from the first documentation of a response > partial response (PR) until to the first documentation of progressive disease or death. In one embodiment, time to response (TTR) means the time from the first dose of compound to the first documentation of a response. In one embodiment, TTR means the time from the first dose of compound to the first documentation of a response > partial response (PR). In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term “prevention” includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer.

[0052] The term “RASopathies” refers to a group of syndromes, also called conditions or disorders, caused by changes in genes that send signals across the Ras / mitogen-activated protein kinase (Ras / MAPK) pathway. While there are different RASopathies (currently, fewer than 10 disorders) and each syndrome has unique features, some common features include heart defects, skin, bone, eye and muscle problems, short stature, learning problems, differences in appearance and an increased risk of developing benign and cancerous tumors. RASopathies include, but are not limited to, Noonan Syndrome, Costello Syndrome, Cardiofaciocutaneous Syndrome, Legius Syndrome, Capillary Arteriovenous Malformation Syndrome, Hereditary gingival fibromatosis, SYNGAP1 syndrome, Leopard Syndrome, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) see, National Cancer Institute: https: / / dceg.cancer.gov / research / what-we-study / rasopathies).

[0053] The term “Laminopathies” refers to a group of rare genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. They are included in the more generic term nuclear envelopathies that refers to diseases associated with defects of the nuclear envelope. Laminopathies and other nuclear envelopathies have a large variety of clinical symptoms including skeletal and / or cardiac muscular dystrophy, lipodystrophy and diabetes, dysplasia, dermo- or neuropathy, leukodystrophy, and progeria (premature aging). Most of these symptoms develop after birth, typically during childhood or adolescence. Some laminopathies however may lead to an early death, and mutations of lamin Bl (LMNB1 gene) may be lethal before or at birth. Types of known laminopathies and other nuclear envelopathies include, but are not limited to, Atypical Werner syndrome, Buschke-Ollendorff syndrome, Cardiomyopathy, Charcot-Marie-Tooth disease, Emery-Dreifuss muscular dystrophies, Greenberg dysplasia, Hutchinson-Gilford progeria9NAI-5006806042vlAttorney Docket No. 14763-026-228 syndrome (HGPS), Leukodystrophy, demyelinating, adult-onset, autosomal dominant (ADLD), Limb-girdle muscular dystrophy type IB (LGMD1B), Lipoatrophy with diabetes, hepatic steatosis, hypertrophic cardiomyopathy, and leukomelanodermic papules (LDHCP), Mandibuloacral dysplasia, Pelger-Huet anomaly (PHA), Restrictive dermopathy.

[0054] The term “Neurofibromatosis” or “Neurofibromatoses” refers to a group of genetic disorders, belonging to RASopathies as mentioned above, that cause tumors to form on nerve tissue. These tumors can develop anywhere in the nervous system, including the brain, spinal cord, and nerves. There are three types of neurofibromatosis: neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) and schwannomatosis. NF1 is usually diagnosed in childhood, while NF2 and schwannomatosis are usually diagnosed in early adulthood. The tumors in these disorders are usually noncancerous (benign) but sometimes can become cancerous (malignant). Symptoms are often mild. However, complications of neurofibromatosis can include hearing loss, learning impairment, heart and blood vessel (cardiovascular) problems, loss of vision, and severe pain.

[0055] As used herein and unless otherwise indicated, the term “refractory” refers to a disorder, disease, or condition that has not responded to prior treatment that can include one or more lines of therapy, e.g., a BRAF inhibitor, a MEK inhibitor, or any combination thereof. In certain embodiments, a disease, disorder, or condition is refractory due to development of resistance to the prior treatment.

[0056] Cancer showing or developing “resistance” or being or becoming “resistant” to a therapy, as used herein, includes a cancer that is not responsive and / or exhibits reduced ability of producing a significant response, e.g., partial response and / or complete response to treatment. Resistance may be de novo (primary) resistance or acquired resistance that arises during treatment. Resistance may be “acquired resistance”, which can describe a cancer that becomes resistant and / or substantially less responsive to a prior line of therapy after being exposed to it for a certain period of time.

[0057] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percents of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.10NAI-5006806042vlAttorney Docket No. 14763-026-228

[0058] Unless otherwise specified, to the extent that there is a discrepancy between a depicted chemical structure of a compound provided herein and a chemical name of a compound provided herein, the chemical structure shall control.2. Compound

[0059] In certain embodiments, provided herein are formulations comprising (5R,6S)-10,l l- difluoro-12-((2 -fluoro-4-iodophenyl)amino)-5,6-dihydroxy -4,5,6, 7-tetrahydro-lH- spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide having the following formula:Compound 1.

[0060] In one embodiment, Compound 1 used in the formulations provided herein is a crystalline solid. In one embodiment, Compound 1 used in the formulations provided herein is Form A. In one embodiment, Compound 1 used in the formulations provided herein is Form B. In one embodiment, Compound 1 used in the formulations provided herein is Form C.

[0061] In one embodiment, Compound 1 used in the formulations provided herein is a solid form comprising a free base of Compound 1, characterized by an XRPD pattern comprising peaks at approximately 8.5, 15.1, and 18.3° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 9.2, 12.0, and 17.0° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.8, 22.0, 24.1, and 27.4° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 8.5, 9.2, 10.7, 11.6, 12.0, 12.8, 15.1, 17. 0, 18.3, 20.8, 22.0, 24.1, and 27.4° 29. In some such embodiments, Compound 1 is solid Form A. In one embodiment, the solid Form A comprising a free base of Compound 1 is an anhydrate.

[0062] In one embodiment, Compound 1 used in the formulations provided herein is a solid form comprising a free base of Compound 1, characterized by an XRPD pattern comprising peaks at approximately 8.4, 12.5, and 16.9° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 17.6, 17.9, and 18.1° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.4, 23.5, and 23.8° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 25.2, 27.1, and 29.2° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 16.9, and 17.9029. In one embodiment, the XRPD11NAI-5006806042vlAttorney Docket No. 14763-926-228 pattern comprises peaks at approximately 16.9, 17.6, 17.9, and 18.1° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 14.8, 14.9, and 15.3° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 21.9, 23.5, 23.82029. In one embodiment, the XRPD pattern comprises peaks at approximately 8.4, 9.9, 19.3, 11.5, 12.5, 14.8, 14.9, 15.3, 16.9,17.6, 17.9, 18.1, 19.3, 19.9, 29.4, 21.9, 23.5, 23.8, 24.1, 24.9, 25.2, 25.6, 27.1, 28.5, 28.9, 29.2, 39.3, 31.7, 32.9, 32.4, 32.8, 35.7, and 36.7° 29. In some such embodiments, Compound 1 is solid form B. In one embodiment, the solid Form B comprising a free base of Compound 1 is a solvate. In some such embodiments, Compound 1 is solid Form B. In one embodiment, the solid Form B comprising a free base of Compound 1 is an acetonitrile solvate.

[0063] In one embodiment, Compound 1 used in the formulations provided herein is a solid form comprising a free base of Compound 1, characterized by an XRPD pattern comprising peaks at approximately 8.3, 12.6, and 16.6° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 17.4, 18.1, and 18.4° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.7, 23.4, and 23.6° 29. In one embodiment, the XRPD pattern further comprises peaks at approximately 25.4, 26.9, 27.9, and 29.9° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 16.6, 17.4, 18.1, and 18.4° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 20.7, 21.1, 21.4, and 21.9° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 23.4, 23.6, and 24.1° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 24.8, 25.0, 25.4, 25.9, and 26.9° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 27.9 and 28.4° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 29.9, 31.0° 29. In one embodiment, the XRPD pattern comprises peaks at approximately 8.3, 9.1, 10.5, 11.5, 11.7,12.6, 16.6, 17.4, 18.1, 18.4, 20.7, 21.1, 21.4, 21.9, 23.4, 23.6, 24.1, 24.8, 25.0, 25.4, 25.9, 26.9, 27.9, 28.4, 29.9, 31.0, 31.3, 31.7, and 32.7° 29. In some such embodiments, Compound 1 is solid Form C. In one embodiment, the solid Form C comprising a free base of Compound 1 is a solvate. In one embodiment, the solid Form C comprising a free base of Compound 1 is a methanol solvate.3. Formulations

[0064] In certain embodiments, the formulations provided herein are pharmaceutical compositions comprising Compound 1 and a pharmaceutically acceptable excipient. In certain embodiments, pharmaceutical composition is an oral pharmaceutical composition such as a tablet or a capsule. In certain embodiments, the pharmaceutical composition comprises about 2 mg to about 45 mg of Compound 1, for example, 2 mg, 4 mg, 8 mg, 19 mg, 15 mg, 22 mg, 39 mg, 37 mg, or 45 mg of Compound 1.12NAI-5006806042vlAttorney Docket No. 14763-026-228

[0065] In certain embodiments, the pharmaceutical composition comprises about 4 mg, 8 mg, 12 mg, or 18 mg of Compound 1.

[0066] In certain embodiments, the formulations provided herein are tablets comprising Compound 1 and a pharmaceutically acceptable excipient. In certain embodiments, the tablet provided herein comprises Compound 1 in about 1% to about 10% by weight based on total weight of the tablet. In certain embodiments, the tablet provided herein comprises Compound 1 in about 2% to about 3% by weight based on total weight of the tablet. In certain embodiments, the tablet provided herein comprises Compound 1 in about 3% to about 4% by weight based on total weight of the tablet. In certain embodiments, the tablet provided herein comprises Compound 1 in about 4% to about 5% by weight based on total weight of the tablet. In certain embodiments, the tablet composition provided herein comprises Compound 1 in about 1%, about 2%, about 3%, about 4%, or about 5% by weight based on total weight of the tablet. In certain embodiments, the tablet provided herein comprises Compound 1 in about 5% by weight based on total weight of the tablet.

[0067] In certain embodiments, the formulations provided herein are capsules comprising Compound 1 and a pharmaceutically acceptable excipient. In certain embodiments, the capsule provided herein comprises Compound 1 in about 1% to about 10% by weight based on total weight of the capsule. In certain embodiments, the capsule provided herein comprises Compound 1 in about 2% to about 3% by weight based on total weight of the capsule. In certain embodiments, the capsule provided herein comprises Compound 1 in about 3% to about 4% by weight based on total weight of the capsule. In certain embodiments, the capsule provided herein comprises Compound 1 in about 4% to about 5% by weight based on total weight of the capsule. In certain embodiments, the capsule composition provided herein comprises Compound 1 in about 1%, about 2%, about 3%, about 4%, or about 5% by weight based on total weight of the capsule. In certain embodiments, the capsule provided herein comprises Compound 1 in about 5% by weight based on total weight of the capsule.

[0068] In certain embodiments, the tablet provided herein comprises Compound 1 and one or more excipients selected from a binder, a diluent, a disintegrant, a flow agent, a surfactant, a glidant and a lubricant. In certain embodiments, the tablet provided herein comprises Compound 1 and one or more excipients selected from a diluent, a disintegrant, a glidant, and a lubricant.

[0069] In certain embodiments, the binder is povidone. In certain embodiments, the binder is present in an amount from about 10% to 50% by weight based on total weight of the tablet.

[0070] In certain embodiments, the diluent is microcrystalline cellulose, lactose monohydrate, or pregelatinized starch, mannitol, anhydrous dibasic calcium phosphate, or a mixture thereof. In certain embodiments, the diluent is present in an amount from about 10 to 65% by weight based on13NAI-5006806042vlAttorney Docket No. 14763-026-228 total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 10 to 50% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 14% to 45% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 20% to 45% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 30% to 45% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 42% to 46% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 22% to 26% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount from about 13% to 17% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount of about 15%, about 20%, about 23%, about 24%, about 30%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 44.2%, about 44.4%, about 62%, about 63%, about 64%, or about 65% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount of about 15%, about 24%, or about 44.2% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount of about 15%, about 24%, or about 44.4% by weight based on total weight of the tablet. In certain embodiments, the diluent is present in an amount of about 15%, about 24%, or about 44% by weight based on total weight of the tablet. In certain embodiments, the diluent is mannitol, which is present in an amount of about 30% by weight based on total weight of the tablet. In certain embodiments, the diluent is anhydrous dibasic calcium phosphate, which is present in an amount of about 30% by weight based on total weight of the tablet. In certain embodiments, the diluent is microcrystalline cellulose, which is present in an amount of about 44.4% by weight based on total weight of the tablet. In certain embodiments, the diluent is lactose monohydrate, which is present in an amount of about 24% by weight based on total weight of the tablet. In certain embodiments, the diluent is pregelatinized starch, which is present in an amount of about 15% by weight based on total weight of the tablet.

[0071] In certain embodiments, the disintegrant is present in an amount from about 2 to 15% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is present in an amount from about 8 to 12% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is present in an amount from about 5 to 10% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is present in an amount from about 5 to 7% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is present in an amount of about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight based on total weight of the tablet. In certain embodiments, the disintegrant14NAI-5006806042vlAttorney Docket No. 14763-026-228 is present in an amount of about 5% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is present in an amount of about 10% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is croscarmellose sodium, which is present in an amount of about 5% by weight based on total weight of the tablet. In certain embodiments, the disintegrant is crospovidone, which is present in an amount of about 10% by weight based on total weight of the tablet.

[0072] In certain embodiments, the glow agent is silicified microcrystalline cellulose. In certain embodiments, the flow agent is present in an amount from about 10% to 50% by weight based on total weight of the tablet.

[0073] In certain embodiments, the surfactant is sodium lauryl sulfate. In certain embodiments, the surfactant is present in an amount from about 1% to 10% by weight based on total weight of the tablet.

[0074] In certain embodiments, the glidant is colloidal silicon dioxide. In certain embodiments, the glidant is present in an amount from about 0.01% to 1% by weight based on total weight of the tablet. In certain embodiments, the glidant is present in an amount from about 0.1% to 0.6% by weight based on total weight of the tablet. In certain embodiments, the glidant is present in an amount from about 0.2% to 0.6% by weight based on total weight of the tablet. In certain embodiments, the glidant is present in an amount from about 0.3% to 0.7% by weight based on total weight of the tablet. In certain embodiments, the glidant is present in an amount from about 0.4% to 0.5% by weight based on total weight of the tablet. In certain embodiments, the glidant is present in an amount of about 0.5% by weight based on total weight of the tablet. In certain embodiments, the glidant is colloidal silicon dioxide, which is present in an amount of about 0.5% by weight based on total weight of the tablet.

[0075] In certain embodiments, the lubricant is magnesium stearate or sodium stearyl fumarate. In certain embodiments, the lubricant is present in an amount from about 0.05% to 5% by weight based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount from about 0.1% to 5% by weight based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount from about 0.1% to 2% by weight based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount from about 0.1% to 1% by weight based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount from about 0.05% to 0.7% by weight based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount of about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5% by weight15NAI-5006806042vlAttorney Docket No. 14763-026-228 based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount of about 0.5% by weight based on total weight of the tablet. In certain embodiments, the lubricant is present in an amount of about 0.5% by weight based on total weight of the tablet. In certain embodiments, the lubricant is magnesium stearate, which is present in an amount of about 0.1% by weight based on total weight of the tablet. In certain embodiments, the lubricant is magnesium stearate, which is present in an amount of about 0.5% by weight based on total weight of the tablet. In certain embodiments, the lubricant is magnesium stearate, which is present in an amount of about 1% by weight based on total weight of the tablet. In certain embodiments, the lubricant is sodium stearyl fumarate, which is present in an amount of about 1% by weight based on total weight of the tablet.

[0076] In certain embodiments, the tablet provided herein comprises Compound 1, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. In certain embodiments, the tablet provided herein comprises Compound 1, mannitol, anhydrous dibasic calcium phosphate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and sodium stearyl fumarate.

[0077] In certain embodiments, the tablet provided herein comprises Compound 1, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, and magnesium stearate. In certain embodiments, the tablet provided herein comprises Compound 1, microcrystalline cellulose, lactose monohydrate, pregelatinized starch, crospovidone, colloidal silicon dioxide, and magnesium stearate.

[0078] In certain embodiments, the tablet provided herein comprises about 1% to about 10% Compound 1, about 42% to about 46% microcrystalline cellulose, about 22% to about 26% lactose monohydrate, about 13% to about 17% pregelatinized starch, about 8% to about 12% crospovidone, about 0.3% to about 0.7% colloidal silicon dioxide, and about 0.05% to about 0.7% magnesium stearate, by weight based on total weight of the tablet.

[0079] In certain embodiments, the tablet provided herein comprises about 5% Compound 1, about 44.4% microcrystalline cellulose, about 24% lactose monohydrate, about 15% pregelatinized starch, about 10% crospovidone, about 0.5% colloidal silicon dioxide, and about 0.1% magnesium stearate, where the percentages are by weight based on total weight of the tablet. In some such embodiments, the tablet further comprising 0.5% magnesium stearate. In some such embodiments, the tablet further comprises 0.5% colloidal silicon dioxide.

[0080] In certain embodiments, the tablet provided herein comprises about 5% Compound 1, about 44.4% microcrystalline cellulose, about 24% lactose monohydrate, about 15% pregelatinized16NAI-5006806042vlAttorney Docket No. 14763-026-228 starch, about 10% crospovidone, about 1% colloidal silicon dioxide, and about 0.6% magnesium stearate, where the percentages are by weight based on total weight of the tablet.

[0081] In certain embodiments, the tablet provided herein comprises intra-granular components and extra-granular components. In certain embodiments, the tablet provided herein comprises intragranular components comprising about 5% Compound 1, about 44.4% microcrystalline cellulose, about 24% lactose monohydrate, about 15% pregelatinized starch, about 10% crospovidone; about 0.5% colloidal silicon dioxide, and about 0.1% magnesium stearate; and extra-granular components comprising about 0.5% magnesium stearate and about 0.5% colloidal silicon dioxide.

[0082] In certain embodiments, each tablet weighs about 1 mg to about 200 mg. In certain embodiments, each tablet weighs about 1 mg to about 100 mg. In certain embodiments, each tablet weighs about 1 mg to about 80 mg. In certain embodiments, each tablet weighs about 1 mg to about 60 mg. In certain embodiments, each tablet weighs about 1 mg to about 40 mg. In certain embodiments, each tablet weighs about 1 mg to about 20 mg. In certain embodiments, each tablet weighs about 1 mg to about 10 mg. In certain embodiments, each tablet weighs about 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In certain embodiments, each tablet weighs about 1 mg, 3 mg, 4 mg, 5 mg, 10 mg, or 20 mg, about 80 mg, or about 200 mg. In certain embodiments, each tablet weighs about 20 mg. In certain embodiments, each tablet weighs about 80 mg. In certain embodiments, each tablet weighs about 200 mg.

[0083] In certain embodiments, each tablet comprises Compound 1 at a weight of about 1 mg to about 200 mg. In certain embodiments, each tablet comprises Compound 1 at a weight of about 1 mg to about 100 mg. In certain embodiments, each tablet comprises about 1 mg to about 80 mg of Compound 1. In certain embodiments, each tablet comprises about 1 mg to about 60 mg ofCompound 1. In certain embodiments, each tablet comprises about 1 mg to about 40 mg ofCompound 1. In certain embodiments, each tablet comprises about 1 mg to about 20 mg ofCompound 1. In certain embodiments, each tablet comprises about 1 mg to about 10 mg of Compound 1. In certain embodiments, each tablet comprises about 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of Compound 1. In certain embodiments, each tablet comprises about 1 mg, 3 mg, 4 mg, 5 mg, 10 mg, or 20 mg, about 80 mg, or about 200 mg of Compound 1. In certain embodiments, each tablet comprises about 20 mg of Compound 1. In certain embodiments, each tablet weighs about 80 mg of Compound 1. In certain embodiments, each tablet comprises about 200 mg of Compound 1.17NAI-5006806042vlAttorney Docket No. 14763-026-228

[0084] In certain embodiments, each tablet comprises about 4 mg of Compound 1. In certain embodiments, each tablet comprises about 8 mg of Compound 1. In certain embodiments, each tablet comprises about 12 mg of Compound 1. In certain embodiments, each tablet comprises about 18 mg of Compound 1.

[0085] In certain embodiments, each tablet has a diameter of about 1 mm to 10 mm. In certain embodiments, each tablet has a diameter of about 2 mm to 8 mm. In certain embodiments, each tablet has a diameter of about 3 mm to 5 mm. In certain embodiments, each tablet has a diameter of about 1 mm, 2 mm, 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm. In certain embodiments, each tablet has a diameter of about 3 mm. In certain embodiments, each tablet has a diameter of about 5.5 mm. In certain embodiments, each tablet has a diameter of about 5 mm. In certain embodiments, each tablet has a diameter of about 8 mm.

[0086] In certain embodiments, the tablet comprises a coating. In certain embodiments, the coating is Opadry. In certain embodiments, the coating is Opadry yellow. In certain embodiments, the coating provides a weight gain of about 1 to 5%. In certain embodiments, the coating provides a weight gain of about 2 to 3%. In certain embodiments, the coating provides a weight gain of about 1%, 2%, or 3%. In certain embodiments, the coating provides a weight gain of about 3%.4. Methods of Preparation

[0087] Any conventional method for obtaining tablets, for example, the methods described in pharmacopoeias such as the U.S. Pharmacopeia, and the European Pharmacopoeia, may be used.

[0088] In certain embodiments, the method for making a tablet comprises the steps of mixing, blending, roller compaction, final blending, and compression.

[0089] In some embodiments a process for preparing a tablet comprises: i) screening the excipients (except lubricant); ii) blending intra-granular components to obtain an intra-granular blend, iii) roller compacting the intra-granular blend to obtain roller compacted granules, iv) blending extra-granular components to obtain an extra-granular blend, v) blending the roller compacted granules with the extra-granular blend to obtain a final blend, and vi) compressing the final blend to obtain the tablet. In some such embodiments, the intra-granular blend comprises Compound 1, a diluent, a disintegrant, a glidant, and a lubricant, and the extra-granular blend comprises a glidant, and a lubricant.

[0090] In some embodiments, the method for making a tablet is as described in Examples 2 and Example 3.5. Method of Use18NAI-5006806042vlAttorney Docket No. 14763-026-228

[0091] In one embodiment, provided herein is a method of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, which comprises administering to a patient a formulation of Compound 1 provided herein. In one embodiment, provided herein is a method of treating cancer. In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, wherein the method comprises administering said formulation to a patient. In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of treating cancer.

[0092] In one embodiment, provided herein is a method of preventing a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, which comprises administering to a patient a formulation of Compound 1 provided herein. In one embodiment, provided herein is a method of preventing cancer. In one particular embodiment, provided herein is a method of preventing neurofibromatosis 1 (NF1). In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of preventing a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, wherein the method comprises administering said formulation to a patient. In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of preventing cancer. In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of preventing neurofibromatosis 1 (NF1).

[0093] In one embodiment, provided herein is a method of managing a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, which comprises administering to a patient a formulation of Compound 1 provided herein. In one embodiment, provided herein is a method of managing cancer. In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of managing a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, wherein the method comprises administering said formulation to a patient. In one embodiment, provided herein is a formulation of Compound 1 provided herein for use in a method of managing cancer. In one embodiment, provided herein is a method of managing neurofibromatosis 1 (NF1) in a subject having NF 1, the method comprising administering to the subject a formulation of Compound 1 provided herein. In some embodiments, a formulation of Compound 1 provided herein prevents proliferation, growth, and viability of NF1 cells. In one embodiment, a formulation of Compound 1 provided herein slows down NF1 disease progression.

[0094] In some embodiments, RASopathies include, but are not limited to, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), Noonan Syndrome, Costello Syndrome, Cardiofaciocutaneous19NAI-5006806042vlAttorney Docket No. 14763-026-228Syndrome, Legius Syndrome, Capillary Arteriovenous Malformation Syndrome, Hereditary gingival fibromatosis, or SYNGAP1 syndrome. In certain embodiments, NF1 is associated with cutaneous and / or plexiform neurofibromas.

[0095] In some embodiments laminopathies include, but are not limited to, the Atypical Werner syndrome, Buschke-Ollendorff syndrome, Cardiomyopathy, Charcot-Marie-Tooth disease, Emery-Dreifuss muscular dystrophies, Greenberg dysplasia, Hutchinson-Gilford progeria syndrome (HGPS), Leukodystrophy, demyelinating, adult-onset, autosomal dominant (ADLD), Limb-girdle muscular dystrophy type IB (LGMD1B), Lipoatrophy with diabetes, hepatic steatosis, hypertrophic cardiomyopathy, and leukomelanodermic papules (LDHCP), Mandibuloacral dysplasia, Pelger-Huet anomaly (PHA), or Restrictive dermopathy.

[0096] In one particular embodiment of the methods described herein, the disease or disorder is aNeurofibromatosis (NF) related disorder. In some embodiments, the neurofibromatosis is neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), or schwannomatosis. In some such embodiments, the disease or disorder is cancer. In one particular embodiment of the methods described herein, the disease or disorder is a Neurofibromatosis Type 1 (NFl)-associated cancer. In one embodiment, the methods provided herein comprise treating a tumor or cancer. In some embodiments, the tumor or cancer is a neurofibroma. In some embodiments, the tumor or cancer is a neurofibroma associated with Neurofibromatosis Type 1 (NF1). In some embodiments, the tumor or cancer is selected from cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, Langerhans cell histiocytosis (LCH), and malignant peripheral nerve sheath tumor. In one particular embodiment, provided herein is a method of treating NF 1 in a subject having NFL In some embodiments, the methods provided herein comprise treating cutaneous and / or plexiform neurofibromas in NF1 in a subject having NFL

[0097] In one embodiment, the methods provided herein comprise treating plexiform neurofibromas in a subject having NFL In one embodiment, the plexiform neurofibromas are symptomatic and inoperable, incompletely resected, and / or recurrent (e.g., grow back after surgical removal). In one embodiment, the methods provided herein comprise treating symptomatic and inoperable, incompletely resected, or recurrent plexiform neurofibromas in a subject having NFL In one embodiment, the methods provided herein comprise treating symptomatic and inoperable, incompletely resected, or recurrent plexiform neurofibromas in an adult subject having NFL In one embodiment, the methods provided herein comprise treating symptomatic and inoperable, incompletely resected, or recurrent plexiform neurofibromas in a pediatric subject having NFL

[0098] In one embodiment of the methods provided herein, the subject has progressive plexiform neurofibromas.20NAI-5006806042vlAttorney Docket No. 14763-026-228

[0099] In one embodiment, the methods provided herein are effective to treat cutaneous neurofibromas in a subject having neurofibromatosis, e.g., NF1. In one embodiment, the methods provided herein are effective to treat both plexiform neurofibromas and cutaneous neurofibromas in a subject having neurofibromatosis, e.g., NF1.

[0100] In one embodiment, treating a subject having NF, e.g., NF1 or treating NF 1 reduces the size of one or more plexiform neurofibromas and / or cutaneous neurofibromas. In one embodiment, treating a subject having NF, e.g., NF1 or treating NF1 reduces one or more symptoms of NF1, such as, but not limited to, skin discoloration (e.g., cafe-au-lait spots), freckling (axillary and / or inguinal), pain, and nerve-related issues like numbness or weakness. Other more serious symptoms may also be treated, such as deformity (e.g., dysplasia of the sphenoid bone or long bone cortex), breathing or swallowing difficulties, vision or hearing loss (e.g., due to optic pathway glioma or iris hamartomas), bowel or bladder-related issues, growth changes, and / or neurological difficulties.

[0101] In one embodiment of the methods described herein, the disease or disorder is a Neurofibromatosis Type 2 (NF2)-associated cancer. In one embodiment of the methods described herein, the disease or disorder is schwannomatosis. In one embodiment of the methods described herein, the disease or disorder is a schwannomatosis-associated cancer.

[0102] In other aspects, provided herein is a method for the treatment, prevention or prophylaxis of cancer comprising administering to a subject in need thereof a formulation of Compound 1 described herein or a pharmaceutical composition that includes one or more of the formulations of Compound 1 described herein. In certain embodiments, the cancer is selected from skin cancer, malignant peripheral nerve sheath cancer, lymphoma, histiocytic neoplasm, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, kidney cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, oral cancer, cervical cancer, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum. In certain embodiments, the cancer may be selected from brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, and leukemia. In further or additional embodiments, the cancer is brain cancer or achenocortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, the cancer is pancreatic cancer. In further or additional embodiments, the cancer is stomach cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or21NAI-5006806042vlAttorney Docket No. 14763-026-228 additional embodiments, the leukemia is selected from acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the lymphoma is selected from B-cell lymphoma, T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, and Waldenstrom macroglobulinemia. In further or additional embodiments, the cancer is follicular lymphoma. In further or additional embodiments, the cancer is pre-B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell lung cancer. In a particular embodiment, the cancer is low grade serious ovarian cancer.

[0103] In some embodiments, the lung cancer is lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.

[0104] In further or additional embodiments, the cancer is melanoma. In further or additional embodiments, the cancer is non-small cell lung cancer. In further or additional embodiments, the cancer is a metastatic adenocarcinoma.

[0105] In one embodiment, the methods provided herein reduce the tumor or cancer size. In one embodiment, the methods provided herein reduce the tumor or cancer volume by at least 20% as determined by volumetric magnetic resonance imaging analysis. In one embodiment, the methods provided herein reduce the tumor or cancer volume by at least 20%, at least 10%, or at least 5% as determined by volumetric magnetic resonance imaging analysis.

[0106] In some embodiments, provided herein is a method of inhibiting proliferation of a cell having a RAS mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, the cancer is associated with a RAS mutation. In certain embodiments, provided herein is a method of inducing apoptosis in a cell having a RAS mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, provided herein is a method of inhibiting proliferation of a cell having a KRAS mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, the cancer is associated with a KRAS mutation. In some embodiments, provided herein is a method of inducing apoptosis in a cell having a KRAS mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, provided herein is a method of inhibiting proliferation of a cell having a NRAS mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, the cancer is associated with a NRAS mutation. In some embodiments, provided herein is a method of inducing apoptosis in a cell having a RAS mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments,22NAI-5006806042vlAttorney Docket No. 14763-026-228 the KRAS mutation is at codons 12, 13, 59, 61 and / or 146. In some embodiments, the mutant form of the KRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, GBP, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H. In some embodiments, the mutant form of the KRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59E, A59G, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T and A146V.

[0107] In certain embodiments, the RAS mutation is a HRAS or MRAS mutation. In one embodiment, the mutant form of the HRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12D, G12F, G12N, G12S, G12V, G13C, G13D, G13E, G13R, G13S, G13V, Q61H, Q61K, Q61L, and Q61R.

[0108] In one embodiment, the mutant form of the MRAS protein has one or more amino acid substitutions selected from G23V and T68I.

[0109] In some embodiments, provided herein is a method of treating cancer in a subject having a RAF mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, provided herein is a method of inhibiting proliferation of a cell having a RAF mutation, comprising administering a formulation of Compound 1 described herein. In some embodiments, the cancer is associated with a RAF mutation. In some embodiments, the BRAF mutation is a K601E mutation. In some embodiments, the BRAF mutation is a V600E mutation.

[0110] In some embodiments, provided herein is a method of treating cancer in a subject having a NF1 mutation, comprising administering a formulation of Compound 1 described herein.[OHl] In certain embodiments, the cancer is resistant to treatment of one or more MEK protein kinase inhibitors. In other embodiments, the cancer is resistant to treatment of one or more RAF protein kinase inhibitors. In some embodiments, the cancer is resistant to BRAF / MEK inhibition. In some such embodiments, the cancer is an advanced solid tumor. In some embodiments, the cancer is associated with a RAS, RAF, and / or NF 1 mutation. In some embodiments, the BRAF mutation is a K601E mutation. In some embodiments, the BRAF mutation is a V600E mutation. In still further embodiments, the resistance is acquired resistance. In other embodiments, the resistance is de novo resistance. In further or additional embodiments, the cancer is resistant to an anticancer agent.

[0112] In some embodiments, provided herein is a method of treating a subject having a MAPK pathway-driven advanced solid tumor with a documented RAS, NF1, or RAF mutation or a subject who has failed BRAF / MEK inhibition comprising administering to the subject a formulation of23NAI-5006806042vlAttorney Docket No. 14763-026-228Compound 1 described herein or a pharmaceutical composition that includes one or more of the formulations of Compound 1 described herein.

[0113] In one embodiment, the advanced solid tumor is selected from skin cancer, brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, lymphoma, and leukemia.

[0114] In some embodiments, a formulation of Compound 1 provided herein can be administered once daily (QD or qd) or divided into multiple daily doses. In some embodiments, a formulation of Compound 1 provided herein can be administered once every other day ( / .< ., altemate-day dosing). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). In some embodiments, a formulation of Compound 1 provided herein is administered at least once every day, at least once every other day, at least once every two days, at least once every three days, at least once every week, at least once every other week, or at least once every three weeks. In some embodiments, a formulation of Compound 1 provided herein is administered once every day, once every other day, once every two days, once every three days, once every week, once every other week, or once every three weeks. Cycling therapy can reduce the development of resistance, avoid or reduce the side effects, and / or improves the efficacy of the treatment.

[0115] As used herein, the term “daily” is intended to mean that a therapeutic compound is administered once or more than once each day, for example, for a period of time.

[0116] In some embodiments, about 1 mg to about 200 mg of Compound 1 is administered to a subject, e.g., to treat a cancer, RASopathy, or laminopathy. In some embodiments, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 2 mg to about 200 mg, about 2 mg to about 100 mg, or about 2 mg to about 50 mg of Compound 1 is administered to a subject, e.g., to treat a cancer, RASopathy, or laminopathy. In some such embodiments, the administration of Compound 1 can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). In some embodiments, Compound 1 provided herein is administered every day, every other day, every two days, every three days, every week, every other week, or every three weeks. In some embodiments, 2 mg to 45 mg of Compound 1 is administered daily to a subject, e.g., to treat a cancer, RASopathy, or laminopathy. In certain embodiments, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 g, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 3524NAI-5006806042vlAttorney Docket No. 14763-026-228 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48mg, about 49 mg, or about 50 mg of Compound 1 is administered to the subject. In certain embodiments, 2 mg, 4 mg, 8 mg, 10 mg, 15 mg, 22 mg, 30 mg, 37 mg, or 45 mg of Compound 1 is administered daily to the subject. In certain embodiments, 4 mg to 45 mg, 8 mg to 45 mg, 10 mg to 45 mg, 15 mg to 45 mg, 22 mg to 45 mg, 30 mg to 45 mg, or 37 mg to 45 mg of Compound 1 is administered daily to the subject. In certain embodiments, 4 mg to 22 mg, 8 mg to 22 mg, 10 mg to 22 mg, or 15 mg to 22 mg of Compound 1 is administered daily to the subject. In certain embodiments, at least 22 mg of Compound 1, e.g., 22 mg to 30 mg, 22 mg to 37 mg, or 22 mg to 45 mg is administered daily to the subject. In certain embodiments, 2 mg, 4 mg, 8 mg, 10 mg, 15 mg, 22 mg, 30 mg, 37 mg, or 45 mg of Compound 1 is administered once per day to the subject. In certain embodiments, 4 mg, 8 mg, 15 mg, or 22 mg of Compound 1 is administered once per day to the subject. In certain embodiments, 4 mg, 8 mg, 10 mg, 15 mg, 22 mg, 30 mg, 37 mg, or 45 mg of Compound 1 is administered once per day to the subject.

[0117] In some embodiments, 2 mg to 45 mg of Compound 1 is administered daily every other day to a subject e.g., to treat a cancer, RASopathy, or laminopathy. In certain embodiments, 2 mg, 4 mg, 8 mg, 10 mg, 15 mg, 22 mg, 30 mg, 37 mg, or 45 mg of Compound 1 is administered daily every other day to the subject. In certain embodiments, 4 mg to 45 mg, 8 mg to 45 mg, 10 mg to 45 mg, 15 mg to 45 mg, 22 mg to 45 mg, 30 mg to 45 mg, or 37 mg to 45 mg of Compound 1 is administered daily every other day to the subject. In certain embodiments, 4 mg to 22 mg, 8 mg to 22 mg, 10 mg to 22 mg, or 15 mg to 22 mg of Compound 1 is administered daily to the subject. In certain embodiments, at least 22 mg of Compound 1, e.g., 22 mg to 30 mg, 22 mg to 37 mg, or 22 mg to 45 mg is administered daily every other day to the subject. In certain embodiments, 2 mg, 4 mg, 8 mg, 10 mg, 15 mg, 22 mg, 30 mg, 37 mg, or 45 mg of Compound 1 is administered every other day to the subject. In certain embodiments, 4 mg, 8 mg, 15 mg, or 22 mg of Compound 1 is administered every other day to the subject. In certain embodiments, 4 mg, 8 mg, 10 mg, 15 mg, 22 mg, 30 mg, 37 mg, or 45 mg of Compound 1 is administered every other day to the subject.

[0118] In some embodiments, 4 mg to 18 mg of Compound 1 is administered daily every other day to a subject e.g., to treat a cancer, RASopathy, or laminopathy. In certain embodiments, 4 mg, 8 mg, 12 mg, or 18 mg of Compound 1 is administered daily every other day to the subject. In some embodiments, 4 mg to 18 mg of Compound 1 is administered daily every other day to a subject e.g., to treat a cancer, RASopathy, or laminopathy. In certain embodiments, 4 mg, 8 mg, 12 mg, 16 mg, 18 mg, 24 mg, or 36 mg of Compound 1 is administered daily every other day to the subject.25NAI-5006806042vlAttorney Docket No. 14763-026-228

[0119] In some embodiments, a formulation of Compound 1 provided herein can be administered less frequently, such as twice per week or three times per week.

[0120] In one embodiment, a method provided herein comprises administering the formulations provided herein in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or greater than 40 cycles. In certain embodiments, the formulation provided herein for methods described herein is administered for 1 to 25 cycles. In one embodiment, the median number of cycles administered in a group of patients is about 1. In one embodiment, the median number of cycles administered in a group of patients is about 2. In one embodiment, the median number of cycles administered in a group of patients is about 3. In one embodiment, the median number of cycles administered in a group of patients is about 4.

[0121] In certain embodiments, treatment cycles comprise multiple doses of the formulations provided herein administered to a patient in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days), optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than 28 days).

[0122] In certain embodiments, the formulations provided herein are administered in one or more 28-day cycles in the methods described herein. In certain embodiments, the formulations provided herein are administered in a 28-day cycle in the methods described herein.

[0123] In certain embodiments, the formulations provided herein are administered orally in the methods described herein. In certain embodiments, the formulations provided herein are administered with food or without food.

[0124] In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is about 2 years old or older. In some embodiments, the subject is about 2 to about 18 years old. In some embodiments, the subject is at least 12 years old. In some embodiments, the subject is an adult subject.

[0125] In one embodiment, the subject has not been treated with prior therapy, e.g., to treat the cancer, RASopathy, or laminopathy. In one embodiment, the subject already received a different first, second, or further line treatment. A different treatment comprises administration of a therapy, drug, or agent different from and not comprising Compound 1. The previously performed first, second, or further line treatment is not correlated with administration of Compound 1, and the fig previously performed first, second, or further line treatment is finished or has ended before a treatment comprising the administration of Compound 1 is performed.26NAI-5006806042vlAttorney Docket No. 14763-026-228

[0126] In one embodiment, the subject has been treated with one prior therapy e.g., to treat the cancer, RASopathy, or laminopathy. In one embodiment, the subject has been treated with one prior therapy. In one embodiment, the subject has been treated with at least two prior therapies. In one embodiment, the subject has been treated with two prior therapies. In one embodiment, the prior therapy comprises a therapy selected from the group consisting of a MEK inhibitor, a BRAF inhibitor, or a combination thereof. In one embodiment, the therapy is a MEK inhibitor. In one embodiment, the prior therapy is a BRAF inhibitor. In one embodiment, the prior therapy is a combination of a MEK inhibitor and a BRAF inhibitor. In one embodiment, the subject has failed BRAF / MEK inhibition. In one embodiment, the subject has been treated with a MEK inhibitor and a BRAF inhibitor in two separate lines of prior therapy. Examples of MEK inhibitors that a subject may have been previously treated with include, but are not limited to, trametinib (e.g., MEKINIST®), cobimetinib (e.g., COTELLIC®), binimetinib (e.g., MEKTOVI®), refametinib, mirdametinib (e.g., GOMELKI®), and selumetinib (e.g., KOSELUGO®). Examples of BRAF inhibitors that a subject may have been previously treated with include, but are not limited to, vemurafenib (e.g., ZELBORAF®), dabrafenib (e.g., TAFINLAR®), and encorafenib (e.g., BRAFTOVI®). Examples of particular combinations of MEK and BRAF inhibitors that a subject may have been previously treated with include, but are not limited to, binimetinib / encorafenib, trametinib / dabrafenib, and cobimetinib / vemurafenib. In one embodiment, the subject has been treated with a MEK inhibitor and a BRAF inhibitor in two separate lines of prior therapy and was additionally treated with at least one another therapy prior to treatment with Compound 1.

[0127] In one embodiment, the cancer is relapsed after, refractory to, or resistant to the one or more prior therapies as described herein, e.g., after treatment with a MEK inhibitor, BRAF inhibitor, or a combination thereof.

[0128] It is understood that the foregoing detailed description and accompanying examples are merely illustrative, and are not to be taken as limitations upon the scope of the subject matter. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the methods of use provided herein, may be made without departing from the spirit and scope thereof.EXAMPLES

[0129] The embodiments described below are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are27NAI-5006806042vlAttorney Docket No. 14763-026-228 considered to be within the scope of the claimed subject matter and are encompassed by the appended claims.

[0130] The following abbreviations are used:Abbreviations:

[0131] “BU” is blend uniformity.

[0132] “ CU” is content uniformity.

[0133] “ SDS” is sodium dodecyl sulfate solvent.

[0134] “Mm” is millimeter.

[0135] “ pm” is micrometer.

[0136] “ TTP” is time to progression.

[0137] “PFS” is progression free survival.

[0138] “ OS” is overall survival.

[0139] “EFS” is event free survival.

[0140] “ORR” is overall response rate.

[0141] “DoR” is duration of response.

[0142] “PR” is partial response.

[0143] “ TTR” is time to response.

[0144] “NF” is neurofibromatosis.

[0145] “XRPD” is x-ray powder diffraction.

[0146] “PSD” is particle size distribution.

[0147] “ AV” acceptance value

[0148] “RPM” is rotations per minute.

[0149] “ Cmax is the maximum plasma concentration.

[0150] “ Tmax” is the time to get to maximum concentration.

[0151] “ AUC” is the area under the concentration-time curve.

[0152] “ AUCo-inf” is the area under the concentration-time curve, from time is 0 to time is infinity.

[0153] Example 1: Formulation Development

[0154] During the formulation development, it was discovered that the big particle size of Compound 1 had a negative influence on the blending uniformity. After dry milling, D90 of Compound 1 particle size decreased from around 400 pm to less than 100 pm. Four formulations were made and tested. The final blending process was robust based on current blending uniformity (BU) data. Tablets with good appearance, low friability (< 0.1%) and rapid disintegration (< 50 s) were obtained by gravity feeder, the content uniformity (CU) reached more than 99%. For coating, tablets with 3% (2.7%-3.3%) weight gain had a smooth appearance.28NAI-5006806042vlAttorney Docket No. 14763-026-228

[0155] Based on the development process of 1 mg and 4 mg tablets the same granulation parameters and forced feeder were used for 10 mg uncoated tablets. Coating was optional. White round tablets with low friability (< 0.1%) and rapid disintegration (< 120 s) were obtained, CU reached more than 99%.

[0156] Detailed development: Compound 1 was pre-screened prior to the tablet manufacturing process through 0.38 mm and 0.11 mm screens. This procedure improved the blend uniformity (BU) and tablet content uniformity (CU).

[0157] The powder properties of the milled Compound 1 were evaluated and are shown in Table 1. The assay and purity of the original Compound 1 were both 100.0%. Based on assay, purity, and X-Ray Powder Diffraction (XRPD) of milled Compound 1, the milling process had no influence on assay, purity, and crystal form. Particle size distribution (PSD) data are also shown in Table 1.Table 1: Powder Properties of Milled Compound 1 with 0.38 mm Screen and 0.10 mm Screen

[0158] Based on the results of pre-screening Compound 1 as shown in Table 1, the 0.10 mm screened Compound 1 was selected for the initial Prototype 1 and Prototype 2 formulations for a 10 mg tablet which are shown in Table 2 and Table 3 below. The excipients from Prototypes 1 and 2 were blended to test the compression characteristics of the prototype formulations. While both were similar in bulk density, tap density, Hausner ratio, tensile strength vs compaction pressure, Prototype 1 was selected to move to the next stage.Table 2: Composition of Compound 1 Prototype 1 Formulation29NAI-5006806042vlAttorney Docket No. 14763-026-228Table 3: Composition of Compound 1 Prototype 2 Formulation

[0159] Two batches of Formulation 1 (Prototype 1 formulation) final blend were manufactured by a blending and screening process. Drug substance was screened through a #35 mesh for one batch and a #60 mesh screen for the second batch to evaluate differences. The final blend was both tableted and encapsulated with hypromellose capsules in order to evaluate differences in release. Batches were sampled for blend uniformity, content uniformity, and dissolution using pH 6.8 sodium phosphate buffer with 3% sodium dodecyl sulfate. The results of this study showed that screening the drug substance through a #60 mesh screen yielded superior results for content uniformity than the batch with the drug substance screened through a #35 mesh screen. Additionally, the dissolution of the tablets was faster than the dissolution of the capsules containing the same powder blend. Based on this data from Formulation 1, it was decided that tablets would be carried forward for further development.

[0160] Since the results for the blend uniformity and content uniformity for Formulation 1 tablets did not have the desired mean or AV, changes were made to the formulation along with a process change to roller compaction (Formulation 2, Table 4). The disintegrant was changed from croscarmellose sodium to crospovidone which has a better drug substance carrying capability than croscarmellose sodium. Additionally, the microcrystalline cellulose amount was increased, and the amount of lactose monohydrate decreased.Table 4: Composition of Compound 1 Formulation 230NAI-5006806042vlAttorney Docket No. 14763-026-228Table 5: BU Results and CU Results for Formulation 2

[0161] Formulation 3 (Table 6) was developed to improve the tablet content uniformity mean by adding pregelatinized starch (Starch 1500). The content uniformity values were improved using Formulation 3.Table 6: Composition of Compound 1 Formulation 331NAI-5006806042vlAttorney Docket No. 14763-026-228Table 7: BU Results and CU Results for Formulation 3

[0162] To improve the tabletability of Formulation 3, Formulation 4 (Table 8) was manufactured with an increase in the amount of lactose monohydrate and a decrease in the amount of pregelatinized starch. Changes implemented in the formulation of Formulation 4 yielded improved tabletability and further improvement in the content uniformity.Table 8: Composition of Compound 1 Formulation 4

[0163] The formulations for 1 mg and 4 mg tablets are proportional to the 10 mg formulation based on the amount of the drug substance. These formulations are shown in Table 9 below.32NAI-5006806042vlAttorney Docket No. 14763-026-228Table 9: Quantitative Composition of Compound 1, 1 mg, 4 mg, and 10 mg TabletsExample 2: Process Formulation of Compound 1 and 4 mg Uncoated Tablets

[0164] A flow chart of the process for the formulation of Compound 1 mg and 4 mg tablets is shown in FIG. 1.Manufacturing process for Compound 1, 1 mg, 4 mg, and 10 mg tablets

[0165] Step 1 : The Compound 1 and excipients were dispensed and weighed. Compound 1, Microcrystalline Cellulose, Crospovidone, Lactose Monohydrate, Pregelatinized Starch, and 50% of the Colloidal Silicon Dioxide were hand screened through a #35 mesh screen.

[0166] Step 2: The screened Compound 1 and Crospovidone were then added to a diffusion mixer and blended for approximately 200 revolutions.

[0167] Step 3 : The screened Pregelatinized Starch was added to the mixture of Step 2 by passing through the screen in Step 2.

[0168] Step 4: The mixture in paragraph step 3 was then blended in a diffusion mixer for approximately 200 revolutions.

[0169] Step 5: Sixty-five percent (65%) of the screened Microcrystalline Cellulose were added to the mixture in step 4 and blended for approximately 200 revolutions.

[0170] Step 6: The remainder of the screened Colloidal Silicon Dioxide (50%), Lactose Monohydrate, and remainder of Microcrystalline Cellulose (35%) were added to the mixture in Step 5 and blended for approximately 400 revolutions.

[0171] Step 7: Samples were removed for measurements of Blend Uniformity.

[0172] Step 8: Fifty percent (50%) of the Magnesium Stearate, previously screened through a #60 mesh screen, was added to the mixture in Step 6 and blended for 60 revolutions.

[0173] Step 9: The blend in Step 8 was dry granulated using a roller compactor.33NAI-5006806042vlAttorney Docket No. 14763-026-228

[0174] Step 10: The remainder of the screened Colloidal Silicon Dioxide (50%) was added to the granulation from Step 9 in a diffusion mixer and blended for 400 revolutions.

[0175] Step 11 : The remainder of the Magnesium Stearate (50%), previously screened through a #60 mesh screen, was added to the blend in Step 11 and blended for 60 revolutions.

[0176] Step 12: Samples were removed for Blend Uniformity measurements.

[0177] Step 13: The tablets were compressed on a rotary tablet press fitted with a 3 mm standard concave tooling for Compound 1, 1 mg tablets, 5.5 mm standard concave tooling for Compound 1, 4 mg tablets and 8 mm standard concave tooling for Compound 1, 10 mg tablets. Appearance, Tablet Weight, Tablet Hardness, Tablet Thickness, Friability, and Disintegration were measured during the compression process.

[0178] Step 14: The compressed tablets were discharged into a container lined with two low- density polyethylene bags, with a 200 g desiccant bag between the two low-density polyethylene bags, and the bags with tablets inside were then placed into an aluminum foil bag.Stability testing

[0179] Initial data of stability for 1 mg and 4 mg strength were also collected and listed in Table 10. The assay and impurity complied with the limit, and the water contents for 1 mg and 4 mg strength tablets were 4.3% and 4.6%, respectively. CU results for releasing are shown in Table 11. For 1 mg tablets, AV was 11% and it was increased compared to stratified CU. The corrected CU results were also listed, which indicated that the increase in AV was mainly caused by weight variation. CU results of 4 mg tablets were similar to stratified CU.Table 10: Initial Data for Stability StudyTable 11: CU Results for Releasing

[0180] In addition, dissolution data and plots are shown in Table 12 and FIG. 2, respectively. 1 mg and 4 mg tablets showed similar dissolution behavior under the conditions of pH 6.8 NaH2PC>434NAI-5006806042vlAttorney Docket No. 14763-026-228 buffer with 0.5% SDS, 50 rpm. For the 1 mg strength minitablet, the weight control during tablet compression was critical for product quality.Table 12: Dissolution Data for 1 mg and 4 mg Tablets Under Conditions of pH 6.8 NaHiPCh buffer with 0.5% SDS, 50 rpmExample 3: Process for Formulation of Compound 1, 10 mg Uncoated Tablets

[0181] A flow chart of the process for the formulation of Compound 1, 10 mg tablets is shown in FIG. 3Stability Testing of 10 mg Tablet

[0182] Initial data of stability for 10 mg uncoated tablets were also collected and listed in Table 13. The assay and impurity complied the limit, water content was 4.6%. CU results for releasing were showed in Table 14. AV was 1.9% and it was similar to stratified CU. Besides, dissolution data and plot were showed in Table 15 and FIG. 4, respectively. 10 mg uncoated tablets showed similar dissolution characters to 1 mg and 4 mg uncoated tablets under the condition of pH 6.8 NaH2PC>4 buffer with 0.5% SDS, 50 rpm.Table 13: Initial Data for Stability Study for 10 mg tablet35NAI-5006806042vlAttorney Docket No. 14763-026-228Table 14: CU Results for ReleasingTable 15: Dissolution Data for 10 mg uncoated demo batch under the Condition of pH 6.8Nal ’Or buffer with 0.5% SDS, 50 rpmImprovement using wet milling

[0183] The previous formulation process was repeated using Compound 1 which was wet milled at the end of the drug substance manufacturing process. The particle size distributions for Dio, Dso and D90 were 9, 38 and 92 pm, respectively. Performing the milling during the drug substance manufacturing process is more efficient, less cumbersome, and decreases occupational exposure risk relative to screening the drug substance at the beginning of the drug product manufacturing process.

[0184] The data from the BU and CU after wet milling were similar to the results of the batch of Formula 4 tablets produced using the previous formulation process. Additionally, the dissolution36NAI-5006806042vlAttorney Docket No. 14763-026-228 was similar to the previous formulation results. An additional dissolution test was performed on 1 and 4 mg tablets which were manufactured using the same process and formulation except that the tablet weights were adjusted to 10% and 40% of the 10 mg tablet weight for the 1 and 4 mg tablets, respectively. The data shows that the dissolution profile of all strengths is similar.Example 4: Dissolution Studies Comparing Capsules and Tablets

[0185] A study was conducted to compare the dissolution of 1, 4 and 10 mg capsules versus the 1, 4 and 10 mg tablets, respectively. The capsules used consisted of 1, 4, or 10 mg of unmilled Compound 1. The tablets used were manufactured using the formulations and processes described herein. The dissolution method used a pH 6.8 NaH2PO4 Buffer with 0.5 % SDS. The data is presented in Tables 16-21 and FIG. 5. The data showed that the capsules containing the drug substance were much slower in dissolution than the tablets, and that Compound 1 when prepared in capsule form could not release completely.Table 16: Dissolution Results for Compound 1 Capsules (1 mg)NAI-5006806042vlAttorney Docket No. 14763-026-228Table 17: Dissolution Results for Compound 1 Capsules (4 mg)Table 18: Dissolution Results for Compound 1 Capsules (10 mg)38NAI-5006806042vlAttorney Docket No. 14763-026-228Table 19: Dissolution Results for Compound 1 Tablets (1 mg)Table 20: Dissolution Results for Compound 1 Tablets (4 mg)39NAI-5006806042vlAttorney Docket No. 14763-026-228Table 21: Dissolution Results for Compound 1 Tablets (10 mg)Example 5: Results of Animal Studies

[0186] Animal studies in beagle dogs were performed to determine the differences between the capsule formulation (drug-in-capsule) versus tablets versus tablet blend in capsules in vivo. The studies were designed to control for different variables between the dosage forms tested.

[0187] In one study, Compound 1, 10 mg capsules were compared to Compound 1, 10 mg tablets in a single dose study. Table 22 shows the pharmacokinetic data of this dissolution study, which demonstrates that the amount of drug released from the Compound 1, 10 mg tablet is much greater than the amount of drug released from the Compound 1, 10 mg capsule.Table 22: Selected pharmacokinetic data for study of Compound 1, 10 mg capsule vsCompound 1, 10 mg tablet in dogs

[0188] A second in-vivo dog study was conducted to study the effect of the Compound 1 tablet blend equivalent to 10 mg of Compound 1 filled into a capsule versus a 10 mg Compound 1 tablet. The data shown in Table 23 are the same selected results as presented in Table 22 where the values are for the dogs with the initial single dose given of the test drug products.

[0189] The data from Table 23 shows that the tablet blend filled in a capsule had a slightly lower Cmax and AUC than the tablet which could have been a result of the longer time to reach Tmaxinthe40NAI-5006806042vlAttorney Docket No. 14763-026-228 tablet blend capsule. Based on this data, the amount of drug released, as indicated by the AUC, is consistent with the tablet formulation as a blend or tablet delivering much greater amount of Compound 1 than in the case of the Compound 1 drug substance placed in a capsule shell.Table 23: Selected Pharmacokinetic Data for Compound 1, 10 mg tablet blend vs Compound 1, 10 mg tablet in dogs

[0190] The tablet formulations disclosed herein unexpectedly showed beneficial properties such as improved maximum plasma concentration (Cmax) and area under the curve (AUC) as demonstrated by in vivo dog pharmacokinetic studies. In addition, the tablet formulations disclosed herein demonstrated superior properties when compared to capsule formulations of similar or equivalent strength, such as improved amount of drug release in plasma.Example 6: Phase 1 Clinical Trial of Compound 1

[0191] A phase 1 open-label study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 in patients with MAPK Pathway-driven advanced solid tumors with a documented RAS, NF1, or RAF mutation or patients who have failed BRAF / MEK inhibition is described.

[0192] The Phase 1 clinical trial is a multi-center, open-label, dose escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of Compound 1 in patients with MAPK pathway driven advanced solid tumors with a documented RAS, NF1 or RAF mutation or patients who have failed BRAF / MEK inhibition.

[0193] Compound 1 in a 4 mg strength tablet form was tested in people with advanced solid tumors with rat sarcoma virus (RAS), neurofibromatosis type I (NF1), or rapidly accelerated fibrosarcoma (RAF) mutations.

[0194] Patients with histologically or cytologically diagnosed MAPK pathway driven advanced solid tumors with all of the following characteristics qualified for enrollment: i. tumor could not be surgically resected ii. patient failed or was ineligible for standard of care therapy iii. patient had no available treatment options with known clinical benefit iv. documented evidence of rat sarcoma virus (RAS), neurofibromatosis type I (NF1), and / or rapidly accelerated fibrosarcoma (RAF) mutations. Patients with RAF mutations41NAI-5006806042vlAttorney Docket No. 14763-026-228 had previously failed v-Raf murine sarcoma viral oncogene homolog B (BRAF) / MEK inhibition.

[0195] Patients in the study were administered Compound 1 in capsule or tablet form by mouth as a single dose, followed by one week observation, then once a day during the study, in 28-day cycles.

[0196] Patients continued on daily tablets of Compound 1 for up to 2 years, or until: i. they decided to withdraw from the study, or ii. they experienced unacceptable side effects, or iii. their disease progressed, or another illness interferes with taking the study drug, or iv. the sponsor stopped the study.

[0197] In this study, Compound 1 was presented in 1 mg, 4 mg, and 10 mg strength capsules with a sequential dose escalation of 2 mg, 4 mg, 8 mg, 15 mg, and 22 mg, 30 mg, 37 mg, and 45 mg Compound 1, for oral administration once daily.

[0198] In some embodiments, the tablet formulation comprised a solid form of Compound 1 described herein.

[0199] Eligibility CriteriaInclusion Criteria.1. Capable of giving signed informed consent which included compliance with the requirements, prohibitions and restrictions listed in the informed consent form (ICF).2. Patient had been informed both verbally and in writing about the objectives of the clinical study, the methods, the anticipated benefits, the potential risks, and the discomfort to which they may have been exposed and has given written consent to participation in the study prior to study start and any study-related procedure.3. Patient must have been at least 18 years of age at the time of signing the ICF.4. Patient must have been able to swallow oral medication.5. Patient with histologically or cytologically diagnosed mitogen-activated protein kinase (MAPK) pathway driven advanced solid tumors with all of the following characteristics:• Tumor could not be surgically resected• Patient had failed or was ineligible for standard of care therapy• Patient had no available treatment options with known clinical benefit• Documented evidence of rat sarcoma virus (RAS), neurofibromatosis type I (NF1), and / or rapidly accelerated fibrosarcoma (RAF) mutations. Patients with RAF mutations must have previously failed v-Raf murine sarcoma viral oncogene homolog B (BRAF) / MEK inhibition.42NAI-5006806042vlAttorney Docket No. 14763-026-2286. Prior to enrollment, patients without an existing prior genetic test result or adequate tumor tissue sample must have agreed to provide tumor tissue via biopsy (paraffin section or fresh tissue specimens) to be sent for analysis to confirm eligibility.7. Patient must have had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.8. Patient must have had an estimated life expectancy of at least 12 weeks in the opinion of the Investigator at the time of informed consent.9. Patient must have had adequate organ function at screening as indicated by the following laboratory value ranges:• Serum total bilirubin < 1.5 x upper limit normal (ULN) (Serum total bilirubin can be < 3.0 x ULN if patients have hemolysis or congenital hemolytic diseases)• Aspartate aminotransferase (AST) < 2.5 x ULN or 5 * ULN for patient with liver metastases• Alanine aminotransferase (ALT) < 2.5 x ULN or 5 x ULN for patient with liver metastases• Albumin >2 mg / dL• Creatinine clearance > 45 mL / min (as calculated per Cockcroft-Gault)• Absolute neutrophil count (ANC) > 1.5x 109 / L• Platelets > 100x 109 / L• Hemoglobin > 90 g / L (Note: Criteria must be met without a transfusion within 2 weeks of obtaining the sample)10. Must agree to maintain abstinence (no heterosexual intercourse) or use a highly effective form of contraception during study treatment and for at least 90 days after the last dose of Compound 1. Male patients must have agreed not to donate sperm while receiving the investigational product (IP) and for at least 90 days after the last dose of Compound 1.Exclusion Criteria:1. Participation in another therapeutic clinical trial within 3 weeks of enrollment.2. Received chemotherapy, radiotherapy, major surgery, targeted therapy, immunotherapy, or other antitumor treatment within 21 days of enrollment or five half-lives of the administered therapy, whichever occurs first.3. Known or active central nervous system metastases.• Patients with untreated brain metastases < 30 mm that are asymptomatic, did not have significant edema, and did not require steroids or anti-seizure medications are eligible after discussion with the Medical Monitor.43NAI-5006806042vlAttorney Docket No. 14763-026-228• Patients with previously treated brain metastases may participate provided they were stable after treatment and without evidence of progression by imaging for at least 4 weeks prior to the first dose of Compound 1 administration and were not using corticosteroids for at least 7 days prior to Compound 1 administration.• Patients with confirmed leptomeningeal disease were excluded.4. Unresolved toxicity from prior antitumor therapy defined as AEs: Grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for alopecia; neurotoxicity AEs of patients who had received prior chemotherapy needed to be restored to Grade 2 or below. Patients with > Grade 3 bleeding within 4 weeks of first study treatment dose were excluded.5. Taken a medication that is a strong cytochrome P450 (CYP3A) inhibitor or inducer within 14 days of initiation of study therapy dosing.6. Taken a known corrected QT (QTc) interval prolongating medication within 7 days of initiation or longer if the half-life of the QTc prolonging medication is such that the drug was not cleared from the body within 7 days (5 half-lives) of initiation of study therapy dosing.7. Active dysphagia, digestive system disease, malabsorption syndrome, or other conditions affecting Compound 1 absorption.8. Previous or current retinal vein stenosis, retinal detachment, central retinal vein occlusion, or currently active glaucoma.9. Active interstitial pneumonia, including clinically significant radiation pneumonitis.10. Impaired cardiac function or cardiac disease as indicated by:• Average QTc interval: 470 ms as calculated according to the QTc formula of the instrument at the research center where electrocardiogram (ECG) measurements are performed.• Grade > 3 congestive heart failure per New York Heart Association (NYHA) guidelines.• Clinically significant arrhythmias, including but not limited to, complete left bundle branch conduction abnormalities and 2nd degree atrioventricular block.11. Pregnant or lactating female patients.12. Known allergy or hypersensitivity to the investigational product (IP), including excipients, or history of severe adverse reaction to any drug, or sensitivity to components of the IP.44NAI-5006806042vlAttorney Docket No. 14763-026-22813. Clinically active bacterial, fungal, or viral infections, hepatitis B (hepatitis B virus surface antigen positive and hepatitis B virus DNA over 1000 lU / ml) or hepatitis C (hepatitis C virus RNA positive), human immunodeficiency virus infection (HIV positive).Primary Outcomes MeasuresSecondary Outcome Measures45NAI-5006806042vlAttorney Docket No. 14763-026-228Example 7: Preliminary Results of the Phase 1 Clinical Trial of Compound 146NAI-5006806042vlAttorney Docket No. 14763-026-228

[0200] Following the protocol described in Example 6, a total of 9 patients have been enrolled in dose escalation in 3 dose cohorts (2 mg, 4 mg, and 8 mg). 55.6% of the patients were female with a median age of 60 years. Most common tumor types included colorectal (n=5, 55.56%), pancreatic (n=2, 22.22%), gastroesophageal (n=l, 11.11%), and of unknown type (n=l, 11.11%). Treatment Related Adverse Events (TRAE) were reported in 44.44% of patients. TRAEs were all low grade (n=7, 100% were Grade 1-2). No Grade 3, 4 or 5 TRAEs were reported. The most common TRAEs were gastrointestinal disorders (n=4, 57.14%), dehydration (14.29%), arthralgia (14.29%) and urinary incontinence (14.29%). No rash was observed in any dose cohort. No dose limiting toxicities were detected, and the MTD has not been reached. Preliminary PK analysis of Compound 1 suggests linear PK with estimated 11 / 2 of 70h, C max / Cmin ratio of 1.4 at steady state, achieving potentially sufficient exposures for target engagement at the highest dose tested. In the efficacy evaluable population (n=6), early response evaluation reveals stable disease (SD) by RECIST 1.1 was observed in 2 patients, with progression free survival (PFS) of up to 159 days and overall survival of up to 253 days.

[0201] Compound 1 is shown to be a safe and well-tolerated MEK inhibitor, with dosedependent PK profile and preliminary clinical activity in monotherapy in patients with heavily pretreated refractory solid tumors.Example 8: Interim PK results at Day 22 (Steady State)

[0202] Following the Secondary Outcome Measures described in Example 6, interim PK data for Compound 1 were collected measuring the Area Under the Concentration versus time curve and peak plasma concentration (Cmax) at Day 22, assuming steady state had been reached. See, FIG. 6 and Table 24.Table 24: PK Results at Day 22

[0203] Results: Following multiple QD dosing, accumulation was consistent with estimated half-life suggesting linear PK. QD dosing resulted in stable concentrations at steady state with low C max tO Cmin ratio. Exposure increased with an increase in dose and dose normalized exposure ranges overlapped. Half-life was estimated to be > 60 hours.Example 9: Updated Preliminary Results of the Phase 1 Clinical Trial of Compound 1

[0204] Following the protocol described in Example 6 and expanding on the findings reported in Examples 7 and 8, a total of 21 patients have been enrolled in 6 dose escalation cohorts (Capsules:47NAI-5006806042vlAttorney Docket No. 14763-026-2282 mg, 4 mg, 8 mg, 15 mg, and 22 mg and Tablets: 4 mg). Six (28.6%) patients presented with pancreatic cancer, six (28.6%) patients presented with colorectal cancer, and five (23.8%) patients presented with melanoma. One patient did not complete DLT observation period and was replaced. All patients had received at least two prior lines of treatments.

[0205] No DLTs and no treatment-related SAEs observed and the MTD was not reached with the 22 mg dosing level. All AEs were grade 1 or 2. No drug-related grade 3, 4 or 5 AEs were reported. No known MEK inhibitor class related AEs such as ocular toxicities, cardiotoxicities, or skin toxicities were observed during the DLT observation period. The most common drug related AEs were gastrointestinal toxicities, including nausea, diarrhea, and vomiting.

[0206] Results of additional preliminary PK analysis are shown in FIG. 7 and Table 25.Table 25: Additional PK Results at Steady State

[0207] Results: Following multiple QD dosing, accumulation was consistent with estimated half-life suggesting linear PK with an estimated half-life of >60 hours. Systemic exposure to Compound 1 increases with an increase in dose and dose-normalized exposure ranges overlap. The C max / Cmin ratio is <2 at steady state, indicating that the highest dose tested should provide enough exposure for sufficient target engagement. This is supported by preliminary pERK inhibition observed in cohort 3 (8 mg capsule), with pERK inhibition of up to 91%.

[0208] In the efficacy evaluable population (n = 16), early response evaluation reveals stable disease (SD) as assessed by RECIST 1.1 in 10 patients, with progression free survival (PFS) of up to 159 days and overall survival of up to 253 days. Results are shown in FIGs. 8, 9, and 10.

[0209] In Cohort 4A (15 mg capsule), two out of three patients achieved stable disease and remain on therapy. One patient with Stage 4 KRAS G12R-mutated pancreatic cancer, having progressive disease while on three prior lines of therapy, achieved a tumor diameter reduction of - 9.8% and remained on the study for over 5 months. The second patient with Stage 4 BRAF mutated melanoma, having failed 2 prior lines of therapy including a prior MEK inhibitor + BRAF inhibitor combination therapy achieved tumor diameter reduction of -14.9%.48NAI-5006806042vlAttorney Docket No. 14763-026-228

[0210] Conclusions:

[0211] Compound 1 has been shown to be a safe and well-tolerated next-generation MEK inhibitor at all doses tested. No DLTs have been observed and the MTD has not yet been reached. Compound 1 presents a dose-dependent linear PK profile with a half-life > 60h. The Cmax (peak) to Cmin (trough) ratio below 2 provides the potential to achieve sustained target inhibition.Compound 1 has demonstrated promising preliminary clinical activity as a monotherapy in patients with heavily pre-treated refractory solid tumors. Particularly, Compound 1 has demonstrated promising clinical benefit in a re-challenge patient who failed a prior MEK inhibitor.Example 10: Compound 1 Demonstrated Favorable Human Pharmacokinetics Properties as compared to known MEK 1 / 2 inhibitors

[0212] Compound 1 demonstrated favorable human pharmacokinetics properties when compared to known MEK 1 / 2 inhibitors Mirdametinib and Selumetinib. As shown in FIGs. 11A and 11B, Compound 1 was dosed once a day (QD) resulting in stable concentration, while Mirdametinib and Selumetinib were dosed twice a day (BID), FIG. 11A and FIG. 11B, respectively. Table 26 shows the PK data comparison between Compound 1, Mirdametinib and Selumetinib. The data shows that Compound 1 has favorable human pharmacokinetics properties.Table 26: PK data comparison between Compound 1, Mirdametinib, and Selumetinib.

[0213] Compared to Mirdametinib and Selumetinib, Compound 1 showed the advantageous property of once daily dosing while still maintaining favorable exposure. The once-a-day dosing regimen is potentially beneficial to overcome the side effects (e.g., skin rash, ocular toxicity, cardio- vascular toxicity, etc.) and high drug discontinuation rate observed in patients treated with Selumetinib or Mirdametinib (see, e.g., Campagne et al., Clin Pharmacokinet. 2021 March; 60(3): 283-303; see also, Koselugo® (Selumetinib) and Gomekli® (Mirdametinib) Prescribing Information).

[0214] Example 11: NF1 Cell Growth Inhibition

[0215] Schwann cells are a primary component of PN in NF1. Compound 1 was tested for the ability to inhibit the growth of three NF 1 mutant neurofibroma-derived Schwann cell lines and two wild-type Schwann cell lines. Cells were treated for 48 hours and all Compound 1 treated cell lines showed growth inhibition, with 60-80% growth inhibition in the three neurofibroma-derived49NAI-5006806042vlAttorney Docket No. 14763-026-228NFI mutant cell lines (NFI’7’) and less than 20% inhibition of the wild-type cell lines (NF I"1"1) tested FIG. 12A shows Compound 1 percent inhibition and FIG. 12B shows Selumetinib (AZD6244) percent inhibition. Growth inhibition with Compound 1 was greater than the maximal growth inhibition seen with equivalent doses of AZD6244 (Selumetinib). In addition, the inhibition did not plateau at the highest doses used in the study compared to Selumetinib.

[0216] Example 12: Effects on Tumor Growth in In Vivo NFI Model

[0217] The efficacy of Compound 1 was tested in a transgenic mouse model of NFI (Nflflox / flox;Postn-Cre mice) and compared with AZD6244. Compound 1 was administered orally at 10 mg / kg / day and AZD6244 (Selumetinib) was administered orally at 10 mg / kg / twice daily, the maximum tolerated dose of AZD6244 (Selumetinib) in this NFI model.

[0218] Both Compound 1 and AZD6244 (Selumetinib) significantly reduced the dorsal root ganglion (DRG) volume compared to vehicle-treated mice (p = 0.0048 and 0.0123, respectively; FIG. 13A) and tumor number was significantly reduced by both treatments (FIG. 13B).

[0219] In summary, the totality of the nonclinical pharmacology and early clinical data were consistent with MAPK / ERK pathway inhibition and suggested Compound 1 effectiveness in NFI.

[0220] Example 13: Phase 1 / lb Clinical Trial of Compound 1

[0221] A Phase 1 / lb clinical study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 in adult NFI patients with at least one and up to two additional plexiform neurofibromas (PNs) that are symptomatic and inoperable, incompletely resected, or recurrent is described.

[0222] The Phase 1 / lb clinical trial is a multi-center, open-label, dose escalation 3+3 study to evaluate the preliminary efficacy of Compound 1 in adult NFI patients with at least one and up to two additional PNs that are symptomatic and inoperable, incompletely resected, or recurrent. Certain NFI patients have both plexiform neurofibromas and cutaneous neurofibromas (CNs).

[0223] Compound 1 in 1 mg and 4 mg strength tablet form is tested in people with at least one and up to two additional PNs that are symptomatic and inoperable, incompletely resected, or recurrent.

[0224] Patients in the study are administered Compound 1 in tablet form by mouth as a single dose once a day during the study, in 28-day cycles.

[0225] In Part A of the study, patients are administered one of four dose levels of Compound 1 tablets (4 mg, 8 mg, 12 mg, and 18 mg) in a modified 3+3 design. Part A is used to identify the recommended Phase 2 dose (RP2D) in Part B.50NAI-5006806042vlAttorney Docket No. 14763-026-228

[0226] In Part B, patients are administered either one of two dose levels of Compound 1 tablets. Patients are dosed at the RP2D level and at a dose level below the RP2D according to continuous 28-day treatment cycles to identify a recommended phase 2 dose (RP2D).

[0227] This is summarized in the table below.

[0228] Eligibility CriteriaInclusion Criteria:1. Diagnosed with NF1 based upon the following diagnostic criteria qualify for enrollment:2. Clinical and imaging confirmation meeting at least two of the following NF 1 diagnostic criteria in accordance with the clinical NIH consensus criteria: i. more than six (6) cafe-au-lait macules greater than 1.5 cm in maximum diameter ii. axillary and / or inguinal freckling iii. more than two neurofibromas of any type, or > 1 plexiform neurofibroma; iv. an optic pathway glioma (prior diagnosis without concurrent disease is acceptable) v. five (5) Lisch nodules (iris hamartomas) as confirmed on slit lamp exam by an ophthalmologist vi. a distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex vii. a biologic parent with confirmed diagnosis of NF1 viii. genetic testing demonstrating a pathogenic NF1 germline mutation per CLIA- certified laboratory (or equivalent) testing.NF1 germline pathologic mutation positive must either be confirmed by the central laboratory or have documentation of NF1 mutation issued by a CLIA-certified laboratory (or equivalent).3. A low likelihood as assessed by a medical professional, e.g., a clinician, that the apparent NF1 diagnosis is not an NF1 mimic, for example, Noonan Syndrome, Legius Syndrome, or schwannomatosi s .51NAI-5006806042vlAttorney Docket No. 14763-026-2284. Has at least one symptomatic PN measuring at least 3 cm on maximal cross-sectional (axial) diameter that is judged by a medical professional (e.g., clinician) to be likely responsible for patient’s symptoms (such as pain, deformity, or neurologic disability), and unable to be completely resected without causing substantial damage / functional deficit, or unsuitable for surgery with high surgical risks.5. Has an incompletely resected symptomatic PN with a postoperative residual of at least 15% of the primary lesion and measuring at least 3 cm on cross-sectional (axial) diameter.6. Has a recurrent symptomatic PN measuring at least 3 cm in maximal cross-sectional (axial) dimension after prior resection.7. Has a minimum of seven measurable CN measuring 6-15 mm. Measurable is defined according to one of the following criteria: 1. non-pedunculated (no stalk) 2. surrounded by visually uninvolved skin and not in physical contact with another CN, 3. measuring between 6 and 15 mm in the longest diameter and exophytic on visual exam (not macular). At least seven CN are located on the trunk, neck, and / or limbs measuring between 6 and 15 mm in maximal diameter, and "measurable" as per the definition listed above.8. Have an international normalized ratio (INR) and activated partial thromboplastin time (APTT) < 1.5 x ULN.9. Have adequate organ and bone marrow function at screening as indicated by the following laboratory value ranges:• Absolute neutrophil count (ANC) > 1.5 x 109 / L• Hemoglobin > 90 g / dL• Platelets > 100 * 109 / L• Serum total bilirubin < 1.5 x ULN for age (< 3.0 x ULN in patients with Gilbert's syndrome)• Serum total bilirubin < 1.5 x ULN (or < 3.0 x ULN if patient has hemolysis or congenital hemolytic disease)• Aspartate aminotransferase (AST) < 2.0 x ULN• Alanine aminotransferase (ALT) < 2.0 x ULN• Albumin > 3 g / dL• Creatinine clearance > 60 mL / min.10. Must agree to maintain abstinence (no heterosexual intercourse), or to use one highly effective form of contraception during study treatment and for at least 90 days after the last dose of Compound 1. Sperm-producing patients must agree not to donate sperm while being administered Compound 1 and for at least 90 days after the last dose of Compound 1.52NAI-5006806042vlAttorney Docket No. 14763-026-228Exclusion criteria:1. Participation in another interventional clinical study within 28 days of initiating administration of Compound 1.2. Received chemotherapy for any indication within 90 days of initiating administration of Compound 1.3. Experiencing ongoing side effects from prior chemotherapy that are worse than mild (except alopecia). ("Mild" is defined as Asymptomatic or mild symptoms, clinical or diagnostic observations only, or intervention not indicated.)4. Received treatment with any PN-directed drug or biologic therapy within 14 days of starting administration of Compound 1.5. Received treatment with a strong CYP3A4 inhibitor or inducer, or moderate inducers for CYP2C8 and CYP2C9 within 14 days of starting Compound 1, or any drug considered a major substrate of the enzymes above with a narrow therapeutic index except for topical skin use.6. Received growth factors to increase the number or function of platelets or white blood cells within 7 days of starting Compound 1.7. Received radiotherapy, major surgery, or immunotherapy within 28 days of starting Compound 1.8. Has malignant tumors associated with NF1 requiring chemotherapy, radiotherapy, or surgery, such as intermediate- to high-grade gliomas or malignant peripheral nerve sheath tumors.9. Has a current malignancy (excluding cured non-melanomatous skin cancer, breast carcinoma in situ, or cervical cancer in situ) or has history of malignancy requiring active treatment within the past 5 years (excluding cured non-melanomatous skin cancer, breast carcinoma in situ, and cervical cancer in situ).10. Has uncontrolled hypertension defined as blood pressures >150 / 90 mm Hg on repeat examinations despite maximal medical management. Patients with controlled hypertension with anti-hypertension therapy are permitted on a case-by-case basis.11. Has active dysphagia, digestive system disease, malabsorption syndrome, or other conditions that might affect the absorption of Compound 1.12. Has previous or current retinal vein occlusion (RVO), retinal pigment epithelial detachments (RPED), clinically active glaucoma, or other significant abnormality in screening ophthalmic examination.53NAI-5006806042vlAttorney Docket No. 14763-026-22813. Has interstitial pneumonia, NF 1 -related pulmonary disease, including existing clinically significant radiation pneumonitis.14. Has impaired cardiac function or cardiac disease as indicated by:• Average QTc interval > 480 ms calculated using the Fridericia's QT interval correction formula.• Grade > 3 congestive heart failure per New York Heart Association (NYHA) guidelines.• Clinically significant arrhythmias, including but not limited to, complete left bundle branch conduction abnormalities and 2nd degree atrioventricular block.• Known concurrent clinically significant coronary artery disease, cardiomyopathy, or severe valvular disease.• Echocardiogram or multi-gated acquisition (MUGA) scan performed during the screening showing impaired left ventricular ejection fraction (LVEF) < 45%.15. Has taken a QTc-prolonging medication within seven days of initiating administration of Compound lor longer if the half-life of the QTc prolonging medication is such that the drug is not cleared from the body within 7 days (5 half-lives) of initiating administration of Compound 1.16. Has an uncontrolled bacterial, fungal, or viral infections, including active hepatitis B (hepatitis B virus surface antigen positive and hepatitis B virus DNA > 1000 lU / ml or meeting the study site's diagnostic criteria for active hepatitis B infection), hepatitis C (hepatitis C virus RNA positive), or HIV infection with detectable viral load.17. Has any clinically significant active or known history of liver disease or known hepatobiliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).18. Has a known hypersensitivity to Compound 1, its excipients, or another MEK 1 / 2 inhibitor.19. Is pregnant or lactating.Primary Outcome Measures54NAI-5006806042vlAttorney Docket No. 14763-026-228Secondary Outcome Measures55NAI-5006806042vlAttorney Docket No. 14763-026-228

[0229] Example 14: Interim Phase 1 Results in patients with MAPK Pathway-driven advanced solid tumors with a documented RAS, NF1, or RAF mutation or patients who have failed BRAF / MEK inhibition

[0230] Following the clinical trial study disclosed in Examples 6-9, updated interim results demonstrated the safety, PK, and anti -tumor activity of Compound 1.

[0231] Initial Signals of Clinical Activity

[0232] Among 21 efficacy evaluable patients (as per RECIST 1.1):• Partial Response: o A BRAF V600E melanoma patient in Cohort 4A (15mg capsule) achieved an unconfirmed partial response -31.9% tumor reduction and remains on trial for56NAI-5006806042vlAttorney Docket No. 14763-026-228>11 months; prior best response when treated with a MEK + BRAF combination therapy was stable disease• Disease Control Rate (DCR): o 71.4% (5 of 7) of patients identified with BRAF -mutated tumors achieved stable disease or partial response. o 42.8% (9 of 21) of patients achieved stable disease or partial response.• Durable Stable Disease: o A second BRAF V600E melanoma patient previously treated with MEK + BRAF combination therapy in Cohort 6 (30 mg capsule) remains on trial for >6 months with a stable disease and tumor shrinkage of -1.6%

[0233] Safety and Tolerability

[0234] Among 27 dosed patients through the Dose Limiting Toxicity (DLT) period (Day 28) through the cutoff:• Compound 1, dosed once daily (QD), has been well-tolerated across all dose levels.• No dose-limiting toxi cities (DLTs), no dose interruptions, and no discontinuations have been reported.• All treatment-related adverse events (TRAEs) at least possibly related to Compound 1 were Grade 1 or 2, with limited rash (7.4%), nausea (18.5%), vomiting (14.8%), diarrhea (7.4%), and no ocular retinal abnormalities or cardiovascular toxicities observed.

[0235] Example 15: Pharmacokinetics (PK) from Interim Results

[0236] Compound 1 has demonstrated through Cohort 6 (30 mg capsule):• Linear PK and dose-proportionality• PK curve with C max / Cmin ratio <2, with Cmax and Cmin above the ICso (half-maximal inhibitory concentration) from cellular assay.• Long half-life (~60 hours)• Cohort 6 (30 mg capsule) has demonstrated: o AUC: -5,480 ng h / mLO Cmax^ 249 ng / mLO Cmin 215 ng / mL

[0237] Conclusion: The above results support Compound l’s potential to be a best-in-class MEK inhibitor for the treatment of NF1-PN. Achieving a monotherapy partial response in an advanced cancer patient who had previously received a MEK + BRAF inhibitor combination therapy, and whose prior best response had been stable disease, is remarkable and unexpected.57NAI-5006806042vlAttorney Docket No. 14763-026-228Significant drug exposures (AUC) greater than 5,400 ng h / mL at the 30 mg capsule dose, with a relatively flat PK curve, suggests sustained pathway inhibition. Without wishing to be bound by theory, it is believed that this profile is well aligned with what is needed to drive meaningful clinical responses in NF1-PN patients. Maintaining NF 1-PN patients on treatment for extended periods of time is paramount to achieving maximum tumor control, and Compound l’s response profile and low rate of adverse side effects may translate into better tolerability and longer time-on- treatment for plexiform neurofibromas associated with NF 1 compared with current FDA-approved therapies that have reported discontinuation rates as high as 40-50% before year two.

[0238] Example 16: Preliminary Results from the Phase 1 / lb Clinical Trial of Compound 1

[0239] Following the protocol described in Example 13, patients were evaluated for the size of cutaneous neurofibromas (CNs) over time among other secondary outcomes. Cutaneous neurofibromas were measured using digital calipers. Six patients were administered Compound 1, 4 mg or 8 mg tablet, and their CNs evaluated at the end of cycle 1 (28 days). Of the six patients, three patients who completed 4-month administration showed at least 20% size reduction at 4- month with some patients showing CNs reduction up to 40-50%. For those who completed only the first cycle (28 days), results were consistent with those at 4-month. All patients remain on study.

[0240] Compound 1 has demonstrated• Long half-life (-57 hours)• Cohort 1 (4 mg tablet) has demonstrated: o AUC: -1,120 ng h / mL O Cmax: 58.1 ng / mL O Cmin 37.6 ng / mL• Cohort 2 (8 mg tablet) has demonstrated: o AUC: -2,290 ng h / mLO Cmax: 118 ng / mL O Cmin 75.4 ng / mL

[0241] Dose normalized exposures following administration of Compound 1 tablets were approximately 3-fold higher than those following administration with the capsule formulation, resulting in the 8 mg tablet area under the curve (AUC) and Cmax being slightly greater than those of the 22 mg capsule, as shown in FIG. 14 and Table 27 below. This is consistent with the pre- clinical evaluation of the two formulations in the dog toxicology studies.58NAI-5006806042vlAttorney Docket No. 14763-026-228Table 27: Dose normalized exposures between 4 mg tablet, 8 mg tablet, and 22 mg capsule of Compound 1.

[0242] In addition to the various embodiments described herein, the present disclosure includes the following embodiments numbered El through E49. This list of embodiments is presented as exemplary list and the application is not limited to these embodiments.

[0243] El. A pharmaceutical composition comprising about 1% to about 10% (5R,6S)-10,l l- difluoro-12-((2 -fluoro-4-iodophenyl)amino)-5,6-dihydroxy -4,5,6, 7-tetrahydro-lH- spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide or a pharmaceutically acceptable salt or solid form thereof (Compound 1), about 42% to about 46% microcrystalline cellulose, about 22% to about 26% lactose monohydrate, about 13% to about 17% pregelatinized starch, about 8% to about 12% crospovidone, about 0.3% to about 0.7% colloidal silicon dioxide, and about 0.05% to about 0.7% magnesium stearate, where the percentages are by weight based on total weight of the tablet.

[0244] E2. The pharmaceutical composition of El, further comprising about 5% Compound 1, about 44.4% microcrystalline cellulose, about 24% lactose, about 15% starch, about 10% crospovidone, about 0.5% colloidal silicon dioxide, and about 0.1% magnesium stearate, wherein the percentages are by weight based on total weight of the tablet.

[0245] E3. The pharmaceutical composition of El or E2, further comprising 0.5% magnesium stearate.

[0246] E4. The pharmaceutical composition of any one of E1-E3, further comprising 0.5% colloidal silicon dioxide.

[0247] E5. The pharmaceutical composition of any one of E1-E4, comprising about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 80 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 40 mg, about 1 mg to about 20 mg, or about 1 mg to about 10 mg of Compound 1.

[0248] E6. The pharmaceutical composition of any one of E1-E5, comprising about 1 mg, about 4 mg, about 8 mg, about 10 mg, about 12 mg, or about 18 mg of Compound 1.

[0249] E7. The pharmaceutical composition of any one of E1-E6, wherein the composition is59NAI-5006806042vlAttorney Docket No. 14763-026-228 filled in a capsule or tablet.

[0250] E8. A method of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, comprising administering to a subject having the disease or disorder, the pharmaceutical composition of any one of E1-E7.

[0251] E9. A method of treating a disease or disorder in which the RAS pathway is upregulated comprising administering (5R,6S)-10,l l-difluoro-12-((2-fluoro-4-iodophenyl)amino)-5,6- dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2- di oxide or a solid form thereof (Compound 1) to a subject having the disease or disorder.

[0252] E10. The method of E8 or E9, wherein the disease or disorder is cancer or a tumor.

[0253] El l. The method of E10, wherein the cancer or tumor is a neurofibroma.

[0254] E12. The method of El 1, wherein the cancer or tumor is a neurofibroma associated with neurofibromatosis 1 (NF1).

[0255] E13. The method of any one of E8-E12, wherein the cancer or tumor is selected from cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, and malignant peripheral nerve sheath tumor.

[0256] E14. The method of E13, wherein the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.

[0257] El 5. The method of E8 or E9, wherein the subject has been diagnosed with a Rasopathy disorder selected from neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Noonan syndrome.

[0258] E16. The method of E10, wherein the cancer is selected from gastroesophageal cancer, colorectal cancer, melanoma, lung cancer, pancreatic cancer, ovarian cancer, skin cancer, breast cancer, brain cancer, stomach cancer, thyroid cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, lymphoma, and leukemia.

[0259] El 7. A method of treating a subject having a MAPK pathway-driven advanced solid tumor with a documented RAS, NF1, or RAF mutation or a subject who has failed BRAF / MEK inhibition comprising administering to the subject a pharmaceutical composition of any one of El- E7.

[0260] E18. The method of E17, wherein the solid tumor is selected from skin cancer, brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, lymphoma, and leukemia.

[0261] E19. A method of treating, preventing, or managing neurofibromatosis 1 (NF1) in a subject having neurofibromatosis 1 (NF1), comprising administering to the subject the pharmaceutical composition of any one of E1-E7.60NAI-5006806042vlAttorney Docket No. 14763-026-228

[0262] E20. A method of preventing or inhibiting proliferation, growth and / or viability of neurofibromatosis 1 (NF1) cells in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of any one of E1-E7.

[0263] E21. The method of El 9 or E20, wherein the subject has a cutaneous neurofibroma and / or a plexiform neurofibroma.

[0264] E22. The method of E21, wherein the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.

[0265] E23. The method of any one of E8-E22, wherein Compound 1 is administered or formulated to be administered in an amount of about 1 mg to about 200 mg to the subject.

[0266] E24. The method of E23, wherein Compound 1 is administered or formulated to be administered daily.

[0267] E25. The method of E23, wherein Compound 1 is administered or formulated to be administered at least once every day, at least once every other day, at least once every two days, at least once every three days, at least once every week, at least once every other week, or at least once every three weeks.

[0268] E26. The method of any one of E8-E10, wherein the subject has been previously treated with one or more lines of therapy prior to being administered Compound 1.

[0269] E27. The method of E26, wherein the one or more lines of therapy comprises a MEK inhibitor, or a BRAF inhibitor, or a combination thereof.

[0270] E28. A method of preventing or inhibiting proliferation, growth, and / or viability of neurofibromatosis 1 (NF1) cells, comprising contacting the NF 1 cells with the pharmaceutical composition of any one of E1-E6.

[0271] E29. Use of the pharmaceutical composition of any one of E1-E7, for treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies.

[0272] E30. Use of (5R,6S)-10,l l-difhioro-12-((2-fhioro-4-iodophenyl)amino)-5,6-dihydroxy- 4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-dioxide or a solid form thereof (Compound 1), for treating a disease or disorder in which the RAS pathway is upregulated.

[0273] E31. The use of E29 or E30, wherein the disease or disorder is cancer or a tumor.

[0274] E32. The use of E31, wherein the cancer or tumor is a neurofibroma.

[0275] E33. The use of E32, wherein the cancer or tumor is a neurofibroma associated with neurofibromatosis 1 (NF1).61NAI-5006806042vlAttorney Docket No. 14763-026-228

[0276] E34. The use of any one of E29-E33, wherein the cancer or tumor is selected from cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, and malignant peripheral nerve sheath tumor.

[0277] E35. The use of E34, wherein the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.

[0278] E36. The use of E29 or E30, wherein the subject has been diagnosed with a Rasopathy disorder selected from neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Noonan syndrome.

[0279] E37. The use of E31, wherein the cancer is selected from gastroesophageal cancer, colorectal cancer, melanoma, lung cancer, pancreatic cancer, ovarian cancer, skin cancer, breast cancer, brain cancer, stomach cancer, thyroid cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, lymphoma, and leukemia.

[0280] E38. Use of a pharmaceutical composition of any one of E1-E7, for treating a MAPK pathway-driven advanced solid tumor with a documented RAS, NF1, or RAF mutation or solid tumor that has failed BRAF / MEK inhibition.

[0281] E39. The use of E38, wherein the solid tumor is selected from skin cancer, brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, lymphoma, and leukemia.

[0282] E40. Use of the pharmaceutical composition of any one of E1-E7 for treating, preventing, or managing neurofibromatosis 1 (NF1).

[0283] E41. Use of the pharmaceutical composition of any one of E1-E7, for preventing or inhibiting proliferation, growth, and / or viability of neurofibromatosis 1 (NF1) cells.

[0284] E42. The use of E40 or E41, wherein the subject has a cutaneous neurofibroma and / or a plexiform neurofibroma.

[0285] E43. The use of E42, wherein the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.

[0286] E44. The use of any one of E29-E43, wherein Compound 1 is administered or formulated to be administered in an amount of about 1 mg to about 200 mg.

[0287] E45. The use of E44, wherein Compound 1 is administered or formulated to be administered daily.

[0288] E46. The use of E44, wherein Compound 1 is administered or formulated to be administered at least once every day, at least once every other day, at least once every two days, at least once every three days, at least once every week, at least once every other week, or at least once every three weeks.62NAI-5006806042vlAttorney Docket No. 14763-026-228

[0289] E47. The use of any one of E29-E31, wherein the treatment comprises one or more lines of therapy prior to the administration of the pharmaceutical composition of Compound 1.

[0290] E48. The use of E47, wherein the one or more lines of therapy comprises a MEK inhibitor, BRAF inhibitor, or a combination thereof.

[0291] E49. The pharmaceutical composition of any one of E1-E6 for use in a method of preventing or inhibiting proliferation, growth, and / or viability of neurofibromatosis 1 (NF1) cells.

[0292] The embodiments provided herein are not to be limited in scope by the specific embodiments provided in the examples which are intended as illustrations of a few aspects of the provided embodiments and any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments provided herein are in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[0293] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.63NAI-5006806042vl

Claims

Attorney Docket No. 14763-026-228CLAIMSWhat is claimed:

1. A tablet comprising about 1% to about 10% (5R,6S)-10,l l-difluoro-12-((2-fluoro-4- iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'- cyclopropane] 2,2-dioxide or a pharmaceutically acceptable salt or solid form thereof (Compound 1), about 42% to about 46% microcrystalline cellulose, about 22% to about 26% lactose monohydrate, about 13% to about 17% pregelatinized starch, about 8% to about 12% crospovidone, about 0.3% to about 0.7% colloidal silicon dioxide, and about 0.05% to about 0.7% magnesium stearate, where the percentages are by weight based on total weight of the tablet.

2. The tablet of claim 1, comprising about 5% Compound 1 or a pharmaceutically acceptable salt or a solid form thereof, about 44.4% microcrystalline cellulose, about 24% lactose, about 15% starch, about 10% crospovidone, about 0.5% colloidal silicon dioxide, and about 0.1% magnesium stearate, where the percentages are by weight based on total weight of the tablet.

3. The tablet of claim 1 or 2, further comprising 0.5% magnesium stearate.

4. The tablet of any one of claims 1-3, further comprising 0.5% colloidal silicon dioxide.

5. The tablet of any one of claims 1-4, comprising 1 mg, 4 mg, 8 mg, 10 mg, 12 mg, or 18 mg of Compound 1.

6. The tablet of any one of claims 1-5, having a diameter of about 3, about 8, or about 10 mm.

7. The tablet of any one of claims 1-6, further comprising a coat.

8. The tablet of claim 7, wherein the coat produces a weight gain of about 3%.

9. A process for preparing a tablet comprising: i) screening the excipients (except lubricant); ii) blending intra-granular components to obtain an intragranular blend, ii) roller compacting the intragranular blend to obtain roller compacted granules, iii) blending extra-granular components to obtain an extra-granular blend, iv) blending the roller compacted granules with the extra-granular blend to obtain a final blend, and v) compressing the final blend to obtain the tablet, wherein the intra-granular blend comprises (5R,6S)-10,l l-difluoro-12-((2-fluoro-4-iodophenyl)amino)-5,6- dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2-64NAI-5006806042vlAttorney Docket No. 14763-026-228 dioxide or a solid form thereof (Compound 1), a diluent, a disintegrant, a glidant, and a lubricant, and the extra-granular blend comprises a glidant, and a lubricant.

10. A method of treating a disease or disorder in which the RAS pathway is upregulated such as cancer, RASopathies and laminopathies, comprising administering to a subject having the disease or disorder, the tablet of any one of claims 1-8.

11. The method of claim 10, wherein the disease or disorder is a neurofibromatosis (NF) related disorder.

12. The method of claim 11, wherein the NF related disorder is a neurofibromatosis 1 (NF1) related disorder.

13. The method of claim 12, wherein the NF1 related disorder is a cutaneous or plexiform neurofibroma.

14. The method of claim 13, wherein the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.

15. A method of treating a disease or disorder in which the RAS pathway is upregulated comprising administering (5R,6S)-10,l l-difhioro-12-((2-fhioro-4-iodophenyl)amino)-5,6- dihydroxy-4,5,6,7-tetrahydro-lH-spiro[benzo[b][l,5,4]oxathiazecine-3,l'-cyclopropane] 2,2- di oxide or a solid form thereof (Compound 1) to a subject having the disease or disorder.

16. The method of claim 15, wherein the disease or disorder is cancer.

17. The method of claim 16, wherein the cancer is gastroesophageal cancer, colorectal cancer, melanoma, non-small cell lung cancer, pancreatic cancer, or ovarian cancer.

18. The method of claim 17, wherein the disease or disorder is a neurofibromatosis (NF) related disorder.

19. The method of claim 18, wherein the NF-related disorder is a neurofibromatosis 1 (NF1) related disorder.

20. The method of claim 19, wherein the NF 1 related disorder is a cutaneous or plexiform neurofibroma.65NAI-5006806042vlAttorney Docket No. 14763-026-22821. The method of claim 20, wherein the plexiform neurofibroma is symptomatic and inoperable, incompletely resected, and / or recurrent.

22. The method of any one of claims 15 to 21, wherein Compound 1 is administered in an amount of about 2 mg to about 45 mg per day to the subject.

23. The method of any one of claims 15 to 22, wherein the subject has been previously treated with one or more lines of therapy prior to being administered Compound 1.

24. The method of claim 23, wherein the one or more lines of therapy comprises a MEK inhibitor, BRAF inhibitor, or a combination thereof.66NAI-5006806042vl

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