New application and preparation of quinazolinone compound

Abstract

The present invention relates to (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl) oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof, for new use in the treatment of locally advanced solid tumors, in particular melanoma with brain metastasis. The present invention also relates to a pharmaceutical composition comprising (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl) oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof, as well as to a pharmaceutical composition comprising the same.

Description

[0001] The present invention provides a BRAF inhibitor of formula (I),

[0002]

[0003] or a pharmaceutically acceptable salt thereof, which is used for the treatment of melanoma with brain metastases.

[0004] The present invention further relates to novel methods and uses of the compound of formula (I) as defined above, and to pharmaceutical formulations comprising the compound of formula (I).

[0005] The chemical name of the compound of formula (I) is (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide. Herein, the compound of formula (I) is also referred to as compound Ia. Brief Description of the Drawings

[0006] Overview of the design of the Ia / b phase study.

[0007] Flowchart of the manufacturing method of the film-coated tablets containing compound Ia.

[0008] Preliminary PK data on the effect of food on the PK of compound Ia.

[0009] Simulation based on the PopPK model to estimate the C trough coverage range of compound Ia. Background Art

[0010] Oncogenic mutations in the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase gene have been observed in approximately 8% of all solid tumors. Such mutations result in constitutive activation of the BRAF kinase, which causes dysregulation of downstream signaling via MAPK / extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK), leading to excessive cell proliferation and survival. Three approved BRAF inhibitors (BRAFi) have shown efficacy in indications such as BRAF V600E / K-positive melanoma. However, the low survival rate of patients with metastatic melanoma, including those with tumors carrying the BRAF oncogene, highlights the need for improved drugs targeting these mutations.

[0011] One of the most common and severe complications of cutaneous melanoma is the formation of metastatic sites in the central nervous system (CNS). Although recently developed BRAFi has significantly increased the median progression-free survival (PFS) of patients with metastatic melanoma, disease control is significantly shorter in patients with melanoma brain metastases (including those with BRAF-mutant melanoma with brain metastases) compared to patients with only extracranial disease. For patients with brain metastases receiving BRAFi therapy, disease progression most frequently occurs in the CNS. In addition, patients with BRAF-mutant melanoma in whom both checkpoint inhibitor (CPI) therapy and BRAF-targeted therapy have failed (i.e., line 3 patients) have very few treatment options and represent a patient population with a highly unmet medical need.

[0012] Compound Ia, previously disclosed in WO2021116055A1, is a potent RAF inhibitor targeting mutant BRAF V600E / K, designed to avoid paradoxical MAPK induction in non-BRAF V600E / K mutant cells and exhibiting high brain permeability to achieve effective drug exposure in the CNS. The present invention relates to the new use of compound Ia for the treatment of locally advanced solid tumors and / or metastatic cancers, particularly cutaneous melanoma with brain metastases, and to a suitable pharmaceutical composition comprising compound Ia. Preliminary data from our current phase Ia / Ib clinical trial indicate that compound Ia has an excellent safety profile, with less than 25% drug-related grade 3 adverse events, a result unexpectedly far lower than that of currently approved BRAF inhibitors. Given its excellent safety profile, the compounds of the present invention have the potential to be dosed at a much higher inhibitory concentration coverage range and thus have the potential to provide significant benefits to patients in terms of efficacy and / or safety.

[0013] Compound Ia shows low and pH-dependent solubility and behaves like a weak acid over the entire physiological pH range, being poorly soluble at low pH and increasing in solubility at neutral and alkaline pH. Thus, a particular embodiment of the present invention relates to a film-coated tablet comprising compound Ia, wherein the tablet composition further comprises a pH regulator and thereby enhances the dissolution characteristics of compound Ia. An embodiment of the present invention relates to an effective and safe dosing regimen of compound Ia alone or in combination with cobimetinib for the treatment of solid tumors and particularly melanoma with brain metastases. Detailed Description

[0014] The term "inhibitor" refers to a compound that competes with a specific ligand for binding to a specific receptor, or reduces or prevents the binding of the specific ligand to the specific receptor, or that reduces or prevents the function of a specific protein. Specifically, the inhibitors used herein refer to compounds that target, reduce or inhibit the activity of the corresponding targets selected from BRAF and MEK, and a specific inhibitor has an IC50 value of less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 50 nM, less than 25 nM, less than 10 nM, less than 5 nM, 2 nM or less than 1 nM. In some embodiments of the present invention, the term "BRAF inhibitor" refers to a compound that reduces BRAF kinase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 99%. In some embodiments of the present invention, the term "MEK inhibitor" refers to a compound that reduces MEK kinase activity by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 99%.

[0015] The term "IC50" refers to the concentration of a specific compound required to inhibit 50% of a specific measured activity. Similarly, IC80, IC90 and IC95 refer to the concentrations that inhibit 80%, 90% and 95% of a specific measured activity, respectively.

[0016] The term "BRAF mutant" refers to those BRAF mutations that are involved in causing cancer, such as, for example, BRAF V600E and V600K mutations.

[0017] The term "pharmaceutically acceptable salts" refers to those salts of the compounds of formula (I) or MEK inhibitors that retain the biological effectiveness and properties of the free base or free acid and are not biologically or otherwise undesirable. For example, these salts are formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., especially hydrochloric acid) and organic acids (such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc.). In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc.). Particular pharmaceutically acceptable salts of the compounds of formula (I) are hydrochloride, mesylate and citrate. Particular pharmaceutically acceptable salts of [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone or cobimetinib are fumarate and succinate, especially hemifumarate and hemisuccinate.

[0018] Certain embodiments of the invention relate to a compound of formula (I)

[0019]

[0020] or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the patient suffering from said cancer has been previously treated with a different BRAF inhibitor.

[0021] Certain embodiments of the invention relate to a compound of formula (I)

[0022]

[0023] or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein the patient suffering from said cancer has not previously been treated with a BRAF inhibitor, especially a BRAF inhibitor selected from dabrafenib, vemurafenib and encorafenib.

[0024] Certain embodiments of the invention relate to a compound of formula (I)

[0025]

[0026] or a pharmaceutically acceptable salt thereof, which is used for treating cancer, especially melanoma with brain metastasis, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0027] Non-limiting examples of MEK inhibitors for use in the uses according to the present invention include cobimetinib, binimetinib, trametinib, selumetinib, pimasertib, refametinib, N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide (PD-325901), 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (Cl-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733).

[0028] In one embodiment of the present invention, the MEK inhibitor is cobimetinib. Cobimetinib is an oral, potent, and highly selective inhibitor of MEK1 and MEK2, key components of the RAS / RAF pathway. The chemical name of cobimetinib is [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone and it has the following structure:

[0029]

[0030] Cobimetinib can be prepared according to the method described in WO 2007 / 044515. Cobimetinib is commercially available and has the following CAS registration number: 934660-93-2.

[0031] In one embodiment of the present invention, the MEK inhibitor is binimetinib. Binimetinib is an oral, potent, and highly selective inhibitor of MEK1 and MEK2, key components of the RAS / RAF pathway. The chemical name of binimetinib is 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide and it has the following structure:

[0032]

[0033] Binimetinib can be prepared according to the method described in WO 2003 / 077914. Binimetinib is commercially available and has the following CAS registration number: 606143-89-9.

[0034] In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab (GP-675,206). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab nivolumab and RN888. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab avelumab and durvalumab (Imfinzi TM ). In some embodiments, the PD-L1 inhibitor is atezolizumab

[0035] Abbreviations:

[0036] BID = bis in die (Latin), twice a day; PCR = polymerase chain reaction; PD = pharmacodynamics; PK = pharmacokinetics; PO = per os (Latin), orally; QD = quaque die (Latin), once a day; TID = ter in die (Latin), three times a day. (Latin), three times a day. Test agents: Example A - film-coated tablets

[0037] Example B - film-coated tablets

[0038] Compound Ia can be synthesized according to the method described in WO2021116055A1 or according to methods known to those skilled in the art.

[0039] The following examples and figures are provided to illustrate the invention and are not of a limiting character.

[0040] Biological Example - An open-label IA / B study to evaluate the safety, pharmacokinetics, and preliminary clinical activity of compound Ia in solid tumors with BRAF-V600 mutations.

[0041] Part 1 - Pilot PK: Dose escalation has started with a pilot PK cohort of 2 participants to assess the PK of compound Ia at a single dose of 25 mg, with the aim of refining the starting dose for dose escalation by using the actual exposure in humans and a safety margin of at least 2-fold of the human equivalent dose redefined against the safety benchmark dose of 200 mg / kg / day in rats. Once PK sampling is completed (up to 72 hours after the first dose), the participants will continue to receive compound Ia treatment daily. The participants in the pilot PK cohort were enrolled and treated in a staggered manner (with at least a 3-day interval between the first and the second participant). Preliminary analysis of the available PK data for the first 2 participants indicated that the drug exposure at 25 mg was lower than expected, based on the preliminary unbound C max or AUC 0-∞ yielding a safety margin of 32-fold or 174-fold, corresponding to the safety benchmark dose of 200 mg / kg / day in rats (10% toxic dose in animals). No dose-limiting toxicity (DLT) occurred in this cohort at 25 mg of compound Ia. Therefore, the dose for the first dose escalation cohort was redefined by applying a safety margin of 4-fold or 22-fold based on the preliminary unbound C max or AUC 0-∞ of the first two patients at 25 mg. The dose for the first dose escalation cohort will be 200 mg QD of compound Ia administered. After completion of the DLT period for the 25 mg QD dose of the pilot PK cohort, these two participants were included in the dose escalation part of the study with compound Ia at a dose of 200 mg QD. They were considered DLT evaluable for this dose, with a 14-day DLT period starting from the time point when they increased the compound Ia dose from 25 mg to 200 mg. No DLT occurred during the 14-day period after the increase of compound Ia from 25 mg to 200 mg.

[0042] Part 1 (Dose Escalation): The escalating doses of compound Ia alone (Part 1a, monotherapy) and in combination with cobimetinib (Part 1b) will be evaluated in participants with BRAF-V600 mutation-positive solid tumors (e.g., melanoma, non-small cell lung cancer (NSCLC), thyroid cancer, colorectal cancer (CRC) [with or without brain metastases]) to determine the maximum tolerated dose (MTD) and / or the recommended phase 2 dose (RP2D). The starting dose for dose escalation was refined by using the actual exposure of the first two patients at 25 mg in the pilot PK cohort. The dose escalation part will start with the administration of compound Ia at a dose of 200 mg once daily (QD). Then, based on the emerging PK data, the dosing regimen will be changed to twice daily (BID) or three times daily (TID) administration.

[0043] Part 1a - Dose Escalation of Compound Ia Monotherapy: Dose escalation will be conducted according to the mCRM-EWOC design. The upper limit of the number of patients with leptomeningeal tumor involvement in each cohort is 33%. To avoid exposing participants to excessive toxicity risks, the maximum allowable dose increment recommended by the mCRM EWOC (Modified Continual Reassessment Method combined with dose escalation for overdose control) design will be 100% (i.e., a two-fold increase). The maximum dose of Compound Ia to be explored is 4000 mg / day. If any dose level in the QD or BID regimens exhibits unacceptable toxicity or adverse PK characteristics, additional participant cohorts can be evaluated in the TID regimen. mCRM-EWOC will be adapted to the new dosing regimen.

[0044] Part 1b - Combination of Compound Ia and Cobimetinib: Dose escalation in Part 1b will be conducted as parallel groups, where Compound Ia will be administered in combination with a standard dose of cobimetinib (60 mg QD for 21 consecutive days, followed by a 7-day interruption). The starting dose for the combination of Compound Ia and cobimetinib will be at least one dose level lower than the latest dose confirmed to be safe and considered tolerable based on a review of all Part 1a data. The escalation of the combination of Compound Ia and cobimetinib will be guided by the mCRM EWOC model until the MTD and / or RP2D are reached. The maximum dose of Compound Ia to be explored is 4000 mg / day. If any dose level in the QD or BID regimens of Compound Ia in combination with cobimetinib exhibits unacceptable toxicity or adverse PK characteristics, additional participant cohorts can be evaluated in the TID regimen. mCRM-EWOC will be adapted to the new dosing regimen. Based on emerging PK and safety data, other cobimetinib doses can also be explored. For the monotherapy cohorts and the combination cohorts containing cobimetinib, the upper limit of the number of patients with leptomeningeal tumor involvement at the cohort level is 33%.

[0045] Part 1 - Food Cohorts: The effect of food on the PK of Compound Ia (FE) will be evaluated at the MTD and / or RP2D or at a dose level close to the RP2D and / or MTD of Compound Ia with or without cobimetinib in Part 1a (Compound Ia monotherapy) or in Part 1b (combination of Compound Ia and cobimetinib). To explore the effect of food intake, participants will receive Compound Ia using a parallel design either after a high-fat meal (Group 1) or after a 10-hour fast (Group 2). For this pilot FE assessment, at least 6 evaluable participants will be enrolled. Once PK sampling is completed (up to 72 hours after the first dose), participants will continue with daily, BID, or TID Compound Ia treatment according to the selected dosing schedule for the study of FE.

[0046] Part 2 (Dose Escalation): After determination of the MTD and / or RP2D and potential for FE, the investigational treatment will begin to evaluate safety and preliminary clinical activity in the following four cohorts.

[0047]

[0048] The investigational medicinal products are compound Ia and cobimetinib. All participants will receive compound Ia (25 mg tablets or 200 mg tablets) PO QD or BID on each day of each 28-day cycle. Participants will receive 60 mg (3 x 20 mg tablets) cobimetinib PO QD on Days 1 to 21 of each 28-day cycle (i.e., for 21 consecutive days), followed by a 7-day break.

[0049] On the date participants are required to attend the clinic, a single dose of compound Ia and cobimetinib (if applicable) will be administered to participants in a clinic setting. On all other study days outside of the scheduled clinic visits, participants will self-administer compound Ia and cobimetinib (if applicable) at home. For compound Ia and cobimetinib doses to be self-administered at home, participants will be dispensed a sufficient number of tablets to last until the next clinic visit or until the end of a cycle, at the discretion of the investigator. Participants will self-administer the oral investigational treatment as follows: Unless otherwise instructed, participants should take compound Ia and cobimetinib (if applicable) at approximately the same time each day. Depending on the assigned study cohort, dose level, and schedule, participants will be instructed on the number and strength of tablets to take. Participants will be required to record the time and date of each dose they take in a medication diary. Participants should return all unused tablets at each study visit for assessment of compliance.

[0050] Compound Ia Administration: All participants will receive oral (PO) QD compound Ia (25 mg tablets or 200 mg tablets) with a glass of water on each day of each 28-day cycle. If a dose of compound Ia is missed (i.e., not taken within 4 hours of the scheduled dosing time), the participant should resume dosing at the next scheduled dosing time. Missed or vomited doses will not be replaced. On all clinic visit days where pre-dose blood draws are required for compound Ia PK sampling and / or laboratory assessments, participants will be instructed to take their morning oral dose of study medication in the clinic after completion of the pre-treatment assessment.

[0051] Cobimetinib Administration: Participants will receive 60 mg (3 x 20 mg tablets) PO QD from Day 1 to Day 21 of each 28-day cycle (i.e., for 21 consecutive days), followed by a 7-day break. If there are issues regarding tolerance, lower doses or alternative cobimetinib dosing schedules may be explored. Cobimetinib should be taken at approximately the same time each day as the morning dose of Compound Ia and no later than 4 hours after the scheduled time. Cobimetinib should be swallowed whole with a glass of water and should not be chewed, cut, or crushed. If a dose of cobimetinib is missed (i.e., not taken within 4 hours of the scheduled dosing time), the participant should resume dosing at the next scheduled dosing time. Missed or vomited doses will not be made up. On all clinic visit days when pre-dose blood draws for cobimetinib PK (pharmacokinetics) sampling and / or laboratory assessments are required, participants will be instructed to take their morning oral dose of the study drug at the clinic after completion of the pre-treatment assessment.

[0052] Diet and Dietary Restrictions: In general, no dietary restrictions are expected for participants receiving Compound Ia. A preliminary assessment of the FE (food effect) on the PK of Compound Ia will be completed in Part 1 to understand potential dietary requirements for dose escalation (Part 2) if an FE is observed. For participants receiving cobimetinib, grapefruit juice (a potent CYP3A4 enzyme inhibitor) is prohibited during the study and for 30 days after the last dose of study treatment. For food cohort participants in the food cohort of Part 1, the effect of food on the systemic exposure of Compound Ia will be explored in at least 6 participants at or near the MTD and / or RP2D or relevant dose levels. Participants will receive Compound Ia in the fed or fasted state at C1D1. After at least 10 hours of overnight fasting, Compound Ia will be administered as a single dose after a high-fat meal (i.e., 800 to 1000 calories, 50% fat; the meal should be eaten within 30 minutes or less) on Day 1 of Cycle 1 or in the fasted state. In both cases, Compound Ia should be taken with 240 mL of water. Consumption of additional water is permitted ad libitum except during the 1-hour period before to 1 hour after dosing. In both cases, no food should be consumed for at least 4 hours after dosing. The food intake during the high-fat meal, plus the calorie and fat content, will be recorded.

[0053] Alcohol: Participants must abstain from alcohol within 24 hours before the start of dosing until after the final PK and / or PD samples are collected on the corresponding study day. Participants will be regularly asked about their alcohol consumption, and appropriate notations regarding the amount of alcohol consumed will be recorded.

[0054] Participant Population

[0055] This study will enroll two participant groups. Part 1: Participants with BRAF-V600 mutation-positive metastatic or locally advanced solid tumors. Part 2: Participants with BRAF-V600 mutation-positive cutaneous melanoma with CNS metastases.

[0056] Key inclusion criteria:

[0057] · Male and female participants aged ≥ 18 years, with a life expectancy > 3 months and who have signed a written informed consent form.

[0058] · Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

[0059] · Preference for using FDA-approved or CE-IVD genetic tests to document the BRAF-

[0060] V600 mutation status of tumor tissue.

[0061] · Confirm the availability of archived tumor tissue for submission to the sponsor / central laboratory.

[0062] · Adequate bone marrow and end-organ function, as well as coagulation parameters.

[0063] · Willingness to comply with contraceptive measures during the study.

[0064] · Only applicable to Part 1: Advanced / metastatic solid tumors with histologically confirmed measurable systemic disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (extracranial disease) or modified response assessment for brain metastases in neuro-oncology (mRECIST-BM; intracranial disease).

[0065] · Only applicable to Part 2: Cutaneous melanoma with histologically confirmed, radiologically measurable, asymptomatic brain metastases according to mRECIST-BM. CNS symptoms were stable or improved for at least 14 days before starting study treatment.

[0066] Key exclusion criteria:

[0067] · Only for Part 2: History of or current leptomeningeal metastases.

[0068] · Any metastases requiring immediate local intervention.

[0069] · Uncontrolled tumor-related pain.

[0070] · Ascites, pleural effusion, or pericardial effusion requiring medical intervention (including the use of diuretics) within 6 months before entering the study.

[0071] · Active malignant tumors (except for the tumors under study) or a history of having had a malignant tumor in the two years prior to enrollment, with some exceptions.

[0072] · Active uveitis, or a history of any serous retinopathy or retinal vein occlusion.

[0073] · Current or prior history of CNS diseases (such as stroke, epilepsy, CNS vasculitis, or neurodegenerative diseases) unrelated to the malignant tumor under study.

[0074] · Active autoimmune diseases, or quiescent autoimmune diseases that deteriorated / had an episode within 1 year prior to enrollment.

[0075] · Having had a major cardiovascular disease within 6 months prior to administration of the study treatment.

[0076] · Systemic anti-cancer therapies or small molecule therapeutic agents, including but not limited to chemotherapy, investigational drugs, hormonal therapy, and radiotherapy, as well as antibody-based agents, all within 2 weeks or at least 5 half-lives (whichever is shorter) prior to the start of the study treatment.

[0077] · Treated with stereotactic radiosurgery or craniotomy within 1 week prior to the study treatment, or treated with whole brain radiotherapy within 3 months prior to the study treatment. Participants who received local therapy should have made a full recovery with no neurological sequelae.

[0078] · Received radiotherapy for visceral metastases within 1 week prior to the study treatment. Palliative radiotherapy is permitted.

[0079] · Having a major surgical operation other than for diagnosis within 2 weeks prior to the start of the study treatment or expected to require one during the course of the study.

[0080] · Spinal cord compression that has not been definitively treated with surgery and / or radiotherapy, or previously diagnosed and treated spinal cord compression, but without evidence that the disease was clinically stable for ≥2 weeks prior to screening.

[0081] · Having a contraindication to cobimetinib or known allergy to any of the formulation components of cobimetinib (if applicable).

[0082] · Participants known to be allergic to BRAFi and / or MEK inhibitors (MEKi).

[0083] · Use of strong CYP3A inducers (including St. John's wort and hypericin) is prohibited during the study treatment and within 2 weeks after the last dose of cobimetinib or compound Ia (whichever is later).

[0084] · During the study treatment period and within 2 weeks after the last dose of cobimetinib or compound Ia (whichever is later), concomitant treatment with anticonvulsants other than gabapentin, vigabatrin, and levetiracetam (e.g., carbamazepine, phenytoin, phenobarbital due to strong CYP3A induction) is prohibited.

[0085] · For combination treatment with cobimetinib, during the study treatment period and within 2 weeks after the last dose of cobimetinib or compound Ia (whichever is later), the use of moderate and strong CYP3A inducers and inhibitors is prohibited.

[0086] · Refractory nausea and vomiting, malabsorption, extrahepatic biliary shunting, or severe small bowel resection that would interfere with adequate study treatment absorption.

[0087] · Uncontrolled diabetes or symptomatic hyperglycemia.

[0088] · Any ≥ grade 3 bleeding or bleeding event occurring within 28 days after the start of study treatment.

[0089] · History of positive human immunodeficiency virus (HIV).

[0090] · Hepatitis B virus (HBV) infection (chronic or acute), defined as positive hepatitis B surface antigen (HBsAg) test or positive quantitative HBV DNA test at screening.

[0091] · Hepatitis C virus (HCV) infection (chronic or acute), defined as positive HCV antibody test and positive HCV RNA test at screening.

[0092] · Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis and atypical mycobacteriosis), parasitic, or other infections (excluding onychomycosis) or any major infection episode.

[0093] Study treatment dose, administration, and compliance:

[0094] For detailed instructions on drug preparation, storage, and administration, please refer to the pharmacy manual.

[0095] Participants will need to visit the clinic every two weeks for the first 3 cycles and then monthly thereafter.

[0096] On the date when participants are required to enter the clinic:

[0097] For QD compound Ia administration: A single dose of compound Ia and a single dose of cobimetinib (if applicable) will be administered in a clinic setting.

[0098] For the administration of compound Ia in BID: The first dose of compound Ia and the first dose of cobimetinib (if applicable) will be administered to the participants in a clinic setting. The second dose of compound Ia on the same day will be self-administered at home 10 to 12 hours after the first dose.

[0099] For the administration of compound Ia in TID:

[0100] - The first dose of compound Ia and a single dose of cobimetinib (if applicable) will be administered to the participants in the morning in a clinic setting.

[0101] - The second and third doses of compound Ia on the same day will be self-administered at home 8 to 10 hours after the first dose and 6 to 8 hours after the second dose, respectively. IMPORTANT: The second administration must be carried out after the 8-hour PK blood sampling. In the case where the 8-hour blood sampling is no longer required (depending on emerging data and only after communication with the sponsor), the second dose can be taken 6 to 8 hours after the first dose.

[0102] On all other study days outside the above-scheduled clinic visits:

[0103] The participants will self-administer compound Ia and cobimetinib (if applicable) orally at home. A sufficient number of tablets will be distributed to the participants to last until the next clinic visit.

[0104] The participants should take compound Ia and cobimetinib (if applicable) at approximately the same time each day:

[0105] For the administration of compound Ia in QD: In the morning, compound Ia and cobimetinib (if applicable).

[0106] For the administration of compound Ia in BID: In the morning, compound Ia and cobimetinib (if applicable); only compound Ia will be added in the evening. Compound Ia should be taken at an interval of 10 to 12 hours.

[0107] For the administration of compound Ia in TID: In the morning, compound Ia and cobimetinib (if applicable). Only compound Ia will be added in the afternoon and evening. Compound Ia should be taken at an interval of 6 to 8 hours.

[0108] Based on the designated study cohort, dose level, and schedule, the participants will be instructed on the number and concentration of tablets to take. The participants will be required to record the time and date of each dose they take in a medication diary and should bring this diary to the hospital at each study visit. The participants should return all unused tablets at each study visit to assess compliance.

[0109] Administration of compound Ia:

[0110] All participants will receive the oral (PO) QD, BID, or TID compound Ia (25 mg / tablet or 200 mg / tablet) with a glass of water every day for each 28-day cycle. If a dose of compound Ia is missed (i.e., for QD, not taken within 10 hours after the scheduled dosing time; for BID, not taken within 4 hours; for TID, no window), the participant should resume dosing at the next scheduled dosing time. Missed or vomited doses will not be replaced.

[0111] On all clinic visit days where pre-dose blood draws for compound Ia PK sampling (see Section 1.3) and / or laboratory assessments are required, participants will be instructed to take their morning oral dose of the study drug at the clinic after completion of the pre-treatment assessment.

[0112] For BID and TID doses, all pre-dose and post-dose blood draws and assessments described in the protocol and SoA refer to the morning dose (the first dose of the day).

[0113] Cobimetinib administration:

[0114] Participants will receive 60 mg (3 x 20 mg tablets) PO QD from Day 1 to Day 21 of each 28-day cycle (i.e., for 21 consecutive days), followed by a 7-day break. If there are issues regarding tolerance, lower doses or alternative cobimetinib dosing schedules may be explored.

[0115] Cobimetinib should be taken at approximately the same time each day as the morning compound Ia dose and no later than 4 hours after the scheduled time. Cobimetinib should be swallowed whole with a glass of water and should not be chewed, cut, or crushed. If a dose of cobimetinib is missed (i.e., not taken within 4 hours after the scheduled dosing time), the participant should resume dosing at the next scheduled dosing time. Missed or vomited doses will not be replaced.

[0116] On all clinic visit days where pre-dose blood draws for cobimetinib PK sampling and / or laboratory assessments are required, participants will be instructed to take their morning oral dose of the study drug at the clinic after completion of the pre-treatment assessment.

[0117] Number of participants:

[0118] The exact number of participants will depend on the occurrence of DLT and the number of dose levels required to determine the MTD and / or RP2D. The study will enroll up to 120 participants (60 participants in each of Part 1a and Part 1b) during the dose escalation phase and up to approximately 40 participants in up to 4 expansions in Part 2. For the FE, an additional cohort of 6 to 12 participants will be enrolled. The total number of participants will be at most 292.

[0119] Concomitant medications:

[0120] Any medications or vaccines used by the participants from 30 days after screening until the safety follow-up visit must be recorded, along with the reason for use, administration date, and dose information. As a general rule, no new concomitant medications are permitted, except for medications to treat AEs, unless the reasons for exceptions are discussed and clearly documented between the investigator and the sponsor. If deemed necessary for the treatment of brain metastases, the treating physician may, at their discretion, administer systemic corticosteroids (i.e., dexamethasone at a dose ≤8 mg / day or equivalent) and anti-epileptic medications (i.e., gabapentin, vigabatrin, and levetiracetam).

[0121] Dose rationale:

[0122] Based on the currently available non-clinical drug safety information and predicted human PK, the starting dose of compound Ia is administered at 25 mg QD, which is expected to be safe and pharmacologically active in the participants. Due to the uncertainty of the predicted human PK (estimated half-life between 7 hours and 70 hours), the human dose range that produces unbound exposure equivalent to the safety benchmark dose of 200 mg / kg / day in rats is expected to be between 46 mg and 610 mg, respectively. By applying a 2-fold safety margin, a human starting dose of 25 mg is selected. In the lead PK cohort before dose escalation in Part 1a (monotherapy), the PK of compound Ia was explored in 2 participants after a single oral dose of 25 mg to discuss PK uncertainty. Preliminary analysis of the available PK data for the first 2 participants at 25 mg showed that drug exposure in humans was lower than expected due to an estimated half-life between 2 hours and 4 hours. Based on the preliminary PK profile of 25 mg compound Ia in the first 2 participants in the lead PK cohort, the dose for the first dose-escalation cohort was newly defined as 200 mg QD. It was determined by using the actual exposure of 25 mg compound Ia in humans and applying a 4-fold or 22-fold safety margin based on the unbound C max or AUC 0-∞ The 4-fold or 22-fold safety margin was applied, which corresponds to the no-observed-adverse-effect level (NOAEL) safety benchmark dose of 200 mg / kg / day in rats.

[0123] Food effect assessment:

[0124] Compound Ia is a Biopharmaceutics Classification System class 2 drug; therefore, the PK of compound Ia may be affected by diet. The FE lead assessment conducted during dose escalation at the MTD and / or RP2D or related dose levels was designed to explore whether food has a significant effect on the PK of compound Ia and to provide information on the dietary requirements for oral administration of compound Ia in the expansion cohort in Part 2 and future clinical studies.

[0125] Efficacy assessment:

[0126] In general, tumor assessment must be conducted independently of changes in the schedule of administration of the investigational treatment (i.e., when treatment is interrupted). If tumor assessment must be advanced or delayed, subsequent assessments should be based on the original schedule from the date of the first administration of the investigational treatment. For participants who discontinue treatment for reasons other than disease progression, tumor assessment will continue according to the schedule (unless a subsequent anti-cancer therapy is initiated). Objective response will be confirmed by two consecutive assessments performed at least four weeks apart. Measurable lesions that have previously been irradiated will not be considered target lesions unless an increase in lesion size of ≥20% is observed after completion of radiotherapy.

[0127] Tumor and response assessment of extracranial lesions:

[0128] Tumor assessment will be performed at predefined time points. All known disease sites must be recorded at screening and reassessed at each subsequent tumor assessment. Extracranial tumor assessment during treatment at C2D1 (Cycle 2, Day 1) and C3D1 (Cycle 3, Day 1) must be performed within a time window of ±3 days and at subsequent time points within a time window of ±7 days. Response assessment of participants will be performed according to RECIST v1.1. The extent of tumor disease will be determined by reproducible radiography techniques, preferably CT or MRI scans. Ultrasound and X-rays cannot be used to monitor target lesions. CT (or MRI) scans should include scans of the chest, abdomen, and pelvis, and additional examinations (e.g., bone scans and neck CT scans) should be performed if clinically indicated. All known and suspected tumor disease areas will be evaluated as deemed appropriate by the investigator. The same assessment method and the same technique must be used consistently for each participant throughout the study. Lesions <20 mm at screening require the use of spiral CT or MRI and must be recorded in the medical record and used consistently throughout the study. The use of oral and IV contrast agents should be consistent whenever clinically possible. If contrast-enhanced CT scans are contraindicated (i.e., the participant is allergic to the contrast agent or has reduced renal clearance), MRI of the abdomen and pelvis and non-contrast chest CT may be used. If a PET / CT scanner is used for CT scanning to assess tumors, the CT should have the same diagnostic quality as a full-contrast diagnostic CT scan. Whenever possible, assessments should be performed by the same assessor to ensure intravisit consistency. Other assessment methods for measurable disease according to RECIST v1.1 may be used at the discretion of the investigator. If clinically measurable superficial (such as skin) lesions are present, repeated photographs should be used to record tumor response. For documentation purposes, these photographs must include a scale. Participants with known or suspected bone metastases should undergo radionuclide bone scans. At the discretion of the investigator, CT scans may be repeated at any time if progressive disease is suspected.

[0129] Tumor and Response Assessment of Intracranial Lesions:

[0130] Brain imaging will be performed at predefined time points. All known disease sites must be recorded at screening and re-evaluated at each subsequent tumor assessment. Intracranial tumor assessment during the treatment of C2D1 and C3D1 must be performed within a time window of ±3 days and at subsequent time points within a time window of ±7 days. Response assessment of brain metastases will be performed according to the mRECIST-BM criteria, which include a modified measurability definition for intracranial lesions (MRI ≥ 0.5 cm), and up to five intracranial target lesions (in addition to any extracranial target lesions) are allowed. Brain imaging must be performed using MRI to meet the following imaging acquisition requirements.

[0131] Minimum Required Sequences:

[0132] · Pre-contrast T1, T2 / FLAIR.

[0133] · Post-contrast T1, two orthogonal planes (or volumetric acquisition) are recommended.

[0134] · Recommended slice thickness ≤ 5 mm, no gap.

[0135] If extracranial progressive disease is detected, a brain MRI scan must also be completed within one week after the determination of extracranial PD. In addition to the tumor and response assessment of extracranial and intracranial lesions, further analysis of CT and MRI scans can be performed to further analyze the drug effect.

[0136] [18F]FDG-PET Imaging:

[0137] [18F]-FDG-PET will be performed at predefined time points to determine the effect of the drug on the tumor. The imaging acquisition guidelines as described in the imaging manual should be followed. Prior to the [18F]-FDG-PET study, participants should fast for 4 to 6 hours. After tracer administration, participants will rest in the waiting room to prepare for scanning starting 60 minutes ± 10 minutes after administration. Participants will undergo a sufficient number of bed positions to ensure coverage from the lower brain (inclusive) to the mid-thigh. Equally important, participants will be examined under the same conditions at screening and follow-up scans, specifically the same in terms of uptake time and scan time. It is recommended to use the same model of scanner or at least ensure the same spatial resolution. [18F]-FDG-PET / CT will be performed at screening. For the FDG-PET in the study, this assessment must be performed at the designated time point prior to the administration of compound Ia. The treatment assessments at C1D15 and C2D1 must be performed within a -3-day time window. Participants who show no evidence of FDG uptake on the screening PET scan will not need to undergo subsequent studies. For participants who show progressive disease on subsequent FDG PET assessments, a confirmatory CT / MRI assessment is strongly recommended. Response assessments using FDG-PET will be performed at the site and by an independent reviewer at the study center. Transient unilateral axillary lymphadenopathy has been observed after mRNA-based SARS-CoV-2 vaccination, and this may confound the interpretation for cancer patients using CT, MRI, or PET / CT. Although COVID vaccination of study participants should not be delayed, vaccination should be considered at sites that avoid potential confounding of imaging results (e.g., the contralateral arm or thigh in local cancer). Further, detailed information about vaccination such as vaccination date, anatomical site, laterality, and vaccine manufacturer (if available) should be collected at the time of imaging to facilitate interpretation.

[0138] Safety assessment:

[0139] The safety assessment will consist of the following: monitoring and recording of AEs, including serious AEs (SAEs) and non-SAEs of special interest (NSAESI); the results of protocol-specified safety laboratory assessments; the results of protocol-specified vital signs measurements; ECG; and other protocol-specified tests considered essential for the safety assessment of the study.

[0140] A comprehensive physical examination will be conducted at screening and at the 28-day safety follow-up visit, and will include an assessment of at least the cardiovascular, respiratory, gastrointestinal, skin, and musculoskeletal systems, in addition to the head, eyes, ears, nose, throat, neck, and lymph nodes. The comprehensive physical examination includes weight and height. A complete neurological examination, including an assessment of mental status, cranial nerves, strength, sensation, and coordination and gait, should be performed at screening and documented in the participant's chart. In the event of induced symptoms, other body systems may be examined at the discretion of the investigator. Neurological symptoms may include, but are not limited to: headache, nausea and / or vomiting, vertigo and / or dizziness, restlessness and / or irritability, fatigue or insomnia, hearing loss, muscle weakness, balance problems, speech problems, etc. Any abnormalities detected at screening should be recorded. At other visits, targeted physical examinations should be performed. Targeted physical examinations should be limited to the major relevant systems (i.e., the cardiovascular system, the respiratory system, the nervous system, and any systems that may be associated with tumor assessment [e.g., those associated with symptoms], or potential drug-related toxicities). Targeted neurological examinations should include an assessment of alertness and orientation to person, place, and time. When clinically necessary, the examination should also include a symptom-driven focused examination of other cranial nerves, strength, sensation, coordination, and mental status. It should be noted that targeted physical examinations may cover targeted neurological examinations if relevant to the patient's health status. If a targeted neurological examination is appropriate, it should be performed regardless of the patient's health status. Changes in baseline abnormalities should be recorded in the participant's logbook. New or worsening clinically significant abnormalities should be recorded as AEs. The investigator should pay particular attention to clinical signs related to previous serious illnesses.

[0141] Vital Signs When the participant is in a sitting or semi-recumbent position, vital signs will include measurements of systolic and diastolic blood pressure, respiratory rate, pulse rate, and body temperature. Every effort should be made to ensure that vital signs are obtained from the participant in a consistent manner / position. Blood pressure and pulse measurements should be taken after the participant has been sitting or lying quietly for at least 5 minutes in a quiet setting without distractions (e.g., television, cell phone; consistency should be maintained for individual participants). Blood pressure and pulse measurements may be assessed using a fully automated device. Manual techniques should only be used when no automated device is available. Whenever possible, all blood pressure measurements should be taken using the same arm. When measuring blood pressure, the participant's arm should be unrestricted by clothing or other materials, and the participant should be seated comfortably with legs uncrossed and the back and arm supported so that the midpoint of the upper arm cuff is at the level of the right atrium (midpoint of the sternum). The "ideal" cuff should have a bladder length of 80% of the arm circumference and a width of at least 40% of the arm circumference (aspect ratio 2:1).

[0142] Electrocardiogram:

[0143] Triplicate 12-Lead Electrocardiogram: A triplicate 12-lead ECG will be obtained using an ECG machine that automatically calculates heart rate and measures pulse rate, QRS, QT, and QT corrected for heart rate (QTc) intervals. To minimize variability, it is important that participants remain in a resting position for at least 10 minutes before each ECG assessment. Body position should be consistently maintained during each ECG assessment to prevent changes in heart rate. Environmental distractions (e.g., television, radio, conversation) should be avoided during the rest period before the ECG examination and during the ECG recording. ECG examinations should be performed at 2 hours after administration of the study treatment and at the 2-hour time point after blood sampling for PK / PD samples. If the absolute QTc > 500 ms and the increase in QTc relative to baseline > 60 ms, another triplicate ECG must be recorded within the next 30 minutes. Repeating an abnormal ECG may be appropriate to rule out improper lead placement that could cause the ECG abnormality. If QTc shortening occurs (≤ 340 ms or a decrease > 15% from baseline), another triplicate ECG must be recorded within the next 30 minutes. ECG characteristics, including heart rate, QRS duration, pulse rate, and QT interval, will be recorded. QTcF (Fridericia correction) and RR interval will be automatically calculated and recorded. Changes in T-wave and U-wave morphology and overall ECG interpretation will be recorded. T-wave information will be captured as normal or abnormal, and U-wave information will be captured in two categories: absent / normal or abnormal. If clinically significant changes are identified in the ECHO or MUGA results, additional PK samples should be collected.

[0144] The digital continuous recording (Holter) of 12-lead ECG traces for ambulatory electrocardiogram monitoring will be performed at pre-defined time points. The optimal therapeutic time points for ambulatory ECG may be re-assessed using emerging data and, if considered necessary for clinical evaluation, altered or additional assessments may be made. Participants will wear a digital ambulatory monitoring device for continuous recording of 12-lead ECG traces over a 24-hour period. The ambulatory recordings will be sent to a central ECG analysis laboratory for ECG extraction and potential retrospective expert review with estimation of ECG intervals. At pre-defined time points during the 24-hour recording period, double-replicate ECG traces will be extracted from the continuous recording during a 5-minute time window that coincides with a scheduled ECG time point where the validated heart rate has been stable for 1 minute. At these specific time points, participants should be at rest and maintain a supine position for ≥10 minutes prior to the designated ECG extraction time point and for ≥5 minutes after the designated ECG extraction time point. Double-replicate estimates of the uncorrected QT interval and QTcF will be derived from the ECG traces at each scheduled time point, along with other intervals (PR, RR, and QRS) and information on T-wave and U-wave morphology (where appropriate). When participants are undergoing ambulatory ECG monitoring, it is essential to emphasize the absence of any environmental disturbances (e.g., television, radio, conversation, or telephone) during the rest periods before and after the ECG and at the pre-defined ECG time points. In particular, activities known to cause heart rate changes should be avoided. In the case where PK samples are required at C1D8 before and 2 hours after dosing, the following sequence of events should be followed:

[0145] For pre-dose (up to 2 hours before scheduled drug administration)

[0146] · Collect pre-dose PK sample and record sampling time

[0147] · Install ambulatory device

[0148] · Ensure patient rests for 10 minutes

[0149] · Start ambulatory device

[0150] · Ensure patient rests for a further 5 to 10 minutes

[0151] · The central ECG laboratory will retrospectively extract ECG traces from the ambulatory device within a 5-minute window after the ambulatory device is started

[0152] For 2-hour post-dose PK sample

[0153] · Ensure patient rests for 10 minutes before the 2-hour time point and for 5 minutes after that time point

[0154] · ECG

[0155] · Then draw actual PK blood samples

[0156] · The Central ECG Laboratory will retrospectively extract ECG tracings from the Holter device within a 5 - minute window around the scheduled time points (when the patient is at rest).

[0157] During the course of the study, the assessment time may be modified or the number of assessments increased based on emerging data to achieve the best characterization of the effect profile.

[0158] Left ventricular function assessment:

[0159] Participants will undergo assessment of left ventricular ejection fraction (LVEF) by echocardiogram or MUGA and in the presence of new or worsening symptoms as clinically indicated. Any participant presenting with clinical signs or symptoms suggestive of heart failure should undergo re - assessment of LVEF and additional cardiovascular consultation as needed. If a clinically significant change is identified in the ECHO or MUGA results, additional PK samples should be collected. The same method must be used for each participant to assess left ventricular function.

[0160] Ophthalmic examination:

[0161] For compound Ia monotherapy, signs and symptoms of uveitis in participants will be monitored. Examinations will include visual acuity testing, intraocular pressure measurement by tonometry, slit - lamp biomicroscopy, specular microscopy, and direct or indirect ophthalmoscopy. Ophthalmic examinations must be performed by medical professionals trained in these assessments; otherwise, the participant should be referred to a qualified ophthalmologist. For combination therapy of compound Ia with cobimetinib, signs and symptoms of ocular toxicity will be monitored, including uveitis, serous retinopathy, and retinal vein occlusion. Ophthalmic examinations must be performed by medical professionals trained in these assessments; otherwise, referred to a qualified ophthalmologist. Examinations will include visual acuity testing, intraocular pressure measurement by tonometry, slit - lamp biomicroscopy, direct or indirect ophthalmoscopy (if necessary), and spectral - domain optical coherence tomography (OCT). If spectral - domain OCT is not available, time - domain OCT may be performed as an alternative. Fluorescein angiography may also be performed if necessary.

[0162] Dermatological examination:

[0163] The skin will be evaluated by a qualified medical expert. Unscheduled dermatological examinations may be performed during treatment as clinically indicated to examine for any new skin lesions. Participants with new, relevant skin lesions should be referred to a dermatologist for further assessment, diagnosis, and treatment.

[0164] Clinical safety laboratory assessments:

[0165] Clinical laboratory tests must be conducted in accordance with local laboratory procedures. The investigator must review the laboratory reports, document that review, and record any clinically relevant changes that occur during the study. Laboratory reports must be submitted together with the source documents. Clinically significant abnormal laboratory findings are those that are not related to the underlying disease, unless the investigator determines that the participant's condition is more severe than expected.

[0166] · If unexplained clinically significant abnormal laboratory test values occur, these tests should be repeated immediately and followed up until they return to the normal range and / or a sufficient explanation for the abnormality is found.

[0167] · If laboratory values from non-protocol-specified laboratory assessments conducted at the local laboratory require a change in participant management or are considered clinically significant by the investigator (e.g., SAE or AE or dose adjustment), these results must be recorded in the eCRF.

[0168] Clinical laboratory test results will be recorded on the eCRF or received as electronically generated laboratory reports submitted directly from the local or central laboratory. If the results of any test are outside the reference range or clinical symptoms require additional tests to monitor participant safety, the investigator may, at their discretion, collect additional blood or urine samples. If the clinical significance of abnormal laboratory results at screening is considered uncertain, screening laboratory tests may be repeated before the first dose of study treatment to confirm eligibility. Based on the ongoing analysis of data from this study and other studies, if the sample data collected cannot generate useful information, any sample type not considered critical for safety may be stopped at any time.

[0169] ECOG Performance Status:

[0170] The ECOG Performance Status will be assessed at screening, discontinuation visits, and predefined safety follow-up visits. It is recommended that, whenever possible, the same person assess the participant's performance status throughout the study. If the ECOG Performance Status assessment is conducted within 72 hours before the scheduled dosing, it does not need to be repeated on the scheduled dosing day of that cycle. If it is conducted on the scheduled dosing day, it must be done before the administration of study treatment.

[0171] Adverse Events and Serious Adverse Events:

[0172] The time period and frequency for collecting information on adverse events and serious adverse events: The investigator will seek information on AEs at the contact person for each participant. All AEs (whether reported by the participant or recorded by the research staff) will be recorded.

[0173] Methods for detecting adverse events and serious adverse events: Care should be taken not to introduce bias when detecting AEs and / or SAEs. Open and non-leading oral questioning of participants is a preferred method for asking about the occurrence of AEs. A consistent non-directed questioning method should be used to elicit AE information at all participant assessment time points.

[0174] Pharmacokinetics:

[0175] Blood samples will be collected to assess the concentrations of compound Ia and cobimetinib (and its metabolites, if applicable). The date and time of each sample collection will be recorded. Validated LC-MS / MS assays will be used to analyze compound Ia and cobimetinib levels. PK samples will be collected as outlined in Table 13. Dedicated PK samples will be collected at predefined time points for the lead PK cohort and the food cohort. During the course of the study, PK sampling time points may be modified based on emerging data to ensure adequate characterization of the PK of compound Ia and cobimetinib. Additional PK samples will be collected when the following events occur:

[0176] · At the time of treatment discontinuation.

[0177] · If an AE grade ≥3 is reported resulting in dose reduction or delay in the administration of compound Ia and / or cobimetinib.

[0178] · Clinically significant changes in ECG / echocardiogram or MUGA scan.

[0179] · If a DLT occurs.

[0180] · At the first occurrence of an objective response (i.e., PR or CR).

[0181] · At the time of disease progression.

[0182] CSF samples for assessing the concentration of compound Ia (and its metabolites, if applicable) will be collected from a dedicated group of participants. The date and time of each sample collection will be recorded in the eCRF. Validated LC-MS / MS assays will be used to analyze compound Ia levels in the CSF. CSF samples will be collected as outlined in Table 13.

[0183] · Metabolites can be measured by specific validated LC-MS / MS assays or other methods suitable for the purpose (where appropriate).

[0184] · Any remaining residual PK and CSF samples after designated analysis may also be used for other validation experiments (e.g., metabolite identification).

[0185] If needed, the remaining PK and CSF samples may also be used for assay development / validation experiments. Unless the participant agrees otherwise, the PK and CSF blood samples will be destroyed within 2 years after the date of the Clinical Study Report (CSR).

[0186] Pharmacodynamics and Biomarker Analysis:

[0187] Archived formalin-fixed, paraffin-embedded (FFPE) tumor tissues will be collected from all participants in the NGS study using F1CDx, a qualitative NGS for FDA-approved tissue-based broad companion diagnostics (CDx). Analytical techniques may include, but are not limited to, the BRAF-V600 mutation status, microsatellite instability (MSI), and tumor mutational burden (TMB) in the tumor. Blood and CSF samples for PD will be collected as specified in Table 13. The date and time of collection of each sample should be recorded in the eCRF. Details of the collection and transportation procedures for these samples can be found in the laboratory flow chart. The DNA of these samples or blood- and CSF-derived biomarkers related to PD, as well as the mechanism of action of Compound Ia and cobimetinib, will be tested. Samples include, but are not limited to, assessing the BRAF-V600 mutation status, MSI, TMB, and ctDNA monitoring in blood and CSF. Analytical techniques may include, but are not limited to, NGS and PCR. These analyses will be performed using F1-Tracker, which uses Signatera from Natera, a personalized multiplex PCR that utilizes the power of F1CDx to define a set of tumor-specific variants, and then Signatera ctDNA monitoring will be used to monitor these tumor-specific variants, and F1LCDx, a qualitative NGS for FDA-approved liquid biopsy. PD assessment may be modified during the course of the trial based on assay availability, emerging data, and results from the initial analysis. Samples may also be used for research purposes to identify biomarkers that can be used to predict and monitor response to Compound Ia and cobimetinib treatment, identify biomarkers that can be used to predict and monitor the safety of Compound Ia and cobimetinib, assess the PD effects of Compound Ia and cobimetinib treatment, and study the mechanisms of therapy resistance. If there is strong scientific evidence, additional biomarkers may be measured. During the course of the study, the sampling time points may be modified based on emerging data to ensure that the PD of Compound Ia can be fully characterized (without increasing the overall blood volume). When a participant withdraws from the study, samples taken prior to the withdrawal date may still be analyzed, unless the participant specifically requests destruction of the samples or local law requires destruction of the samples. However, if the samples have been tested prior to withdrawal, the results of these tests will be retained as part of the overall study data. Data derived from all biological samples, including samples for genetic DNA analysis, will comply with the study confidentiality standards.

[0188] Analysis of endogenous CYP3A activity markers:

[0189] Mandatory blood samples will be collected to measure the concentrations of 4βHC, TC, and / or 4αHC to assess CYP3A activity during treatment with compound Ia. The date and time of each sample collection will be recorded in the eCRF. The levels of 4βHC, TC, and / or 4αHC will be analyzed using a validated LC-MS / MS assay. Samples will be collected as outlined in Table 13. During the course of the study, the sampling time points may be modified based on emerging data to ensure adequate characterization of CYP3A activity during treatment with compound Ia. Blood samples will be destroyed after the final clinical study report date or upon approval by the study management team, or earlier in accordance with local regulations. Details regarding the sampling procedure, sample storage, and transportation are provided in the sample document.

[0190] Gene and genomic analysis:

[0191] Archived FFPE tumor tissue for DNA analysis will be collected prior to administration of the investigational treatment. DNA may be used for, but not limited to, detection of the BRAF-V600 gene mutation and exploratory studies of gene biomarkers by F1CDx. Whole blood samples for DNA analysis will be collected at baseline or prior to administration of the investigational treatment and at discontinuation in Part 2. DNA may be used for, but not limited to, BRAF-V600 mutation status and exploratory studies of gene biomarkers by F1LCDx. For F1CDx and F1LCDx tests, samples and / or their derivatives may be sent to one or more laboratories for analysis of germline or somatic mutations via next-generation sequencing (NGS) or other genomic analysis methods that form the basis of F1CDx and F1LCDx. Exploratory studies of gene biomarkers may include, but are not limited to, cancer-related genes, biomarkers associated with common molecular pathways, MSI status, and TMB. Whole blood samples for ctDNA analysis will be collected during the investigational treatment. Analysis of cell-free DNA (cfDNA) extracted from whole blood samples may include, but is not limited to, gene mutations associated with cancer progression, tumor molecules per milliliter, and the number of positive mutations defined by F1-Tracker, which may affect the PK, PD, clinical activity, or safety of the investigational treatment. For this purpose, samples and / or their derivatives may be sent to one or more laboratories for analysis by multiplex PCR or other genomic analysis methods that form the basis of F1-Tracker. Genomics is increasingly informing researchers' understanding of the pathophysiology of disease. Target DNA analysis provides a comprehensive characterization of the genome and, when combined with the clinical data collected in this study, can increase the opportunity to develop new treatments. The data will be analyzed in the context of this study but may also be explored in conjunction with data from other studies. The availability of larger datasets will help to identify important pathways and guide the development of new targeted agents. Given the complexity and exploratory nature of these analyses, the data and analyses will not be shared with investigators or study participants unless required by law. Participants will not be identified by name or any other personal identifying information. Data derived from all biological samples, including those used for genetic DNA analysis, will comply with the confidentiality standards described in the sample documentation. Participants will not be identified by name or any other personal identifying information. Data derived from all biological samples, including those used for genetic DNA analysis, will comply with the confidentiality standards described in the sample documentation.

[0192] Pharmacodynamics and Biomarker Samples:

[0193] Blood, CSF, and archived biopsy samples will be collected. The date and time of collection of each sample should be recorded. In addition, any residual material in the blood can be used for retrospective and longitudinal testing for bacterial or viral infections by serological methods. This testing can be performed for each participant. In addition to serving as an important safety measure, these analyses will reveal any associations between bacterial or viral infections and response to treatment. Any residual material in the blood and tumor tissue samples can also be used for other exploratory analyses and research to identify new biomarkers or develop these laboratory tests for the study drug or similar drugs after the above-mentioned intended uses. Unless otherwise specified below, samples (including blood, slides, extracts, etc.) will be destroyed within 5 years after the final clinical study report, unless the participant explicitly consents to the storage of the remaining material for exploratory research as appropriate.

[0194] Blood Sampling:

[0195] The following blood samples for plasma separation will be collected for PD and exploratory biomarker assessments:

[0196] · Blood will be collected from each participant for BRAF V600 mutation assessment for DNA extraction and clinical genotyping (confirm BRAF V600 mutation). Samples should be collected prior to the start of treatment as specified in the SoA. If samples are not collected prior to C1D1 dosing, they can be collected as early as possible at any other scheduled visit.

[0197] · Blood for ctDNA will be collected from each participant at screening, during treatment, and at the time of progressive disease as specified in the SoA for DNA extraction and ctDNA assessment.

[0198] · Blood samples will be collected to measure 4βHC, TC, and / or 4αHC concentrations to assess compound Ia

[0199] CYP3A activity during treatment.

[0200] Archived tumor tissue should preferably be from the primary tumor, or if not available, from a previous metastasis. Archived specimens can be of any age and must contain sufficient viable tumor tissue for the central laboratory to determine the BRAF V600 mutation status. In addition, these samples will be used for DNA extraction for exploratory research on gene biomarkers, MSI, and TMB.

[0201] Optional Sample CSF for ctDNA CSF Samples The CSF will be optional for all participants in this study and will be collected for PD and exploratory biomarker assessments. CSF collection may be performed via an Ommaya reservoir or via lumbar puncture. The CSF will be used to assess the PD effect of the combination of Compound Ia and cobimetinib on brain lesions by studying changes in ctDNA.

[0202] Statistical Considerations:

[0203] (a) Sample Size Determination: The exact number of participants will depend on the occurrence of DLT and the number of dose levels required to determine the MTD and / or RP2D. This study will enroll up to 120 participants in the dose escalation phase (60 participants in each of Part 1a and Part 1b) and up to approximately 40 participants in up to 4 extensions in Part 2. For the FE, an additional cohort of 6 to 12 participants will be enrolled. The overall maximum number of participants is 292.

[0204] Sample Size Rationale for Dose Expansion Part 2: A sample size of 40 evaluable participants per cohort in Part 2 allows an 80% chance of declaring futility assuming a true objective response rate (ORR) of 10% (based on the posterior probability of the ORR being less than 20% at a 70% confidence level). The 20% futility level is based on the response rate obtained with vemurafenib in patients with melanoma with brain metastases (McArthur et al., 2017). Futility will be assessed after 10, 20, 30, and 40 participants have mature data. Futility is considered if ≤1 out of 10 participants, or ≤2 out of 20 participants, or ≤4 out of 30 participants, or ≤6 out of 40 participants have a CR or PR.

[0205] Sample Size Rationale for Food Cohorts: The sample size was determined by practical considerations and not based on statistical power calculations.

[0206] (b) Analysis Sets: For analysis purposes, the following populations are defined in Table 1.

[0207] Table 1 - Analysis Sets:

[0208]

[0209] DLT = Dose-Limiting Toxicity; PK = Pharmacokinetics.

[0210] (c) Statistical analysis: Where appropriate, data will be summarized by cohort, dose level, and / or dosing schedule within each part of the study. If the number of patients is sufficient, patients with leptomeningeal disease may be analyzed separately within each part. Descriptive statistics will be used to analyze demographic and baseline characteristics (including but not limited to age, sex, biomarker status, prior therapies, and medical history). Descriptive statistics will be used to summarize exposure to the study agent by total duration of study agent, number of cycles initiated, and cumulative dose. Dose interruptions and their reasons will be presented by schedule and dose level. The efficacy analysis investigator will assess the response of participants based on the RECIST v1.1 criteria for extracranial lesions and mRECIST-BM for intracranial lesions. Participants with missing or no response assessment will be classified as "not evaluable". A second assessment will be required four weeks after the first assessment shows a response to confirm the response. Only confirmed responses will be analyzed and used for futility analysis. If a participant's best response to treatment equals "complete response" (CR) or "partial response" (PR), the participant will be considered a "responder". The ORR will be defined as the proportion of responders among the number of participants with evaluable responses. The disease control rate (DCR) will be defined as the proportion of participants who become responders or are in a "stable disease" (SD) state at least once in tumor assessments after the first baseline. The duration of response will be calculated for "responder" participants (i.e., the best "confirmed" overall response of CR or PR) and will be defined as the time from the first recorded response to the time of recorded disease progression or death from any cause (whichever occurs first). Progression-free survival (PFS) will be defined as the time from the first dose of study treatment to the first occurrence of recorded disease progression or death from any cause (whichever occurs first) (Table 2). For participants who have no recorded progressive disease or death before the last response assessment during the study, PFS will be censored on the date of the last study tumor assessment. Participants who have not had any post-baseline assessments or all post-baseline assessments have unknown results / responses but are known to be alive at the clinical cut-off for analysis will be censored on the date one day after the start of study treatment. Both response and PFS analyses will be based on the evaluable population of responses.

[0211] Table 2 - Efficacy statistical analysis methods:

[0212]

[0213] DCR = Disease Control Rate; DOR = Duration of Response; PFS = Progression-Free Survival; ORR = Objective Response Rate.

[0214] Safety Analysis: All safety parameters listed in Table 3 will be analyzed using descriptive statistics presented in tabular and / or graphical form. Safety will be assessed via DLT (for Part 1), AE, changes in laboratory test results, changes in vital signs, ECG, and LVEF and their corresponding relationships to study treatment exposure.

[0215] Table 3 - Safety Statistical Analysis Methods:

[0216]

[0217]

[0218]

[0219] AE = Adverse Event; DLT = Dose-Limiting Toxicity; ECG = Electrocardiogram; ECHO = Echocardiogram; eCRF = Electronic Case Report Form; MUGA = Multigated Acquisition; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

[0220] Pharmacokinetic Analysis:

[0221] The PK parameters for compound Ia administered alone and in combination with cobimetinib will be derived from plasma concentrations and will be listed and summarized using descriptive statistics such as mean, standard deviation, coefficient of variation, median, minimum, and maximum. The actual sampling times are shown in Table 13. PK parameters include, but are not limited to, area under the curve (AUC), maximum concentration (C max ), time to observed maximum concentration (T max ), and apparent oral clearance (CL / F), steady-state volume of distribution (V ss / F), and terminal half-life (t1 / 2). Estimation of PK parameters can be performed using standard non-compartmental methods and / or population PK models. If the data permit, other methods can be used for data analysis, for example, PK and PD data can be used to develop a population PK / PD model. Individual and mean plasma compound Ia concentration versus time data will be tabulated and plotted by dose level. A graphical display of PK data can also be provided. The linearity of PK (AUC and C max ) will be investigated. To assess the FE on the PK of compound Ia, PK parameters such as AUC, C max , T max , and t 1 / 2) Analyze. The estimation of PK parameters can be carried out using standard non-compartmental methods and / or population PK models. In addition, the CSF concentration of compound Ia (if applicable) can be presented by tabulation and descriptive summary statistics such as mean, standard deviation, coefficient of variation, median, minimum, and maximum. If the data permit, other methods can be used for data analysis. For example, PK and PD data can be used to develop a population PK / PD model. For participants receiving cobimetinib, the PK parameters of cobimetinib (such as but not limited to AUC, C max 、T max and t 1 / 2 ) will be listed and compared with the historical exposures observed in previous studies using cobimetinib to evaluate the induction potential of compound Ia. The estimation of PK parameters can be carried out using standard non-compartmental methods and / or population PK models. In addition, the relationships between drug exposure (compound Ia or cobimetinib), safety, PD, and efficacy endpoints will be explored to establish exposure-response relationships. Additional PK analyses of compound Ia (and compound Ia metabolites, if available and appropriate) or cobimetinib will be performed based on the available data as appropriate. The results of PK and / or any exposure-response relationships can be reported outside of the clinical study report.

[0222] Pharmacodynamic analysis:

[0223] All PD parameters will be presented separately by group or cohort using tabulation and descriptive summary statistics. Descriptive statistics will be used to summarize peripheral blood and tumor PD markers. The absolute changes and percentage changes compared to baseline of PD markers will be calculated. Graphical techniques will be employed to better understand the relationships between PD markers, dose, and time.

[0224] Pharmacokinetics / pharmacodynamics relationship:

[0225] The correlations between PK parameters, PD markers, and clinical responses will be evaluated via data tables and graphical techniques. If the data permit, other methods can be used for data analysis. For example, PK and PD data can be used to develop a population PK / PD model.

[0226] Other analyses:

[0227] · Analysis of endogenous CYP3A activity markers: To analyze CYP3A activity during the administration of compound Ia, the plasma concentrations of 4βHC, TC, and / or 4αHC will be determined, and the percentage changes of 4βHC compared to baseline with and without normalization by TC and 4αHC will be obtained. If the data permit, other exploratory methods can be used for data analysis. For example, PK and CYP3A activity data can be used to develop a population PK / CYP3A activity model.

[0228] · [18F]-FDG-PET Imaging: For the analysis of FDG-PET data, participants with baseline and at least one post-baseline scan will be considered evaluable. The uptake of [18F]-FDG-PET performed at baseline and treatment time points will be summarized descriptively. The changes in FDG-PET parameters (such as SUV max 、SUV mean 、total lesion glycolysis, etc.) and the percentage change compared to baseline will be described and evaluated as evidence of treatment response.

[0229] Interim Analysis:

[0230] In Part 2, futility analyses will be conducted after 10, 20, and 30 participants in each expansion cohort, respectively.

[0231] Definition of Adverse Events:

[0232] According to the E2A ICH Good Clinical Practice Guidelines, an adverse event (AE) is any untoward medical occurrence in a participant administered a medicinal product or a participant in a clinical study and which does not necessarily have a causal relationship with this treatment. Thus, an AE can be: any adverse and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the medicinal product, whether or not considered related to the medicinal product.

[0233] Events Meeting the Definition of AE:

[0234] · Deterioration of laboratory values (hematology, clinical chemistry, or urine analysis) or other clinical tests (e.g., ECG, X-ray) associated with symptoms or leading to a change in study treatment or concomitant treatment or discontinuation of study treatment.

[0235] · Worsening of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition.

[0236] · Detection or diagnosis of a new condition after administration of study treatment, even if it may have been present before the start of the study.

[0237] · AEs related to protocol-specified interventions, including AEs occurring before the allocation of study treatment (e.g., screening invasive procedures such as biopsies). "Lack of efficacy" or "failure of the expected pharmacological effect" per se is not reported as an AE or a serious AE (SAE), unless the progression unexpectedly accelerates and does not conform to the natural history of the disease. If "lack of efficacy" does not require safety reporting, such cases will be recorded in the efficacy assessment. However, signs, symptoms, and / or clinical sequelae resulting from lack of efficacy that meet the definition of AE or SAE will be reported as AE or SAE.

[0238] Events Not Meeting the Definition of AE:

[0239] ·Any clinically significant abnormal laboratory findings or other abnormal safety assessments associated with underlying diseases, unless the investigator determines that the participant's condition is more severe than expected.

[0240] ·The disease / illness under study or the expected progression, signs, or symptoms of the disease / illness under study, unless the participant's condition is more severe than expected. Medical or surgical procedures (e.g., endoscopy, appendectomy): The condition leading to the procedure is an AE.

[0241] ·Situations where no adverse medical events occurred (social and / or for convenience of admission).

[0242] ·No worsening of the expected daily fluctuations of pre-existing diseases or conditions present or detected at the start of the study.

[0243] Definition of Serious Adverse Event If an event is not an AE that meets the above definition, then even if it meets a serious condition (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression), it is not an SAE.

[0244] SAE is defined as any of the following adverse medical events occurring at any dose:

[0245] o Resulting in death.

[0246] o Life-threatening.

[0247] o The term "life-threatening" in the "serious" definition refers to an event where the participant is at risk of death at the time of the event; it does not refer to an event that might result in death if it were more severe.

[0248] o Requiring hospitalization or an extension of an existing hospitalization. Generally, hospitalization means that the participant has been detained (usually involving at least an overnight stay) in a hospital or emergency department for observation and / or treatment that would be inappropriate in a physician's office or outpatient setting. Complications occurring during hospitalization are AEs. If the complication extends the hospitalization or meets any other serious criteria, the event is serious. When there is doubt as to whether hospitalization has occurred or is necessary, the AE should be considered serious.

[0249] o Hospitalization for elective treatment of a pre-existing condition that has not worsened compared to baseline is not considered an AE.

[0250] o Resulting in persistent or severe disability / incapacity

[0251] o Disability means that the participant's ability to perform normal life functions is severely impaired.

[0252] o This definition is not intended to include experiences with relatively minor medical significance, such as simple headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., ankle sprain), which may interfere with or impede daily living functions but do not constitute a serious disruption.

[0253] o Congenital anomalies / birth defects.

[0254] o Other significant events: Medical or scientific judgment should be applied to determine whether an SAE report is appropriate for other situations, such as important medical events that may not immediately endanger life or result in death or hospitalization but may endanger the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should generally be considered serious. Examples of such events include invasive or malignant cancer, intensive treatment for allergic bronchospasm, blood dyscrasia, or convulsions in the emergency room or at home (not resulting in hospitalization), or development of drug dependence or drug abuse.

[0255] Severity assessment:

[0256] The terms "severe" and "significant" are not synonyms. Severity refers to the intensity of an AE (e.g., graded as mild, moderate, or severe or according to a predefined grading scale [e.g., National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] criteria]); the event itself may have relatively minor medical significance (such as a severe headache with no further findings). An independent assessment of the severity and significance of each recorded AE is required. The AE Severity Grading Scale of NCI CTCAE (v5.0) will be used to assess AE severity. Table 4 will be used to assess the severity of AEs not specifically listed in NCI CTCAE.

[0257] Table 4 - Adverse Event Severity Grading Scale:

[0258]

[0259] NCI - CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. Note: Based on NCICTCAE (v5.0).

[0260] a Instrumental activities of daily living refer to preparing meals, buying groceries or clothes, using the phone, managing money, etc.

[0261] b Examples of self - care activities in daily life include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, which are performed by non - bedridden patients.

[0262] c If an event is rated as a "significant medical event", it must be reported as a serious adverse event according to the further definition below.

[0263] According to the definition of serious adverse events above, grade 4 and 5 events must be reported as serious adverse events. Grade 4 laboratory abnormalities are only reported as SAEs if they meet one or more of the criteria further outlined below.

[0264] Causality assessment:

[0265] Investigators should use their knowledge of the participant, the circumstances surrounding the event, and the assessment of any potential alternative causes to determine whether the AE is considered related to the study treatment and indicate "Yes" or "No" accordingly. The following guidelines should be considered:

[0266] · Temporal relationship between the occurrence of the event and the start of study treatment.

[0267] · Course of the event, particularly considering the effects of dose reduction, discontinuation of study treatment, or reintroduction of study treatment.

[0268] · Known association of the event with the study treatment or similar treatments.

[0269] · Known association of the event with the disease under study.

[0270] · Presence of risk factors in the participant or use of concomitant medications known to increase the incidence of the event.

[0271] · Presence of non-treatment-related factors known to be associated with the occurrence of the event.

[0272] For participants receiving combination therapy, causality will be assessed separately for each therapy specified in the protocol.

[0273] Measurability of the tumor at baseline

[0274] Definition: At baseline, tumor lesions / lymph nodes will be classified as measurable or non-measurable as described below.

[0275] Measurable tumor lesion - Tumor lesion: The tumor lesion must be accurately measurable in at least one dimension (the longest diameter in the plane of measurement will be recorded), with a minimum size as follows:

[0276] · 10 mm, by computed tomography (CT) or magnetic resonance imaging (MRI) scan (CT / MRI scan slice thickness / spacing not greater than 5 mm)

[0277] · 10 mm caliper measurement, by clinical examination (lesions that cannot be accurately measured with calipers should be recorded as non-measurable)

[0278] · 20 mm, by chest X-ray

[0279] Measurable tumor lesions - Malignant lymph nodes should be considered pathologically enlarged and measurable. When assessed by CT scan, the short axis of the lymph node must be ≥15 mm (it is recommended that the CT scan slice thickness be no greater than 5 mm). At baseline and during follow-up, only the short axis is measured and followed. For information on lymph node measurement, see also the following note on "Baseline documentation of target and non-target lesions".

[0280] Non-measurable tumor lesions: Non-measurable tumor lesions include small lesions (longest diameter <10 mm or pathological lymph nodes with short axis ≥10 mm to ≤15 mm) and truly non-measurable lesions. Truly non-measurable lesions include leptomeningeal disease, ascites, pleural effusion or pericardial effusion, inflammatory breast disease, lymphangitis involving the skin or lungs, peritoneal dissemination, and abdominal masses / abdominal organ enlargement detected by physical examination but not measurable by reproducible imaging techniques.

[0281] Special considerations regarding lesion measurability: Bone lesions, cystic lesions, and lesions previously treated with local therapy require special annotation, as outlined below.

[0282] Bone lesions; Bone scans, positron emission tomography (PET) scans, or plain films are not considered adequate imaging techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or absence of bone lesions. Osteolytic lesions or mixed osteolytic lesions with a distinguishable soft tissue component can be evaluated by cross-sectional imaging techniques (such as CT or MRI) and can be considered measurable lesions if the soft tissue component meets the definition of measurability described above. Blastic bone lesions are non-measurable.

[0283] Cystic lesions: Lesions that meet the criteria of a simple cyst according to the radiological definition should not be considered malignant lesions (neither measurable nor non-measurable) because, by definition, they are simple cysts. Cystic lesions that are considered to represent cystic metastases can be considered measurable lesions if they meet the definition of measurability described above. However, if the same patient has non-cystic lesions, it is preferable to select these lesions as target lesions.

[0284] Lesions previously treated locally: Tumor lesions located in a previously irradiated area or that have undergone other local regional therapies are generally not considered measurable unless progression of the lesion has been demonstrated. The study protocol should detail the conditions under which such lesions are considered measurable.

[0285] Target lesions: Details of the measurement method: Measurement of lesions: If a clinical assessment is performed, all measurements should be recorded in metric notation using calipers. All baseline assessments should be performed as close as possible to the start of treatment and should not exceed 4 weeks before the start of treatment.

[0286] Assessment method: The same assessment method and the same technique should be used to characterize each identified and reported lesion at baseline and during the study. Imaging-based assessment should always be the preferred option.

[0287] Clinical lesions: These clinical lesions are considered measurable only if the clinical lesions are superficial and the diameter measured using calipers is ≥10 mm (e.g., skin nodules). For clinical lesions, documentation by color photography is required, including a scale for estimating the lesion size.

[0288] Chest X-ray: Chest CT is preferred over chest X-ray, especially when progression is the primary endpoint, because CT is more sensitive than X-ray, particularly in identifying new lesions. However, if the lesions on chest X-ray are clearly visible and surrounded by aerated lung, these lesions can be considered measurable.

[0289] CT, MRI: CT is currently the best and reproducible method available for measuring lesions used in response assessment. This guideline defines the measurability of lesions in CT scans based on the assumption that the CT slice thickness is 5 mm or less. When the slice thickness of the CT scan is greater than 5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also acceptable. If it is known before enrollment that a patient cannot undergo intravenous (IV) contrast CT scan due to allergy or renal insufficiency, the decision on whether non-contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the study should be guided by the type of tumor being studied and the anatomic location of the disease. For patients who develop a contrast contraindication after completion of baseline contrast CT, the decision on whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should also be based on the tumor type and the anatomic location of the disease and should be optimized to allow comparison with previous studies (if possible). Each case should be discussed with a radiologist to determine if an alternative method can be used; if not, the patient should be considered non-evaluable from that point on. Caution must be exercised when measuring target lesions and interpreting non-target disease or new lesions in different modalities, as the same lesion may appear to have different sizes when using a new modality.

[0290] Ultrasound: Ultrasound cannot be used to assess lesion size and should not be used as a measurement method.

[0291] Endoscopy, laparoscopy, tumor markers, cytology, histology: In general, these techniques are not recommended for objective tumor assessment.

[0292] Tumor response assessment - Assessment of overall tumor burden and measurable disease:

[0293] To assess objective response or future progression, it is necessary to estimate the total tumor burden at baseline and use it as a comparator for subsequent measurements. Measurable disease is defined by the presence of at least one measurable lesion, as detailed above.

[0294] Tumor response assessment - Baseline documentation of target and non-target lesions:

[0295] When there are more than one measurable lesions at baseline, all lesions in all involved organs (up to a total of five lesions, up to two lesions per organ) should be identified as target lesions and recorded and measured at baseline. This means that for patients with involvement of only one or two organ sites, up to two lesions (one site) and four lesions (two sites) will be recorded respectively. Other lesions in these organs (although measurable) will be recorded as non-measurable lesions (even if the size obtained by CT scan > 10 mm). Target lesions should be selected based on their size (the lesion with the longest diameter) and represent all involved organs, but otherwise, the lesions should be suitable for reproducible repeated measurement. Sometimes there may be a situation where the lesions are not suitable for reproducible measurement, in which case the next largest lesion that can be measured reproducibly should be selected. Lymph nodes should be specifically mentioned as they are normal anatomical structures that can be seen by imaging even when not involved by the tumor. As mentioned above, pathological nodules defined as measurable and identifiable as target lesions must meet the criterion of a short axis ≥ 15 mm by CT scan. Only the short axis of these nodules contributes to the baseline sum. The short axis of a nodule is the diameter that radiologists usually use to determine whether the nodule is involved by a solid tumor. The nodule size is usually reported as two-dimensional in the plane of the image obtained (for CT, this plane is almost always the axial plane; for MRI, the acquisition plane can be axial, sagittal or coronal plane). The smaller of these two measurements is the short axis. For example, an abdominal lymph node reported as 20 mm x 30 mm has a short axis of 20 mm and is identified as a malignant, measurable nodule. In this example, 20 mm should be recorded as the nodule measurement result. All other pathological nodules (those with a short axis ≥ 10 mm but ≤ 15 mm) should be considered non-target lesions. Lymph nodes with a short axis ≤ 10 mm are considered non-pathological and should not be recorded or followed up. The sum of the diameters of all target lesions (the longest axis of non-nodule lesions, the short axis of nodule lesions) will be calculated and reported as the sum of the baseline diameters. If lymph nodes are to be included in the sum, then as mentioned above, only the short axis is added to the sum. The sum of the baseline diameters will be used as a reference to further characterize any objective tumor regression in the measurable dimension of the disease. All other lesions or disease sites, including pathological lymph nodes, should be identified as non-target lesions and also recorded at baseline. No measurement is required, and these lesions should be followed up as "present", "absent" or, in rare cases, as "definite progression". In addition, multiple non-target lesions involving the same organ can be recorded as a single item on the eCRF (e.g., "multiple pelvic lymph node enlargements" or "multiple liver metastases").

[0296] Response Criteria - Assessment of Target Lesions: This section provides the definitions of the criteria used to determine the objective tumor response of target lesions.

[0297] · CR (Complete Response): All target lesions have disappeared

[0298] o Any pathological lymph node (whether target or non-target lymph node) must have a short axis reduced to <10 mm.

[0299] · PR (Partial Response): The sum of diameters of target lesions is reduced by at least 30% with reference to the sum of baseline diameters.

[0300] · Progressive Disease: The sum of diameters of target lesions increases by 20% with reference to the smallest sum (nadir) in the study (including baseline).

[0301] o In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm.

[0302] o The appearance of one or more new lesions can also be considered as progression.

[0303] · SD (Stable Disease): With reference to the smallest sum in the study, there is neither sufficient shrinkage to meet the criteria for PR nor sufficient increase to meet the criteria for progressive disease.

[0304] Special note on target lesion assessment: The lymph nodes identified as target lesions should always record the actual short axis measurement results (measured in the same anatomical plane as the baseline examination), even if the nodules shrink to <10 mm during the study. This means that when a lymph node is classified as a target lesion, even if the CR criteria are met, the sum of lesions may not be zero because normal lymph nodes are defined as having a short axis of <10 mm.

[0305] Target lesion becomes too small to measure: During the study, all lesions (nodules and non-nodules) recorded at baseline should have their actual measurements recorded at each subsequent assessment, even if the actual measurement is very small (e.g., 2 mm). However, sometimes, a lesion or lymph node recorded as a target lesion at baseline becomes very faint on a CT scan, such that the radiologist may be reluctant to assign an exact measurement and may report them as too small to measure. When this occurs, it is important to record values on the eCRF as follows: If the radiologist believes the lesion may have disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present and faintly visible but too small to measure, a default value of 5 mm should be assigned and BML (below measurable limit) should be ticked. (Note: This rule is less likely to apply to lymph nodes as they normally usually have a definable size and are often surrounded by fat, such as in the retroperitoneal cavity; however, if a lymph node is believed to be present and faintly visible but too small to measure, in this case also a default value of 5 mm should be assigned and BML should also be ticked.) Reiterate: If the radiologist can provide an actual measurement, that measurement should be recorded even if it is below 5 mm, and in this case, BML should not be ticked. Lesions that split or coalesce during treatment When a non-nodular lesion breaks up, the longest diameters of the broken parts should be added together to calculate the total target lesion. Similarly, when lesions coalesce, the plane between them can be maintained, which will help obtain the maximum diameter measurement of each individual lesion. If the lesions truly coalesce such that they are no longer separable, in this case the vector of the longest diameter should be the maximum longest diameter of the coalesced lesions.

[0306] Assessment of non-target lesions: This section provides definitions of the criteria used to determine the tumor response of the non-target lesion group. Although some non-target lesions may actually be measurable, they do not need to be measured and should only be qualitatively assessed at the time points specified in the protocol.

[0307] · CR: All non-target lesions have disappeared. The size of all lymph nodes must be non-pathological (short axis < 10 mm).

[0308] · Non-CR / non-progressive disease: One or more non-target lesions persist.

[0309] · Progressive disease: Existing non-target lesions clearly progress. The appearance of one or more new lesions can also be considered progression.

[0310] Special notes on the assessment of non-target disease progression:

[0311] · When the patient also has measurable disease: In this context, for definitive progression based on non-target disease to have occurred, there must be an overall level of subsequent worsening in the non-target disease, even if there is SD or PR in the target disease and the overall tumor burden has increased to an extent sufficient to warrant discontinuation of therapy. A modest increase in the size of one or more non-target lesions is generally not sufficient to meet the criteria for a definitive progression status. Thus, it will be extremely rare to assign overall progression based solely on changes in non-target disease in the face of SD or PR in the target disease.

[0312] · When the patient has only non-measurable disease: This occurs in some Phase III trials because having measurable disease is not a criterion for entry into the study. As noted above, the same general concepts apply here; however, in this case, factors related to the assessment of measurable disease are not introduced when interpreting an increase in non-measurable burden. Since worsening of non-target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable), a useful test that can be applied when assessing whether a patient has definitive progression is to consider whether the increase in overall disease burden based on changes in non-measurable disease is comparable to the increase required to declare measurable progressive disease, i.e., an increase in tumor burden representing an additional 73% in volume (equivalent to a 20% increase in the diameter of a measurable lesion). Examples include pleural effusion increasing from

[0313] “minimal” to “massive”, or lymphatic disease increasing from local to extensive. Examples in the protocol may be described as “sufficient to require a change in therapy”. If definitive progression is found, the patient should be considered to have overall progressive disease at that time. While it would be ideal to establish objective criteria applicable to non-measurable disease, the nature of this disease makes it impossible to do so; thus, the increase must be substantial.

[0314] · New lesions: The appearance of new malignant lesions indicates disease progression; thus, some caveats regarding the detection of new lesions are important. There are no specific criteria for the identification of new radiographic lesions; however, the detection of new lesions should be definitive, i.e., not attributable to differences in scanning technique, changes in imaging modality, or the belief that the test result represents something other than a tumor (e.g., some “new” bone lesions may simply be pre-existing lesions in healing or flare). This is particularly important when the patient's baseline lesions show PR or CR (e.g., hepatic lesion necrosis may be reported as a “new” cystic lesion in a CT scan report, but this is not the case). Lesions found in an anatomical location not scanned at baseline during the study period are considered to be new lesions and will indicate disease progression. If a new lesion is suspect (e.g., due to its small size), continuation of therapy and subsequent evaluations will clarify whether it truly represents new disease. If repeated scans confirm the definite presence of a new lesion, the date of the initial scan should be used to declare progression.

[0315] Assessment of Response

[0316] Response at Time Points (Overall Response): It is assumed that response assessments occur at each protocol-specified time point. Table 5 provides a summary of the overall response status calculated for patients with measurable disease at baseline at each time point. When a patient has only non-measurable (and thus non-target) disease, Table 6 will be used.

[0317] Table 5 - Response at Time Points: Patients with Target Lesions (With or Without Non-Target Lesions)

[0318]

[0319] CR = Complete Response; NE = Not Evaluable; PD = Progressive Disease; PR = Partial Response; SD = Stable Disease.

[0320] Table 6 - Response at Time Points: Patients with Only Non-Target Lesions

[0321]

[0322] CR = Complete Response; NE = Not Evaluable; PD = Progressive Disease.

[0323] Absence of Assessment and Not-Evaluable Designations: When no imaging / measurement is performed at a particular time point, the patient is not evaluable at that time point. If only a subset of lesions is measured during assessment, the case is generally also considered not evaluable at that time point, unless a compelling argument can be made that the impact of a single missing lesion does not alter the specified time point response. This is most likely to occur in the case of progressive disease (e.g., if a patient has a baseline sum of 50 mm for three measured lesions and only two lesions are assessed during the study but their sum is 80 mm, the patient will reach a progressive disease state regardless of the impact of the missing lesion). If one or more target lesions are not assessable due to non-performance of a scan or due to poor image quality or obstructed field of view, the response for the target lesion(s) should be "not assessable" as the patient is not evaluable. Similarly, if one or more non-target lesions are not assessed, the response for the non-target lesion(s) should be "not assessable" unless there is obvious progression. If the target or non-target response is "not assessable", the overall response will be "not assessable" unless it is clear evidence of progression, as this is equivalent to a case that is not evaluable at that time point.

[0324] Table 7 - Best Overall Response When Confirmation is Required

[0325]

[0326] CR = Complete Response; NE = Not Evaluable; PD = Progressive Disease; PR = Partial Response; SD = Stable Disease.

[0327] Special notes regarding response assessment: When nodular disease is included in the sum of target lesions and the nodules decrease to "normal" size (<10 mm), measurements may still be reported on scans. Even if the nodules are normal, the measurements should be recorded to avoid overstating progression (if based on an increase in nodule size). As previously stated, this means that the sum on the eCRF for patients with CR may not be "zero". If the patient's overall health status deteriorates and treatment needs to be discontinued but there is no objective evidence of disease progression at that time, it should be reported as "symptomatic deterioration". Every effort should be made to record objective progression even after treatment has been discontinued. Symptomatic deterioration is not a descriptor of objective response; it is a reason to stop study treatment. The objective response status of such patients will be determined by the assessment of target and non-target diseases, as shown in Tables 5 to 7. For suspicious findings of progression (e.g., very small and indeterminate new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If progression is confirmed at the next scheduled assessment, the date of progression should be the earlier date of suspected progression. In studies where patients with advanced disease are eligible (i.e., the primary disease is still present or partially present), the primary tumor should also be captured as a target or non-target lesion, as appropriate. This is to avoid misclassification of a complete response in cases where the primary tumor is still present but not evaluated as a target or non-target lesion.

[0328] Modified Response Assessment in Neuro-Oncology for Brain Metastases (mRECIST-BM):

[0329] The RANO-BM criteria are referred to as the mRECIST-BM criteria in this protocol. The mRECIST-BM criteria are similar to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and the definition of radiographic response will be based on one-dimensional measurements.

[0330] Measurable disease is defined as a contrast-enhanced lesion that can be accurately measured in at least one dimension, with a minimum size of 10 mm and visible on two or more axial slices, preferably with a slice interval of 5 mm or less and a skip of 0 mm (and ideally, an interval ≤ 1.5 mm and a skip of 0 mm). Additionally, while the longest diameter in the measurement plane will be recorded, for a lesion to be considered measurable, the diameter perpendicular to the longest diameter in the measurement plane should be at least 5 mm. If thicker slices are used for magnetic resonance imaging (MRI), the size of a measurable lesion at baseline should be at least twice the slice thickness. When determining the minimum size of a measurable lesion at baseline, if there are interslice gaps, they should also be taken into account. Measuring tumors around cysts or surgical cavities is a particularly difficult challenge. Generally, such lesions should be considered non-measurable unless there are nodular components with a measured longest diameter of 10 mm or greater and a longest diameter of 5 mm or greater in the perpendicular plane. The cystic or surgical cavity should not be measured to determine response. Non-measurable disease includes all other lesions, including those with a longest size less than 10 mm, lesions with a boundary that cannot be reproducibly measured, dural metastases, bony skull metastases, purely cystic lesions, and leptomeningeal disease. Patients with non-measurable disease may still be included in trials where the response is not the primary endpoint (e.g., trials with progression-free survival, overall survival, or other primary endpoints). For studies where CNS objective response is the primary endpoint, we generally recommend setting the cut-off at 10 mm to limit the study to measurable disease. For investigators who choose to lower the minimum size limit of measurable disease to 5 mm, we strongly recommend using MRI imaging with a slice thickness of 1.5 mm or less. Even lesions as small as 5 mm can be interpreted as complete response and definite progressive disease. However, measuring minor changes, such as an increase in the longest diameter of at least 20% to determine progressive disease, or a decrease in the longest diameter of at least 30% to determine partial response, may not be robust or reproducible. Due to the inherent uncertainty in small lesion measurements, any lesion with a longest diameter less than 10 mm should be considered unchanged compared to baseline unless there is a change in the measured longest diameter of at least 3 mm. If objective response is the primary endpoint, careful consideration should be given to including patients with multiple lesions with a combined diameter of 10 mm or greater but with the largest lesion measuring less than 10 mm. If such patients are included, the sum of the longest diameters of the lesions should be used to assess response, and the response criteria should be clearly defined in the protocol. In this context, thin-slice MRI imaging with a slice thickness of 1.5 mm or thinner is required.

[0331] Measurement method:

[0332] The same assessment methods and the same techniques should be used to characterize each identified and reported lesion at baseline and during follow-up. Consistent use of imaging techniques at all imaging time points is important to ensure that the assessment of the interval of appearance, disappearance, or size change of lesions is not affected by scan parameters (such as slice thickness). The use of thin-slice imaging is particularly important for assessing lesions with a longest diameter less than 10 mm or for lesions with minor size changes or both. Gadolinium-enhanced MRI is the most sensitive and reproducible method available for measuring CNS lesions selected for response assessment (Schellinger et al., 1999; Sze et al., 1990). The use of MRI as the default standard imaging technique is strongly encouraged, although CT with or without contrast may be considered in specific situations (e.g., in countries with limited medical resources or in the presence of MRI contraindications).

[0333] Tumor response assessment:

[0334] Patients with measurable CNS disease only at baseline should be included in protocols with objective CNS tumor response as the primary endpoint. For studies where objective response is not the primary endpoint, the protocol must prospectively specify whether only patients with measurable disease are included or whether patients with non-measurable disease are also eligible. Assignment of CNS response is independent of systemic disease response. CNS lesions will be evaluated according to mRECIST-BM criteria, and non-CNS lesions are most commonly evaluated according to RECIST 1.1 criteria. In general, CNS lesions should initially be re-evaluated by MRI at intervals specified in the protocol (intervals of 6 to 12 weeks), although there may be specific circumstances where longer (or shorter) intervals are required. For patients who remain stable over long periods, longer intervals between scans may be appropriate. All baseline evaluations should be completed as close as possible to the start of treatment and no more than 4 weeks before the start of treatment. For previously treated lesions, we recommend recording the prior treatment modality for each lesion (e.g., stereotactic radiosurgery, whole brain radiotherapy, surgical resection). When there is more than one measurable lesion in the CNS at baseline, all lesions up to a maximum of five CNS lesions should be identified as target lesions and recorded and measured at baseline. All measurements should be recorded in metric notation. Target lesions should be selected based on the size (longest diameter) of the lesion and a dimension that can be reproducibly measured. For patients with recurrent disease who have multiple lesions and only one or two of which have increased in size, the increased lesions should be preferentially selected as target lesions for response assessment. Lesions previously treated with local therapy (i.e., stereotactic radiosurgery or surgical resection) may be considered measurable if there has been progression since local treatment. However, for lesions previously treated with stereotactic radiosurgery, careful consideration should be given considering the potential for treatment effect. Whether measurement of such lesions can be considered should be prospectively specified in the clinical protocol. If there are lesions that have not previously been treated with local therapy, it is preferable to select these lesions as target lesions. The sum of the diameters of all target lesions will be calculated and reported as the sum of the baseline diameters. All other CNS lesions should be identified as non-target lesions and also recorded at baseline. Measurement is not required, and these lesions should be classified as present, absent, or clearly progressive and followed up.

[0335] Definition of best overall CNS response:

[0336] The best overall CNS response is a composite of radiographic CNS target and non-target lesion responses (Table 8). For non-randomized trials with CNS response as the primary endpoint, a partial or complete response confirmed at least 4 weeks later is required to consider either as the best overall response.

[0337] Table 8 - Response assessment for target and non-target lesions

[0338]

[0339] At the time points specified in each protocol, response assessments should be performed, and CNS assessments should be consistent with extra-CNS assessments. Table 9 shows the requirements considered partial or complete response

[0340] Table 9 - Summary of response criteria for CNS metastases proposed by mRECIST - BM

[0341]

[0342]

[0343] * Progression occurs when this criterion is met.

[0344] New lesions are lesions that were not present on previous scans and are visible on at least two projections. If a new lesion is suspicious, e.g., due to its small size, continuation of therapy may be considered and subsequent assessments will clarify whether the new lesion is a new disease. If repeated scans confirm the definite presence of a new lesion, the date of the initial scan showing the new lesion should be used to declare progression. For immunotherapy-based methods, new lesions alone do not define progression.

[0345] Assessment of target and non-target CNS lesions:

[0346] During the study, the actual measurements of all CNS target lesions should be recorded, even if they are very small (e.g., 2 mm). If the lesion has disappeared, the value should be recorded as 0 mm. However, if the lesion is small enough (but still present) to specify an exact measurement, a default value of 5 mm should be recorded on the eCRF. During treatment, lesions may coalesce. When lesions coalesce, the plane between them can be maintained, which will help to obtain the maximum longest diameter value for each individual lesion. If the lesions truly coalesce such that they are no longer separable, then in this case the vector of the longest diameter should be the maximum longest diameter of the coalesced lesions. During treatment, new lesions may appear. The detection of new CNS lesions should be definite and not due to technical or slice changes. A new lesion is one that was not present on previous scans. If the MRI was obtained with a slice thickness of 1.5 mm or less, the new lesion should also be visible on axial, coronal, and sagittal reconstructions with a projection of 1.5 mm or thinner. If the new lesion is suspicious, e.g., due to its small size (i.e., ≤5 mm), then continuation of therapy can be considered and subsequent assessments will clarify whether it is truly a new disease. If repeated scans confirm the new lesion, the date of the initial scan showing the new lesion should be used to declare progression. However, in the case of immunotherapy, the presence of only new lesions does not constitute progressive disease. Definite progression of non-target lesions may require discontinuation of therapy. When a patient still has measurable disease and is to be considered as having definite progression based on non-target disease alone, the non-target disease must also have deteriorated significantly overall such that even if there is stable disease or partial response in the target disease, the overall tumor burden has increased to the extent that therapy should be discontinued. When a patient has only non-measurable disease, there must be a significant overall level of deterioration to be sufficient to discontinue therapy. The mRECIST-BM group acknowledges cases of patients who have been treated with stereotactic radiosurgery or immunotherapy-based approaches for whom there is radiographic evidence of enlargement of target and non-target lesions, which does not necessarily represent tumor progression. If there is radiographic evidence of progression, but clinical evidence indicates that the radiological changes are due to the treatment effect (rather than cancer progression), additional evidence is required to distinguish true progression from treatment effect, and in this case, standard MRI alone is insufficient. The methods used to distinguish true progression and treatment effect should be specified prospectively in the clinical protocol. The patient may continue on protocol therapy, awaiting further investigation using one or more of the following options. The scan can be repeated at the next scheduled assessment according to the protocol or earlier, and generally within about 6 weeks. If progressive symptoms or other clinical problems arise, the investigator may choose a shorter time interval. Persistent tumor growth may be consistent with radiographic progression, in which case the patient should be withdrawn from the study. Stable and atrophic lesions may be consistent with treatment effect, in which case the patient may remain in the study.For patients with equivocal results even on the next restaging scan, repeat scanning may be done at the next scheduled assessment in the protocol or earlier, although surgery or the use of advanced imaging modalities (in the case of stereotactic radiosurgery) or both are strongly encouraged. Surgical pathology may be obtained via biopsy or resection.

[0347] For lesions treated with stereotactic radiosurgery, additional evidence of tumor progression or treatment effect (radiation necrosis) may be obtained using advanced imaging modalities such as perfusion MRI, magnetic resonance spectroscopy, or 18FLT or 18FDG PET. If subsequent testing shows progression has occurred, the date of progression should be recorded as the date of the scan when the question was first raised. The patient may also have equivocal findings on the scan (e.g., small lesions, but not clearly new). Treatment may be allowed to continue until the next scheduled assessment in the protocol. If the subsequent assessment shows that progression has indeed occurred, the date of progression should be recorded as the date of the initial scan when progression was suspected.

[0348] In patients receiving immunotherapy-based treatment, the number and size of metastases initially increase, followed by radiographic stability or regression. This pattern may be related to the mechanism of action of immunotherapy, including immune infiltration and the time to establish an effective immune response. Therefore, progressive disease should not be defined solely by the appearance of new lesions, but rather by an increase of at least 20% in the sum of the longest diameters of CNS target lesions and new lesions, by definite progression of existing enhancing non-target CNS lesions, by definite progression of existing non-enhancing (T2 / FLAIR) CNS lesions, or by tumor-related clinical decline. If radiographic changes suspected to be related to the immune response are seen, we recommend not changing treatment until short-interval scans are obtained.

[0349] Volume criteria:

[0350] First, partial volume response should be defined as a reduction of 65% or greater in the total volume of CNS target lesions. Second, volume response should be reported as a waterfall plot to provide a global sense of potential efficacy. Third, there is a lack of high-quality data in multiple studies to show a clear correlation between lower volume thresholds and some measures of patient benefit such as quality of life, neurocognitive function, or overall survival, so it is premature to formally define a category of minor response or lower the threshold considered to be a volume response. However, we encourage digital archiving of the trial images and the accompanying linked clinical outcome data to allow pooled studies to determine if different cut points can be confirmed in the future.

[0351] Treatment of non-CNS (extracranial) disease:

[0352] Preclinical and clinical data sometimes show differential responses of intracranial locations relative to extracranial locations, which may be related to insufficient drug penetration, differences in the tumor microenvironment, or tumor heterogeneity between organ sites and other possibilities. Many systemic agents are not expected to have CNS activity, mainly due to poor drug permeability. Local CNS therapies, such as whole-brain radiotherapy, stereotactic radiosurgery, or surgery, are not expected to affect extracranial sites at all. Traditionally, RECIST has used the sum of representative target lesions in all organ sites. In the past, patients with brain metastases were excluded from systemic therapy trials. Even when included, patients with brain metastases usually had to have stable, treated CNS lesions at the time of entering the study, and CNS lesions were rarely selected as target lesions. The Macdonald and RANO-HGG criteria do not provide guidelines for the treatment of extracranial disease because extracranial disease is not relevant to most patients with primary brain tumors. As a consequence, in situations where CNS and non-CNS responses or progression are not consistent, there is a lack of flexibility in continuing protocol therapy, hindering the use of brain imaging as part of clinical trials, and the use of different definitions of response and progression endpoints in local and systemic therapy trials. We propose that the CNS and non-CNS should be evaluated as separate compartments (Table 10). Thus, the CNS response will be scored regardless of the extracranial response, and vice versa. For progression, the CNS and non-CNS will be scored according to the mRECIST-BM and RECIST 1.1 criteria, respectively (Table 11). If progression occurs in one or both compartments, the criteria for dual-compartment progression-free survival will be met. The protocol may also prospectively designate CNS progression-free survival and non-CNS progression-free survival as endpoints. The protocol should specify the plan for patients who progress in only one compartment. For example, a patient with isolated CNS progression in a systemic therapy trial may choose to treat their CNS disease with whole-brain radiotherapy, stereotactic radiosurgery, or surgery and continue protocol therapy until non-CNS disease progression, unacceptable toxicity, or death occurs. The date of occurrence of non-CNS progressive disease should be recorded.

[0353] Table 10 - CNS and non-CNS assessment

[0354]

[0355]

[0356] Table 11 - Dual-compartment progression-free survival

[0357]

[0358] Table 12 - Objectives and endpoints

[0359]

[0360]

[0361] Table 13 - Sampling Schedule: Details of Sample Collection per Hour

[0362]

[0363]

[0364]

[0365] (a) "Before dosing" refers to sample collection shortly before the administration of Compound Ia and cobimetinib (if applicable) drugs ("dosing"). Both Compound Ia and cobimetinib (if applicable) will be taken at the same time in the morning. The scheduled time points refer to the time in hours after the administration of Compound Ia and cobimetinib (if applicable) drugs. The PK sample collection times for Compound Ia and cobimetinib (if applicable) need to be recorded and entered into the eCRF.

[0366] (b) In the case of no drug interaction between Compound Ia and cobimetinib, it may not be necessary to further collect cobimetinib PK samples and / or endogenous CYP biomarker samples in the food cohort or Part 2. If Part 2 consists of treatment with Compound Ia alone, no cobimetinib PK samples will be collected.

[0367] (c) In the case of a short half - life of Compound Ia as assessed in the lead PK cohort, it may not be necessary to further collect samples 8 hours after C1D1 and C1D15 dosing and C1D2, C1D3, C1D4, and C1D16 samples in the main dose escalation and / or food cohort and / or expansion cohort (Part 2).

[0368] (d) If there is sufficient data during the study for the PK characterization of Compound Ia, it may not be necessary to further collect these samples in Part 2.

[0369] (e) If the termination visit coincides with an unscheduled visit, all planned assessments for the termination visit need to be carried out.

[0370] Schema Details:

[0371] Overview of the Phase 1Ia / b study design: Part 1 is the dose escalation phase. In the cohorts of Part 1a, compound Ia is used as monotherapy, while in the cohorts of Part 1b, compound Ia is used in combination with cobimetinib. Additionally, Part I includes a lead PK cohort and a food cohort. Part 2 is the expansion phase consisting of four cohorts: BRAFi-naive melanoma with asymptomatic brain lesions corresponds to cohort 1 (compound Ia monotherapy) and cohort 3 (compound Ia plus cobimetinib). BRAFi-treated melanoma with asymptomatic brain lesions corresponds to cohort 2 (compound Ia monotherapy) and cohort 4 (compound Ia plus cobimetinib).

[0372] FIG. 2 Flowchart of the manufacturing method of a film-coated tablet containing compound Ia (Example A). The drug product is manufactured using a dry granulation method:

[0373] · Step 1: Weigh compound Ia, sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, and croscarmellose sodium, and mix them well. Spray drying of compound Ia is carried out as step 0 if necessary.

[0374] · Step 2: Dry granulation of the mixture obtained from step 1. Alternatively, high-shear mixing or fluidized bed granulation can be used for the mixture obtained from step 1 instead of dry granulation.

[0375] · Step 3: Weigh croscarmellose sodium and magnesium stearate. Add them to the granules obtained from step 2 and mix well.

[0376] · Step 4: Compress the mixture obtained from step 3 into tablets, and check the individual weight of the tablet cores (as in-process control).

[0377] · Step 5: Weigh the film coating mixture and suspend it in purified water. Spray the obtained coating suspension onto the tablet cores from step 4. Measure the average weight of the film-coated tablets (as in-process control).

[0378] · Step 6: Package and label the film-coated tablets for clinical use.

[0379] FIG. 3: Preliminary PK data on the effect of food indicate that food intake results in lower C in the postprandial cohort, but unexpectedly, it does not significantly change the AUCINF (AUC max ) of compound Ia (also known as RO7276389). 0-∞ )

[0380] FIG. 4: Trough concentration (C) of compound Ia (also known as RO7276389) based on a preliminary population pharmacokinetic (PopPK) model谷 ) The simulation shows the coverage of approximately IC95 for 1200 mg TID and 1600 mg BID. Such coverage is significantly higher than the C of currently available BRAF inhibitors at the approved doses, 谷 which causes coverage around IC80 and is limited by dose-limiting toxicity. Importantly, the simulation also shows that the highest coverage can be obtained using the dosing regimen referred to herein as 1200 mg TID6, where the first daily dose is administered with the first meal in the morning, then the second daily dose is administered 6 hours later (possibly with the second meal), and the third daily dose is administered 6 hours later (possibly with the third meal).

[0381] Pharmaceutical composition:

[0382] An embodiment of the present invention provides a pharmaceutical composition for use in the present invention, wherein the composition contains a compound of formula (I) and one or more therapeutically inert carriers, diluents or excipients, and a method for preparing such a pharmaceutical composition. In one example, the compound of formula (I) or its pharmaceutically acceptable salt can be mixed with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the doses and concentrations employed) into a galenical administration form at an appropriate pH at ambient temperature and with the required purity. The compound of formula (I) exhibits low and pH-dependent solubility. It behaves like a weak acid throughout the physiological pH range, being poorly soluble at low pH and having increased solubility at neutral and alkaline pH. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized preparation or as an aqueous solution.

[0383] The composition is formulated, dosed and administered in a manner consistent with good medical practice. Factors to be considered in this case include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the medicament, the method of administration, the timing of administration, and other factors known to the practicing physician.

[0384] As used herein, "pharmaceutical carrier" or "pharmaceutical excipient" is intended to include any and all materials compatible with drug administration, including solvents, dispersion media, coatings, enteric coatings, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, and other materials and compounds compatible with drug administration. It is contemplated for use in the compositions of the present invention except in cases where any conventional medium or agent is incompatible with the active compound. Supplementary active compounds can also be incorporated into the composition.

[0385] The pharmaceutical composition can be obtained by processing the compound of formula (I) with a pharmaceutically inorganic or organic carrier or excipient. Such carriers as lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used, for example, for tablets, film-coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the properties of the active substance, a carrier is often not required in the case of soft gelatin capsules. Suitable carriers for producing solutions and syrups are, for example, water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0386] In addition, the pharmaceutical composition may contain fillers, pH regulators, glidants, disintegrants, lubricants, preservatives, solubilizers, stabilizers, enteric coatings, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances. Suitable fillers for tablets are, for example, microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, isomalt and dibasic calcium phosphate. Suitable wetting agents for tablets are, for example, sodium lauryl sulfate, polyvinylpyrrolidone / polyvinyl alcohol (PVP / PVA) copolymer and hypromellose. Suitable pH regulators for tablets are, for example, magnesium oxide, calcium carbonate, calcium hydrogen carbonate, lysine and tromethamine. Suitable glidants for tablets are, for example, colloidal silicon dioxide. Suitable lubricants for tablets are, for example, magnesium stearate, sodium stearyl fumarate and polyethylene glycol 6000.

[0387] The pharmaceutical composition of the compound of formula (I) can be prepared for storage (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.) (1980)) by mixing the active ingredient with the pharmaceutically carrier, excipient or stabilizer as appropriate, in the form of a freeze-dried preparation or an aqueous solution.

[0388] The pharmaceutical compositions of the compounds of formula (I) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the host to be treated and the particular mode of administration. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form is generally the amount of the compound of formula (I) that produces a therapeutic effect. Generally speaking, below one hundred percent, the amount of the active ingredient will range from about 1% to about 90%, preferably from about 2% to about 70%, and most preferably from about 4% to about 40%. The methods of preparing these compositions include the step of associating the compound of formula (I) with a carrier and optionally one or more accessory ingredients. Generally speaking, the pharmaceutical compositions may be prepared by uniformly and intimately associating the compound of formula (I) with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product. Pharmaceutical compositions suitable for oral administration may be capsules, cachets, sachets, pills, tablets, film-coated tablets, troches (using a flavored matrix, usually sucrose and gum acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a lozenge (using an inert matrix, such as gelatin and glycerin, or sucrose and gum acacia) and / or as a mouthwash, etc., each containing a predetermined amount of the compound of formula (I) as the active ingredient. The compound of formula (I) may also be administered as a bolus, a pastille or a paste.

[0389] The active ingredient may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin microcapsules and poly(methylmethacrylate) microcapsules, respectively), entrapped in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. (ed.) (1980).

[0390] The preparations to be used for in vivo administration must be sterile. This may be readily accomplished by filtration through sterile filtration membranes.

[0391] The dosage can vary within a wide range, but will of course have to be adjusted according to the individual needs of each specific case. In the case of oral administration, the dosage for adults can vary between about 100 mg and about 4000 mg per day, preferably between about 1000 mg and about 4000 mg per day, more preferably between about 1600 mg and about 4000 mg per day of the compound of general formula (I) or the corresponding amount of a pharmaceutically acceptable salt or solvate thereof. The daily dose can be administered as a single dose or in multiple divided doses. In addition, when there are indications that the upper limit can be exceeded, the upper limit can also be exceeded.

[0392] The following examples illustrate but do not limit the invention and are merely representative of the invention. The pharmaceutical composition suitably contains from about 5 mg to about 800 mg, especially from about 10 mg to about 700 mg, more especially from about 25 mg to about 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains from about 50 mg to about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains from about 200 mg to about 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains from about 400 mg to about 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains from about 600 mg to about 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains from about 800 mg to about 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a certain embodiment, the pharmaceutical composition containing the compound of formula (I) additionally contains from about 1 mg to 500 mg, especially from 5 mg to 100 mg, more especially a 60 mg fixed-dose combination of a MEK inhibitor (especially, cobimetinib). In a certain embodiment, the pharmaceutical composition containing the compound of formula (I) additionally contains about 20 mg of a fixed-dose combination of a MEK inhibitor (especially, cobimetinib).

[0393] Non-limiting examples of the pharmaceutical composition of the present invention are:

[0394] Example C - film-coated tablets

[0395] Film-coated tablets can be manufactured by conventional dry granulation, followed by tableting and film coating. Non-limiting examples of the film-coated tablets of the present invention can have the following composition:

[0396]

[0397] Table 14: Possible film-coated tablet compositions; 1The film coating mixture consists of pharmacopeial components: partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide, yellow iron oxide, and red iron oxide. 2 Purified water is used for aqueous film coating; it is substantially removed during the processing; qs: quantity sufficient.

[0398] Manufacturing process of film-coated tablets

[0399] The drug can be manufactured using the dry granulation method:

[0400] · Step 1: Weigh compound Ia, sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, and croscarmellose sodium, and mix them evenly. The spray drying of compound Ia is carried out as step 0 if necessary.

[0401] · Step 2: Dry granulation of the mixture obtained from step 1. Alternatively, high-shear mixing or fluidized bed granulation can be used for the mixture obtained from step 1 instead of dry granulation.

[0402] · Step 3: Weigh croscarmellose sodium and magnesium stearate. Add them to the granules obtained from step 2 and mix evenly.

[0403] · Step 4: Compress the mixture obtained from step 3 into tablets, and check the individual weight of the tablet cores (as control during the process).

[0404] · Step 5: Weigh the film coating mixture and suspend it in purified water. Spray the obtained coating suspension onto the tablet cores from step 4. Measure the average weight of the film-coated tablets (as control during the process).

[0405] · Step 6: Package and label the film-coated tablets.

[0406] The components of the tablet cores are:

[0407] · The formulation contains a filler or a combination of at least two fillers to ensure that the tablets have the expected mechanical resistance. The expected mechanical resistance is characterized in that the tablet cores have sufficient tensile strength, low friability, and low abrasion, so that they can withstand the stresses during the coating and packaging operations. These fillers can be, for example, microcrystalline cellulose and lactose monohydrate in a ratio of about 2:1.

[0408] · The formulation contains a wetting agent, such as sodium lauryl sulfate (0.5% by weight relative to the total weight of the uncoated tablets).

[0409] · The formulation contains a glidant, such as colloidal silicon dioxide (0.5% by weight relative to the total weight of the uncoated tablets).

[0410] · The preparation contains a basic pH regulator (such as magnesium oxide) in a ratio of 1:2 to compound Ia. The pH regulator is intended to create a favorable in vivo micro-pH environment for the solubility of the API (active pharmaceutical ingredient).

[0411] · The preparation contains a disintegrant, such as croscarmellose sodium (3.0% by weight relative to the total weight of the uncoated tablets). Half is added before granulation and half is added after granulation.

[0412] · The preparation contains magnesium stearate as a lubricant (1.0% by weight relative to the total weight of the uncoated tablets).

[0413] The components of the film coating are:

[0414] · The film coating mixture contains polyvinyl alcohol as a film-forming agent, polyethylene glycol 3350 as a softening agent, talc as an anti-sticking agent, titanium dioxide, and red and yellow iron oxides as pigments.

[0415] · The film coating mixture is dispersed in purified water at a solids content of 15%. The film coat is sprayed onto the tablet cores in a pan coater, aiming for a 3% weight increase relative to the weight of the tablet cores.

[0416] Description of the film-coated tablets: The drug is a pink, oval film-coated tablet. The 25 mg dose concentration contains 4% of compound Ia. The 200 mg film-coated tablets contain 25% of compound Ia.

[0417] ​

[0418] The film-coated tablets can be manufactured by conventional dry granulation, followed by tableting and film coating. Non-limiting examples of the film-coated tablets of the present invention may have the following composition:

[0419]

[0420]

[0421] Table 15: Possible film-coated tablet compositions; 1 The film coating mixture consists of pharmacopoeial components: partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide, yellow iron oxide, and red iron oxide. 2 Purified water is used for aqueous film coating; it is substantially removed during the processing; qs: quantity sufficient.

[0422] Manufacturing process of the film-coated tablets

[0423] The drug is manufactured using the dry granulation method:

[0424] · Step 1: Weigh compound Ia, hypromellose or PVP / PVA copolymer, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide and crospovidone and mix them evenly.

[0425] · Step 2: Dry granulation of the mixture obtained from Step 1. Alternatively, high-shear mixing or fluidized bed granulation can be used for the mixture obtained from Step 1 instead of dry granulation.

[0426] · Step 3: Weigh crospovidone and sodium stearyl fumarate. Add them to the granules obtained from Step 2 and mix evenly.

[0427] · Step 4: Compress the mixture obtained from Step 3 into tablets and check the individual weight of the tablet cores (as in-process control).

[0428] · Step 5: Weigh the film coating mixture and suspend it in purified water. Spray the obtained coating suspension onto the tablet cores from Step 4. Spray drying is carried out as appropriate. Measure the average weight of the film-coated tablets (as in-process control).

[0429] · Step 6: Package and label the film-coated tablets.

[0430] ​

[0431] Film-coated tablets can be manufactured by conventional dry granulation, followed by tableting and film coating. Non-limiting examples of the film-coated tablets of the present invention may have the following composition:

[0432]

[0433]

[0434] Table 16: Possible film-coated tablet compositions; 1 The film coating mixture consists of pharmacopoeial components: partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide, yellow iron oxide and red iron oxide. 2 Purified water is used for aqueous film coating; it is substantially removed during the processing; qs: quantity sufficient.

[0435] Manufacturing process of film-coated tablets

[0436] Manufacturing drugs using the dry granulation method:

[0437] · Step 1: Weigh compound Ia, sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, calcium carbonate, colloidal silicon dioxide and cross-linked carboxymethylcellulose sodium, and mix them evenly. Spray drying of compound Ia is carried out as Step 0 as appropriate.

[0438] · Step 2: Dry granulation of the mixture obtained from Step 1. Alternatively, high-shear mixing or fluidized bed granulation may be used on the mixture obtained from Step 1 instead of dry granulation.

[0439] · Step 3: Weigh sodium croscarmellose and magnesium stearate. Add them to the granules obtained from Step 2 and mix well.

[0440] · Step 4: Compress the mixture obtained from Step 3 into tablets and check the individual weight of the tablet cores (as in-process control).

[0441] · Step 5: Weigh the film coating mixture and suspend it in purified water. Spray the obtained coating suspension onto the tablet cores from Step 4. Measure the average weight of the film-coated tablets (as in-process control).

[0442] · Step 6: Package and label the film-coated tablets

[0443] Table 17: Equipment used in the manufacturing processes of Examples A, B, and C

[0444]

[0445] The present invention further relates to:

[0446] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used alone or in combination with cobimetinib for the treatment of BRAF mutant metastatic or locally advanced solid tumors;

[0447] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used alone or in combination with cobimetinib for the treatment of BRAF mutant metastatic melanoma with brain metastases;

[0448] An embodiment of the present invention relates to a film-coated tablet comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the tablet composition further comprises a pH regulator and thereby enhances the dissolution characteristics of compound Ia;

[0449] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used alone or in combination with cobimetinib for the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been treated with checkpoint inhibitors;

[0450] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used in combination with cobimetinib for the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been treated with checkpoint inhibitors;

[0451] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases, wherein the melanoma has been treated with a checkpoint inhibitor;

[0452] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases, either alone or in combination with cobimetinib, wherein the melanoma has been previously treated with a checkpoint inhibitor;

[0453] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases in combination with cobimetinib, wherein the melanoma has been previously treated with a checkpoint inhibitor;

[0454] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor;

[0455] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases, either alone or in combination with cobimetinib, wherein the melanoma has been previously treated with a checkpoint inhibitor and a BRAF inhibitor;

[0456] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases in combination with cobimetinib, wherein the melanoma has been previously treated with a checkpoint inhibitor and a BRAF inhibitor;

[0457] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor and a BRAF inhibitor;

[0458] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic or locally advanced solid tumors, wherein the tumor has been previously treated with a checkpoint inhibitor;

[0459] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating BRAF - mutant metastatic or locally advanced solid tumors in combination with cobimetinib, wherein the tumor has been previously treated with a checkpoint inhibitor;

[0460] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the tumor has been previously treated with checkpoint inhibitors;

[0461] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the tumor has been previously treated with checkpoint inhibitors and BRAF inhibitors, either alone or in combination with cobimetinib;

[0462] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally with or without food;

[0463] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally with water;

[0464] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally with food, particularly after a high-fat meal;

[0465] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the compound of formula (I) is not administered orally with food, particularly after a 10-hour fast;

[0466] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic or locally advanced solid tumors, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally three times a day with food, with approximately 6 hours between administrations of each dose, particularly wherein each dose is administered orally with food;

[0467] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is administered orally with or without food;

[0468] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is administered orally with food, particularly after a high-fat meal;

[0469] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the compound of formula (I) is not administered orally with food, particularly orally administered after a 10-hour fast;

[0470] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is orally administered at about 1600 mg / day to about 4000 mg / day, particularly 2000 mg / day to 4000 mg / day, more particularly 3000 mg / day to 4000 mg / day;

[0471] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is orally administered at about 1600 mg / day to about 4000 mg / day, particularly 2000 mg / day to 4000 mg / day, more particularly 3000 mg / day to 4000 mg / day;

[0472] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of non-small cell lung cancer, wherein the compound of formula (I) is orally administered at 200 mg / day to 2000 mg / day, particularly 600 mg / day to 2000 mg / day, more particularly 1000 mg / day to 2000 mg / day;

[0473] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of non-small cell lung cancer, wherein the compound of formula (I) is orally administered at about 1600 mg / day to about 4000 mg / day, particularly about 2000 mg / day to 4000 mg / day, more particularly about 3000 mg / day to about 4000 mg / day;

[0474] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of non-small cell lung cancer, wherein the compound of formula (I) is orally administered at 1200 mg / day to 2000 mg / day, particularly 1400 mg / day to 2000 mg / day, more particularly 1600 mg / day to 2000 mg / day;

[0475] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of non-small cell lung cancer, wherein the compound of formula (I) is orally administered at 800 mg / day to 1600 mg / day, particularly 800 mg / day to 1400 mg / day, more particularly 1000 mg / day to 1400 mg / day;

[0476] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at about 50 mg / day to 800 mg / day during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle;

[0477] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at about 800 mg / day to 2000 mg / day during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle;

[0478] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at about 2000 mg / day to about 4000 mg / day during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle;

[0479] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at about 3000 mg / day to about 4000 mg / day, particularly about 3200 mg / day, during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle;

[0480] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at 1200 mg / day to 2000 mg / day, particularly 1600 mg / day, during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle;

[0481] One embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at about 800 mg / day to 1200 mg / day during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle;

[0482] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used for the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at a dose of 50 mg / day to 800 mg / day, particularly 200 mg / day to 600 mg / day, during each day of a 28-day cycle, and cobimetinib is administered at a dose of 60 mg / day from day 1 to day 21 of the 28-day cycle;

[0483] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, which is used as described herein, wherein the administration is carried out twice a day (BID);

[0484] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), which is used as described herein, wherein 800 mg of the compound of formula (I) is administered twice a day (BID);

[0485] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), which is used as described herein, wherein 1200 mg of the compound of formula (I) is administered twice a day (BID);

[0486] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), which is used as described herein, wherein 1600 mg of the compound of formula (I) is administered twice a day (BID);

[0487] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), which is used as described herein, wherein 2000 mg of the compound of formula (I) is administered twice a day (BID);

[0488] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), which is used as described herein, wherein 800 mg of the compound of formula (I) is administered three times a day (TID);

[0489] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), which is used as described herein, wherein 800 mg of the compound of formula (I) is administered three times a day (TID), with a 6-hour interval between the first daily dose and the second daily dose and between the second daily dose and the third daily dose;

[0490] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), which is used as described herein, wherein 1200 mg of the compound of formula (I) is administered three times a day (TID);

[0491] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), which is used as described herein, wherein 1200 mg of the compound of formula (I) is administered three times a day (TID), with a 6-hour interval between the first daily dose and the second daily dose and between the second daily dose and the third daily dose, respectively;

[0492] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), which is used as described herein, wherein 1600 mg of the compound of formula (I) is administered three times a day (TID);

[0493] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, which is used as described herein, wherein administration is carried out three times a day (TID);

[0494] An embodiment of the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, which is used as described herein, wherein administration is carried out three times a day (TID), with a 6-hour interval between the first daily dose and the second daily dose and between the second daily dose and the third daily dose, respectively;

[0495] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of BRAF-mutant cutaneous melanoma with asymptomatic brain metastases; and

[0496] An embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used alone or in combination with cobimetinib for the treatment of BRAF-mutant cutaneous melanoma with radiologically confirmed asymptomatic brain metastases.

[0497] Specific numbered embodiments:

[0498] 1. A compound of formula (I)

[0499]

[0500] or a pharmaceutically acceptable salt thereof for the treatment of melanoma with brain metastases.

[0501] 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in Example 1, wherein the brain metastases are asymptomatic.

[0502] 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in Example 1 or 2, wherein the melanoma is cutaneous melanoma.

[0503] 4. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 1 to 3, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0504] 5. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in Example 4, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

[0505] 6. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 1 to 3, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0506] 7. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 1 to 6, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0507] 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 1 to 7, wherein the compound of formula (I) is combined with cobimetinib.

[0508] 9. A method for treating or preventing melanoma with brain metastases, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I)

[0509]

[0510] or a pharmaceutically acceptable salt thereof.

[0511] 10. The method of Example 9, wherein the brain metastases are asymptomatic.

[0512] 11. The method of Example 9 or 10, wherein the melanoma is cutaneous melanoma.

[0513] 12. The method of any one of Examples 9 to 11, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0514] 13. The method of Example 12, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

[0515] 14. The method of any one of Examples 9 to 11, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0516] 15. The method of any one of Examples 9 to 14, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0517] 16. A method according to any one of Examples 9 to 14, wherein the compound of formula (I) is combined with cobimetinib.

[0518] 17. The compound of formula (I)

[0519]

[0520] or a pharmaceutically acceptable salt thereof for use in the treatment of melanoma with brain metastases.

[0521] 18. The use according to Example 17, wherein the brain metastases are asymptomatic.

[0522] 19. The use according to Example 17 or 18, wherein the melanoma is cutaneous melanoma.

[0523] 20. The use according to any one of Examples 17 to 19, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0524] 21. The use according to Example 20, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib.

[0525] 22. The use according to any one of Examples 17 to 19, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0526] 23. The use according to any one of Examples 17 to 22, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0527] 24. The use according to any one of Examples 17 to 23, wherein the compound of formula (I) is combined with cobimetinib.

[0528] 25. A pharmaceutical composition comprising a compound of formula (I)

[0529]

[0530] or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically inert carrier, the pharmaceutical composition being for use in the treatment of melanoma with brain metastases.

[0531] 26. The pharmaceutical composition as used in Example 25, wherein the brain metastases are asymptomatic.

[0532] 27. The pharmaceutical composition as used in Example 25 or 26, wherein the melanoma is cutaneous melanoma.

[0533] 28. The pharmaceutical composition as used in any one of Examples 25 to 27, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0534] 29. A pharmaceutical composition as used in any one of Examples 25 to 28, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

[0535] 30. A pharmaceutical composition as used in any one of Examples 25 to 27, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0536] 31. A pharmaceutical composition as used in any one of Examples 25 to 30, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a MEK inhibitor.

[0537] 32. A pharmaceutical composition as used in any one of Examples 25 to 31, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with cobimetinib.

[0538] 33. A pharmaceutical composition comprising a compound of formula (I)

[0539]

[0540] or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises one or more fillers, glidants, disintegrants, and lubricants. Preferably, the pharmaceutical composition comprises one or more fillers, glidants, disintegrants, pH regulators, lubricants, and wetting agents.

[0541] 34. The pharmaceutical composition according to Example 33, wherein the pharmaceutical composition comprises a film coating.

[0542] 35. The pharmaceutical composition according to Example 34, wherein the film coating comprises one or more components selected from polyvinyl alcohol, polyethylene glycol 3350, polyethylene glycol 4000, talc, titanium dioxide, yellow iron oxide, and red iron oxide.

[0543] 36. The pharmaceutical composition according to any one of Examples 33 to 35, wherein the filler is selected from microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, isomalt, and dibasic calcium phosphate.

[0544] 37. The pharmaceutical composition according to any one of Examples 33 to 36, wherein the filler is selected from microcrystalline cellulose and lactose monohydrate.

[0545] 38. The pharmaceutical composition according to any one of Examples 33 to 37, wherein the filler is microcrystalline cellulose and lactose monohydrate in a weight percentage ratio of about 2:1 (microcrystalline cellulose: lactose monohydrate).

[0546] 39. The pharmaceutical composition according to any one of Examples 33 to 38, wherein the weight percentage of the filler or the combined weight percentage of the fillers is about 30% to about 90% by weight of the pharmaceutical composition.

[0547] 40. A pharmaceutical composition according to any one of Examples 33 to 39, wherein the wetting agent is selected from sodium lauryl sulfate, PVP / PVA copolymer, and hypromellose, and the weight percentage range thereof is from about 0.1% by weight to about 5.0% by weight of the pharmaceutical composition.

[0548] 41. A pharmaceutical composition according to any one of Examples 33 to 40, wherein the wetting agent is sodium lauryl sulfate, and the weight percentage thereof is about 0.1% by weight of the pharmaceutical composition.

[0549] 42. A pharmaceutical composition according to any one of Examples 33 to 40, wherein the weight percentage of the glidant is about 0.5% by weight of the pharmaceutical composition.

[0550] 43. A pharmaceutical composition according to any one of Examples 33 to 42, wherein the glidant is colloidal silicon dioxide.

[0551] 44. A pharmaceutical composition according to any one of Examples 33 to 43, wherein the pH regulator is a basic pH regulator.

[0552] 45. A pharmaceutical composition according to any one of Examples 33 to 44, wherein the pH regulator is selected from magnesium oxide, calcium carbonate, calcium bicarbonate, lysine, and tromethamine.

[0553] 46. A pharmaceutical composition according to any one of Examples 33 to 45, wherein the pH regulator is magnesium oxide.

[0554] 47. A pharmaceutical composition according to any one of Examples 33 to 46, wherein the weight percentage ratio of the pH regulator to the compound of formula (I) is between about 3:1 and about 1:5.

[0555] 48. A pharmaceutical composition according to any one of Examples 33 to 47, wherein the weight percentage ratio of the pH regulator to the compound of formula (I) is about 1:2.

[0556] 49. A pharmaceutical composition according to any one of Examples 33 to 48, wherein the disintegrant is selected from crospovidone, sodium carboxymethyl starch, L-HPC, and croscarmellose sodium.

[0557] 50. A pharmaceutical composition according to any one of Examples 33 to 49, wherein the disintegrant is croscarmellose sodium.

[0558] 51. A pharmaceutical composition according to any one of Examples 33 to 50, wherein the weight percentage of the disintegrant is from about 2% by weight to 5% by weight of the pharmaceutical composition.

[0559] 52. The pharmaceutical composition according to any one of Examples 33 to 51, wherein the weight percentage of the disintegrant is about 3% by weight of the pharmaceutical composition.

[0560] 53. The pharmaceutical composition according to any one of Examples 33 to 52, wherein a part of the disintegrant is added before dry granulation and a part of the disintegrant is added after dry granulation.

[0561] 54. The pharmaceutical composition according to any one of Examples 33 to 53, wherein the disintegrant contains at least one precipitation inhibitor selected from HPMC, HPMC-AS, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG), and PVP / PVA copolymer, and the weight percentage range of the at least one precipitation inhibitor is 5% to 10% by weight of the disintegrant.

[0562] 55. The pharmaceutical composition according to any one of Examples 33 to 54, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate, and polyethylene glycol 6000.

[0563] 56. The pharmaceutical composition according to any one of Examples 33 to 55, wherein the lubricant is magnesium stearate.

[0564] 57. The pharmaceutical composition according to any one of Examples 33 to 56, wherein the weight percentage of the lubricant is about 0.5% to about 3.0% by weight of the pharmaceutical composition.

[0565] 58. The pharmaceutical composition according to any one of Examples 33 to 57, wherein the weight percentage of the lubricant is about 0.5% to about 1.0% by weight of the pharmaceutical composition.

[0566] 59. The pharmaceutical composition according to any one of Examples 34 to 58, wherein the film coating contains HPMC.

[0567] 60. The pharmaceutical composition according to any one of Examples 34 to 59, wherein the weight percentage of the film coating is between about 2.0% and about 5.0% by weight of the pharmaceutical composition.

[0568] 61. The pharmaceutical composition according to any one of Examples 34 to 60, wherein the weight percentage of the film coating is about 3.0% by weight of the pharmaceutical composition.

[0569] 62. The pharmaceutical composition according to any one of Examples 25 to 61, wherein the pharmaceutical composition comprises sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.

[0570] 63. A pharmaceutical composition according to any one of Examples 25 to 62, wherein the pharmaceutical composition comprises an enteric coating.

[0571] 64. A pharmaceutical composition according to any one of Examples 25 to 62, wherein the pharmaceutical composition comprises an enteric coating, and the enteric coating comprises at least one, two or three components selected from methyl acrylate - methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate ester), polyvinyl acetate phthalate, (PVAP), methyl methacrylate - methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate and zein.

[0572] 65. A compound, pharmaceutical composition, method or use according to any one of Examples 7, 15, 23 or 31, wherein the MEK inhibitor is selected from binimetinib, trametinib and cobimetinib.

[0573] 66. A compound, pharmaceutical composition, method or use according to any one of Examples 4 to 5, 12 to 13, 20 to 21 or 28 to 29, wherein recurrence occurs under prior treatment with a BRAF inhibitor.

[0574] 67. A compound, pharmaceutical composition, method or use according to any one of Examples 1 to 32 or 65 to 66, wherein the melanoma is associated with BRAF V600 mutation.

[0575] 68. A compound of formula (I)

[0576]

[0577] or a pharmaceutically acceptable salt thereof, which is used for locally advanced solid tumors and / or cancer metastases.

[0578] 69. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 68, wherein the metastatic cancer is characterized by having at least one metastasis site in the brain.

[0579] 70. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to Example 68 or 69, wherein the cancer metastasis is asymptomatic.

[0580] 71. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of Examples 68 to 70, wherein the locally advanced solid tumor is selected from melanoma, non - small cell lung cancer (NSCLC), thyroid cancer, colorectal cancer (CRC), especially non - small cell lung cancer (NSCLC).

[0581] 72. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 68 to 71, wherein the metastatic or locally advanced solid tumor has been previously treated with a BRAF inhibitor.

[0582] 73. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in Example 72, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

[0583] 74. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 68 to 71, wherein the solid tumor has not been previously treated with a BRAF inhibitor.

[0584] 75. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 68 to 74, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0585] 76. The compound of formula (I) or a pharmaceutically acceptable salt thereof as used in any one of Examples 68 to 75, wherein the compound of formula (I) is combined with cobimetinib.

[0586] 77. A pharmaceutical composition having an approximate weight-to-weight ratio (relative to the mass of the entire composition) as in any one of Examples A, B, or C, wherein the weight-to-weight ratio may deviate from the example by no more than 20%, preferably no more than 10%.

[0587] 78. A pharmaceutical composition as in any one of Examples A, B, or C.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used for treating melanoma with brain metastases.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof used as claimed in claim 1, wherein the melanoma has not been previously treated with a BRAF inhibitor.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof used as claimed in claim 1 or 2, wherein the compound of formula (I) is combined with a MEK inhibitor.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof used as claimed in any one of claims 1 to 3, wherein the compound of formula (I) is combined with cobimetinib.

5. A pharmaceutical composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof; and at least one therapeutically inert carrier, wherein the pharmaceutical composition is used for treating melanoma with brain metastases.

6. A method for treating melanoma with brain metastases, the method comprising administering an effective amount of the compound as claimed in claim 1 or the pharmaceutical composition as claimed in claim 5 to a patient in need thereof.

7. The pharmaceutical composition used as claimed in claim 5 or 6, wherein the melanoma has not been previously treated with a BRAF inhibitor.

8. A pharmaceutical composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises one or more fillers, glidants, disintegrants, pH regulators, lubricants and wetting agents.

9. The pharmaceutical composition as claimed in claim 8, wherein the pharmaceutical composition comprises sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.

10. The pharmaceutical composition as claimed in claim 8 or 9, wherein the pharmaceutical composition comprises a film coating.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for treating BRAF-mutated metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered at about 3000 mg / day to about 4000 mg / day, particularly about 3200 mg / day, during each day of a 28-day cycle, and cobimetinib is administered on days 1 to 21 of the 28-day cycle.

12. A compound of formula (I) its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for locally advanced solid tumors and / or cancer metastases, wherein administration is three times a day (TID).

13. A compound of formula (I) its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for locally advanced solid tumors and / or cancer metastases, wherein 1200 mg of the compound of formula (I) is administered three times a day (TID).

14. A compound of formula (I) Its pharmaceutically acceptable salts, or pharmaceutical compositions comprising the compound of formula (I) or its pharmaceutically acceptable salts and at least one therapeutically inert carrier, wherein the compound of formula (I) or its pharmaceutically acceptable salts or the pharmaceutical composition is used for locally advanced solid tumors and / or cancer metastases, wherein 1200 mg of the compound of formula (I) is administered three times a day (TID), with a 6-hour interval between the first daily dose and the second daily dose and between the second daily dose and the third daily dose, respectively.

15. A compound of formula (I), or its pharmaceutically acceptable salts, or pharmaceutical compositions comprising the compound of formula (I) or its pharmaceutically acceptable salts and at least one therapeutically inert carrier, wherein the compound of formula (I) or its pharmaceutically acceptable salts or the pharmaceutical composition is used for treating BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally with food, particularly after a high-fat meal.

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