Quinazolinone compounds as BRAF inhibitors for the treatment of advanced solid tumors or metastases

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 novel use in the treatment of locally advanced solid tumors, particularly melanoma with brain metastases. 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.

Description

[Technical Field]

[0001] The present invention provides a compound of formula (I) for use in the treatment of melanoma with brain metastases The present invention provides a BRAF inhibitor of formula (TIFF2025537786000001.tif43170), or a pharmaceutically acceptable salt thereof.

[0002] The present invention further relates to novel methods and uses of the compounds of formula (I) as defined above, as well as to pharmaceutical formulations containing the compounds of formula (I).

[0003] 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. In this specification, the compound of formula (I) is also referred to as compound Ia. [Brief explanation of the drawings]

[0004] [Figure 1] Overview of Phase Ia / b study plan. [Figure 2] 1 is a process flow chart for manufacturing film-coated tablets containing compound Ia. [Figure 3] Preliminary PK data regarding the effect of food on the PK of compound Ia. [Figure 4] Simulation based on the PopPK model to estimate the Ctrough coverage of compound Ia. [Background technology]

[0005] background 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 dysregulated downstream signaling through MAPK / extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK), resulting in excessive cell proliferation and survival. Three approved BRAF inhibitors (BRAFi) have demonstrated efficacy in indications such as BRAF V600E / K-positive melanoma. However, the poor survival rates of metastatic melanoma patients, including those whose tumors harbor the BRAF oncogene, highlight the need for improved drugs that target these mutations.

[0006] One of the most common and serious complications of cutaneous melanoma is the development of metastatic sites in the central nervous system (CNS). Recently developed BRAFi treatments significantly increase median progression-free survival (PFS) in patients with metastatic melanoma; however, disease control is significantly shorter in patients with melanoma brain metastases, including those with BRAF-mutant melanoma with brain metastases, compared with patients with extracranial disease alone. Disease progression most frequently occurs in the CNS in patients with brain metastases treated with BRAFi. Furthermore, patients with BRAF-mutant melanoma who have failed both checkpoint inhibitor (CPI) therapy and BRAF-targeted therapy (i.e., third-line patients) represent a patient population with few treatment options and a high unmet medical need.

[0007] Compound Ia, previously disclosed in International Publication No. WO 2021116055 A1, is a potent RAF inhibitor targeting mutant BRAF V600E / K, designed to avoid paradoxical MAPK induction in non-BRAF V600E / K-mutated cells and present with high brain penetrance to achieve effective drug exposure in the CNS. The present invention relates to a novel use of compound Ia for the treatment of locally advanced solid tumors and / or metastatic cancers, particularly cutaneous melanoma with brain metastases, as well as suitable pharmaceutical compositions containing compound Ia. Our preliminary data from this Phase Ia / Ib clinical trial suggest that compound Ia has a superior safety profile, with a surprisingly much lower rate of drug-related Grade 3 adverse events (<25%) compared to currently approved BRAF inhibitors. Given its superior safety profile, this compound has the potential to be administered at doses providing a much wider inhibitory concentration range, thus potentially providing significant benefits to patients in terms of efficacy and / or safety.

[0008] Compound Ia exhibits low pH and pH-dependent solubility, behaving like a weak acid across the physiological pH range, being poorly soluble at low pH and exhibiting increased solubility at neutral and alkaline pH. Accordingly, one particular embodiment of the present invention relates to a film-coated tablet comprising compound Ia, wherein the tablet composition further comprises a pH modifier, thereby improving the dissolution characteristics of compound Ia. A particular embodiment of the present invention relates to an efficient and safe dosing regimen of compound Ia, alone or in combination with cobimetinib, for treating solid tumors, particularly melanoma with brain metastases. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description The term "inhibitor" refers to a compound that competes with, reduces, or prevents the binding of a specific ligand to a specific receptor, or reduces or prevents the function of a specific protein. In particular, the term "inhibitor" used herein refers to a compound that targets, reduces, or inhibits the activity of a target selected from BRAF and MEK, and certain inhibitors have 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, less than 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%.

[0010] The term "IC50" refers to the concentration of a particular compound required to inhibit 50% of a particular measured activity. Similarly, IC80, IC90, and IC95 refer to the concentrations at which 90%, 90%, and 95% of the specific measured activity are inhibited.

[0011] The term "BRAF mutant" refers to BRAF mutations that are involved in the pathogenesis of cancer, such as the BRAF V600E and V600K mutations.

[0012] The term "pharmaceutically acceptable salt" refers to a salt of a compound of Formula (I) or a MEK inhibitor that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. These salts can be formed, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, particularly 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, and the like. These salts can also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. 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 compound of formula (I) are hydrochloride, methanesulfonate, 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, particularly hemifumarate and hemisuccinate.

[0013] A particular embodiment of the present invention is a compound of formula (I) TIFF2025537786000002.tif43170 or a pharmaceutically acceptable salt thereof, wherein the patient suffering from said cancer has previously been treated with a different BRAF inhibitor.

[0014] A particular embodiment of the present invention is a compound of formula (I) TIFF2025537786000003.tif43170 or a pharmaceutically acceptable salt thereof, wherein the patient suffering from said cancer has not previously been treated with a BRAF inhibitor, particularly a BRAF inhibitor selected from dabrafenib, vemurafenib and encorafenib.

[0015] A particular embodiment of the present invention is a compound of formula (I) for use in the treatment of cancer, particularly melanoma with brain metastases. With respect to the compound of TIFF2025537786000004.tif43170 or a pharmaceutically acceptable salt thereof, the compound of formula (I) is combined with a MEK inhibitor.

[0016] Non-limiting examples of MEK inhibitors for use 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).

[0017] In one embodiment of the present invention, the MEK inhibitor is cobimetinib. Cobimetinib is an orally available, potent, and highly selective inhibitor of MEK1 and MEK2, which are central components of the RAS / RAF pathway. Cobimetinib has the chemical name [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone and the following structure: TIFF2025537786000005.tif42170.

[0018] Cobimetinib can be prepared according to the methods described in WO 2007 / 044515. Cobimetinib is commercially available and has the following CAS Registry Number: 934660-93-2.

[0019] In one embodiment of the present invention, the MEK inhibitor is binimetinib. Binimetinib is an orally available, potent, and highly selective inhibitor of MEK1 and MEK2, which are central components of the RAS / RAF pathway. Binimetinib has the chemical name 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide and the following structure: TIFF2025537786000006.tif41170.

[0020] Binimetinib can be prepared according to the methods described in WO 2003 / 077914. Binimetinib is commercially available and has the following CAS Registry Number: 606143-89-9.

[0021] 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 (Yervoy®) or tremelimumab (GP-675,206). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (Keytruda®), nivolumab (Opdivo®), and RN888. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®). TM In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®).

[0022] Abbreviation: BID = bis in die (Latin), twice daily; PCR = polymerase chain reaction; PD = pharmacodynamics; PK = pharmacokinetics; PO = oral; QD = quaque die (Latin), once daily; TID = ter in die (Latin), three times daily.

[0023] Test drug: Compound Ia can be synthesized according to the procedures described in WO2021116055A1 or according to methods known to those skilled in the art.

[0024] The following examples and figures are provided to illustrate the invention and do not have a limiting character.

[0025] Biological Example—A Phase IA / B Open-Label Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Clinical Activity of Compound Ia in Solid Tumors Harboring BRAF-V600 Mutations. Part 1 - Pilot PK: Dose escalation began with a pilot PK cohort in two participants to evaluate the PK of Compound Ia at a single dose of 25 mg, with the goal of refining the starting dose for dose escalation by using at least a two-fold safety margin relative to actual exposure in humans and a redefined human equivalent dose for the safety reference dose of 200 mg / kg / day in rats. Once PK sampling was complete (up to 72 hours after the first dose), participants continued daily Compound Ia treatment. Participants in the pilot PK cohort were enrolled and treated in a staggered fashion (at least 3 days between the first and second participant). Preliminary analysis of available PK data from the first two participants indicated lower-than-expected drug exposure at 25 mg and a preliminary unbound C value relative to the safety reference dose of 200 mg / kg / day in rats (a toxic dose in 10% of animals). max or AUC 0-∞This demonstrated a 32-fold or 174-fold margin of safety based on the initial dose-escalation cohort of Compound Ia at 25 mg, based on the preliminary unbound C values ​​from the first two patients at 25 mg. max or AUC 0-∞ The dose of the initial dose-escalation cohort was 200 mg QD of compound Ia. After the completion of the pilot PK cohort DLT period at the 25 mg QD dose, two participants were included in the dose-escalation portion of the study using compound Ia at the 200 mg QD dose. They were considered DLT-evaluable for this dose, and the 14-day DLT period began when they increased the dose of compound Ia from 25 mg to 200 mg. No DLTs occurred during the 14 days following the increase in compound Ia from 25 mg to 200 mg.

[0026] Part 1 (Dose Escalation): 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, and colorectal cancer (CRC) with or without brain metastases) to determine the maximum tolerated dose (MTD) and / or recommended phase 2 dose (RP2D). The starting dose for dose escalation was refined by using the actual exposure at 25 mg from the first two patients in the pilot PK cohort. The dose escalation part will begin with a 200 mg dose of Compound Ia administered once daily (QD). The dosing regimen will then be changed to twice daily (BID) or three times daily (TID) administration depending on emerging PK data.

[0027] Part 1a - Compound Ia Monotherapy Dose Escalation: Dose escalation will be performed according to the mCRM-EWOC plan. In each cohort, the number of patients with leptomeningeal invasion will be limited to 33%. To avoid exposing participants to excessive toxicity, the maximum tolerated dose escalation recommended by the mCRM EWOC (modified continuous reassessment method escalation with overdose control) plan will be 100% (i.e., a 2-fold increase). The maximum dose investigated is 4000 mg / day of Compound Ia. If any dose level within the QD or BID regimen demonstrates unacceptable toxicity or unfavorable PK characteristics, additional cohorts of participants may be evaluated with the TID regimen. Adapt mCRM-EWOC to the new dosing regimen.

[0028] Part 1b - Compound Ia in Combination with Cobimetinib: Dose Escalation Part 1b will be conducted as a parallel group in which 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 rest period). The starting dose of compound Ia in combination with cobimetinib will be at least one dose level below the most recent dose deemed cleared and tolerable based on a review of all Part 1a data. Escalation of compound Ia in combination with cobimetinib will be guided by the mCRM EWOC model until the MTD and / or RP2D are reached. The maximum dose investigated will be 4000 mg / day of compound Ia. If any dose level within the QD or BID regimen of compound Ia and cobimetinib demonstrates unacceptable toxicity or unfavorable PK characteristics, additional cohorts of participants may be evaluated with the TID regimen. mCRM-EWOC will be adapted to the new dosing regimen. Based on emerging PK and safety data, other cobimetinib doses may be investigated as well.As for the monotherapy cohort, the number of patients with leptomeningeal invasion of their tumors is limited to 33% at the cohort level, even for the combination cohort with cobimetinib.

[0029] Part 1 - Food Cohort: The food effect (FE) on the PK of Compound Ia will be evaluated in Part 1a (Compound Ia monotherapy) or Part 1b (Compound Ia in combination with cobimetinib) at the MTD and / or RP2D, or at dose levels close to the RP2D and / or MTD of Compound Ia, with or without cobimetinib. To explore the effect of food intake, participants will receive Compound Ia after a high-fat meal (Group 1) or after a 10-hour fast (Group 2) using a parallel design. A minimum of six evaluable participants will be enrolled for this pilot FE evaluation. Once PK sampling is complete (up to 72 hours after the first dose) to investigate FE, participants will continue either BID or TID Compound Ia treatment daily according to the selected dosing schedule.

[0030] Part 2 (Dose Expansion): Following determination of the MTD and / or RP2D and potential FE, study treatment will be initiated to evaluate safety and preliminary clinical activity in the following four cohorts: [table] TIFF2025537786000007.tif84170

[0031] The study drugs are Compound Ia and cobimetinib. All participants will receive Compound Ia (25 or 200 mg / tablet) orally administered QD or BID every day of each 28-day cycle. Participants will receive 60 mg (3 x 20 mg tablets) of cobimetinib orally administered QD on days 1 to 21 of each 28-day cycle, i.e., for 21 consecutive days, followed by a 7-day break.

[0032] On days when participants are required to attend the clinic, a single dose of Compound Ia and cobimetinib (if applicable) will be administered to participants at the clinic. On all other study days other than the scheduled clinic visits listed above, participants will self-administer Compound Ia and cobimetinib (if applicable) at home. To self-administer Compound Ia and cobimetinib doses at home, participants should be provided with a sufficient number of tablets to last until the next clinic visit or for one cycle, at the investigator's discretion. Participants will self-administer oral study treatment as follows: Participants must take Compound Ia and cobimetinib (if applicable) at approximately the same time each day unless otherwise instructed. Participants will be instructed on the number and strength of tablets to take according to their assigned study cohort, dose level, and schedule. Participants will be asked to record the time and date they take each dose in a medication diary. Participants will return all unused tablets at each study visit to assess compliance.

[0033] Compound Ia Administration: All participants will receive Compound Ia (25 or 200 mg / tablet) QD orally (PO) with a glass of water every 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), participants should resume dosing at the next scheduled dose. Missed or spilt doses will not be replaced. On all clinic visit days requiring pre-dose blood draws for Compound Ia PK sampling and / or laboratory evaluations, participants will be instructed to receive their morning oral dose of study medication at the clinic after completion of pre-treatment evaluations.

[0034] Cobimetinib Administration: Participants will receive 60 mg (3 x 20 mg tablets) orally QD on days 1 through 21 of each 28-day cycle, i.e., for 21 consecutive days, followed by a 7-day rest period. If tolerability concerns exist, a lower dose of cobimetinib or an alternative dosing schedule may be investigated. Cobimetinib should be taken daily at approximately the same time as the morning dose of Compound Ia, within 4 hours of the scheduled time. Cobimetinib should be swallowed completely 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), participants should resume dosing with the next scheduled dose. Missed or spilt doses will not be replaced. On all clinic visit days requiring pre-dose blood draws for cobimetinib PK (pharmacokinetic) sampling and / or laboratory evaluations, participants will be instructed to receive their morning oral dose of study medication at the clinic following completion of pre-treatment evaluations.

[0035] Food and Dietary Restrictions: Generally, no dietary restrictions are anticipated for participants receiving Compound Ia. A preliminary assessment of the food effect (FE) on the PK of Compound Ia will be performed in Part 1 to inform potential dietary requirements for dose escalation (Part 2) if FE is observed. For participants receiving cobimetinib, the use of grapefruit juice, a potent CYP3A4 enzyme inhibitor, will be prohibited during the study and for 30 days after the last dose of study treatment. For participants in the food cohort in Part 1, the effect of food on the systemic exposure of Compound Ia will be investigated at dose levels close to the MTD and / or RP2D or relevant dose levels in a minimum of six participants. Participants will receive Compound Ia under either fed or fasted conditions on C1D1. After at least a 10-hour overnight fast, Compound Ia will be administered as a single dose either after a high-fat meal (i.e., 800-1000 calories, 50% fat; meal should be consumed within 30 minutes) or while fasting on Day 1 of Cycle 1. In both cases, Compound Ia should be taken with 240 mL of water. Additional water is allowed ad libitum, except for the period 1 hour before and 1 hour after drug administration. In both cases, no food should be consumed for at least 4 hours after the dose. Food intake during the high-fat meal plus calorie and fat content should be recorded.

[0036] Alcohol: Participants must abstain from alcohol for 24 hours prior to starting dosing until after the final PK and / or PD sample is collected on each study day. Participants will be questioned periodically about alcohol intake, and appropriate comments regarding this intake will be recorded.

[0037] Participant group Two participant populations will be enrolled in this study: 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.

[0038] Key inclusion criteria: Male and female participants aged 18 years or older with a life expectancy of more than 3 months signed written informed consent. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. ·Documented BRAF-V600 mutation status of tumor tissue, preferentially using an FDA-approved or CE-IVD genetic test. ·Verifying availability of archival tumor tissue for submission to sponsor / central laboratory. · Adequate bone marrow and end-organ function and coagulation parameters. · Willingness to adhere to contraceptive measures for the duration of the study. ·Applicable to Part 1 only: Histologically confirmed advanced / metastatic solid tumors with measurable systemic disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (extracranial disease) or modified Response Evaluation in Neuro-Oncology for Brain Metastases (mRECIST-BM; intracranial disease). Applicable to Part 2 only: Histologically confirmed cutaneous melanoma with measurable, radiologically confirmed, asymptomatic brain metastases per mRECIST-BM. Stable or improvement in CNS disease symptoms for at least 14 days prior to initiation of study treatment.

[0039] Key exclusion criteria: For Part 2 only: History of or current leptomeningeal metastasis. Metastases requiring immediate local intervention. Uncontrolled tumor-related pain. · Ascites, pleural effusion, or pericardial effusion requiring medical intervention (including diuretic use) within 6 months prior to study enrollment. · Active malignancy (other than investigational) or previous malignancy within the past 2 years prior to enrollment, with some exceptions. Active uveitis or any history of serous retinopathy or retinal vein occlusion. · Current or past history of CNS disease unrelated to the malignancy under investigation, e.g., stroke, epilepsy, CNS vasculitis or neurodegenerative disease. Active or quiescent autoimmune disease with exacerbation / flare within 1 year prior to enrollment. Significant cardiovascular disease within 6 months prior to study treatment administration. All systemic anti-cancer therapy or small molecule therapeutic(s), including but not limited to chemotherapy, investigational drugs, hormonal therapy and radiation therapy, and antibody-based agents, will be administered within two weeks or at least five half-lives, whichever is shorter, prior to the start of study treatment. Treatment with stereotactic radiosurgery or craniotomy within 1 week prior to study treatment, or treatment with whole-brain radiation therapy within 3 months prior to study treatment. Participants who received local therapy should recover completely without neurological sequelae. Radiation therapy for visceral metastases within 1 week prior to study treatment. Palliative radiation therapy is permitted. · Major non-diagnostic surgical procedure within 2 weeks prior to the start of study treatment or anticipation of the need for major surgical treatment during the course of the study. Spinal cord compression has not been definitively treated with surgery and / or radiation, or previously diagnosed and treated spinal cord compression has no evidence that the disease has been clinically stable for more than 2 weeks prior to screening. Contraindications to cobimetinib or known hypersensitivity to any formulation component of cobimetinib (if applicable). Participants with known hypersensitivity to BRAFi and / or MEK inhibitors (MEKi). Strong CYP3A inducers (including St. John's wort and hyperforin) are prohibited during study treatment and for 2 weeks after the last dose of cobimetinib or compound Ia (whichever occurs later). Concomitant treatment with anticonvulsants other than gabapentin, vigabatrin, and levetiracetam (e.g., strong CYP3A inducers such as carbamazepine, phenytoin, and phenobarbital) is prohibited during study treatment and for 2 weeks after the last dose of cobimetinib or compound Ia (whichever occurs later). When used in combination with cobimetinib, moderate and strong CYP3A inducers and inhibitors are prohibited during study treatment and for 2 weeks after the last dose of cobimetinib or compound Ia (whichever occurs later). · Refractory nausea and vomiting, malabsorption, extracorporeal biliary shunt, or significant small bowel resection preventing adequate absorption of study treatment. · Uncontrolled diabetes or symptomatic hyperglycemia. Any grade ≥ 3 bleeding or bleeding event within 28 days of starting study treatment. · History of human immunodeficiency virus (HIV) positivity. · Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test or a positive quantitative HBV DNA test at screening. Hepatitis C virus (HCV) infection (chronic or acute) is defined as having a positive HCV antibody test and a positive HCV RNA test at screening. · Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis and atypical mycobacterial disease), parasitic or other infection (excluding fungal infections of the nail bed), or any major infectious episode.

[0040] Dosage, administration, and compliance with study treatment Please refer to the pharmacy manual for detailed instructions regarding formulation, storage and administration.

[0041] Participants will be required to return to the clinic every two weeks for the first three cycles, and monthly thereafter.

[0042] Days participants need to come to the clinic: For QD Compound Ia dosing: A single dose of Compound Ia and a single dose of cobimetinib (if applicable) will be administered at the clinic site.

[0043] For BID Compound Ia dosing: The first dose of Compound Ia and a single dose of cobimetinib (if applicable) will be administered to participants at the clinic. The second dose of Compound Ia that day will be self-administered at home 10-12 hours after the first dose.

[0044] For TID Compound Ia dosing: The first dose of Compound Ia and a single dose of cobimetinib (if applicable) will be administered to participants at the clinic site in the morning.

[0045] The second and third doses of Compound Ia that day will be self-administered at home 8-10 hours after the first dose and 6-8 hours after the second dose, respectively. IMPORTANT: The second dose must occur after the 8-hour PK blood draw. If the 8-hour blood draw is no longer required (depending on new data and only after sponsor communication), the second drug intake may occur 6-8 hours after the first dose.

[0046] All other study days other than the scheduled clinic visits listed above: Participants will self-administer oral Compound Ia and cobimetinib (if applicable) at home. Participants will be dispensed a sufficient number of tablets to last until their next clinic visit.

[0047] Participants should take Compound Ia and cobimetinib (if applicable) at approximately the same time each day.

[0048] For QD Compound Ia dosing: AM, Compound Ia and cobimetinib (if applicable).

[0049] For BID Compound Ia dosing: Compound Ia and cobimetinib (if applicable) in the morning; Compound Ia should only be added in the evening. Compound Ia should be taken 10–12 hours apart.

[0050] For TID Compound Ia dosing: Compound Ia and cobimetinib (if applicable) in the morning. Add Compound Ia only in the afternoon and evening. Compound Ia should be taken 6-8 hours apart.

[0051] Participants will be instructed on the number and strength of tablets to take according to their assigned study cohort, dose level, and schedule. Participants will be asked to record the time and date each dose is taken in a medication diary, which they must bring to each study visit. Participants will be required to return all unused tablets at each study visit to assess compliance.

[0052] Administration of Compound Ia: All participants will receive Compound Ia (25 or 200 mg / tablet) orally (PO) with a glass of water QD, BID, or TID every day of each 28-day cycle. If a dose of Compound Ia is missed (i.e., not taken within 10 hours of the scheduled dosing time for QD; within 4 hours for BID; no window for TID), participants should resume dosing at the next scheduled dose. Missed or spit-out doses will not be replaced.

[0053] On all clinic visit days requiring pre-dose blood draw for Compound Ia PK sampling (see section 1.3) and / or laboratory evaluations, participants will be instructed to receive their morning oral dose of study medication at the clinic following completion of pre-treatment evaluations.

[0054] For BID and TID doses, all pre- and post-dose blood draws and assessments described in the protocol and SoA will refer to the morning dose (first dose of the day).

[0055] Cobimetinib Dosing: Participants will receive 60 mg (3 x 20 mg tablets) orally QD on days 1 through 21 of each 28-day cycle, i.e., for 21 consecutive days, followed by a 7-day rest period. If there are concerns about tolerability, lower doses or alternative dosing schedules of cobimetinib may be investigated.

[0056] Cobimetinib should be taken daily at approximately the same time as the morning dose of Compound Ia, within 4 hours of the scheduled time. Cobimetinib should be swallowed completely 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), participants should resume dosing with the next scheduled dose. Missed or spit-out doses will not be replaced.

[0057] On all clinic visit days requiring pre-dose blood draws for cobimetinib PK sampling and / or laboratory evaluations, participants will be instructed to receive their morning oral dose of study medication at the clinic following completion of pre-treatment evaluations.

[0058] Number of participants: The exact number of participants will depend on the occurrence of DLTs and the number of dose levels required to determine the MTD and / or RP2D. The study will enroll up to 120 participants in the dose escalation phase (60 participants each for Part 1a and Part 1b) and up to approximately 40 participants in up to four expansions in Part 2. For FE, additional cohorts of 6-12 participants will be enrolled. The total number of participants will be up to 292.

[0059] Concomitant medications: Any medications or vaccines used by participants within 30 days after screening and before the safety follow-up visit must be recorded, along with the reason for use, administration date, and dosage information. As a general rule, no new concomitant medications are permitted, except for those used to treat AEs, unless the rationale for the exception is discussed and clearly documented between the investigator and the sponsor. Systemic corticosteroids, i.e., dexamethasone or equivalent at doses up to 8 mg / day, and antiepileptic drugs (i.e., gabapentin, vigabatrin, and levetiracetam), may be administered at the treating physician's discretion if deemed necessary for the treatment of brain metastases.

[0060] Dosage Adequacy: Based on currently available nonclinical drug safety information and predicted human pharmacokinetics (PK), the starting dose of compound Ia was 25 mg QD, which was expected to be safe and pharmacologically active in participants. Due to uncertainty in predicted human PK (estimated half-life of 7-70 hours), the human dose range resulting in unbound exposure equivalent to the safety reference dose of 200 mg / kg / day in rats was predicted to be 46-610 mg, respectively. The 25 mg human starting dose was selected by applying a 2-fold safety margin. In the pilot PK cohort (monotherapy) before dose escalation in Part 1a, the PK of compound Ia was investigated after a single oral dose of 25 mg in two participants to address PK uncertainty. Preliminary analysis of available PK data from the first two participants at 25 mg indicated that drug exposure in humans was lower than expected due to the short half-life estimated to be 2-4 hours. Based on the preliminary PK characterization of Compound Ia at 25 mg from the first two participants in the pilot PK cohort, a new dose of 200 mg QD was defined for the initial dose escalation cohort, using the actual exposure of Compound Ia at 25 mg in humans and the unbound C relative to the no-observed-adverse-effect level (NOAEL) safety reference dose of 200 mg / kg / day in rats. max or AUC 0-∞ The results were determined by applying a 4-fold or 22-fold safety margin based on the

[0061] Dietary Effect Assessment: Compound Ia is a Class 2 biologics drug, and therefore, the PK of Compound Ia may be affected by food. The FE pilot evaluation during dose escalation at the MTD and / or RP2D or relevant dose levels aims to investigate whether food significantly affects the PK of Compound Ia and to inform Part 2 expansion cohorts and future clinical studies regarding food requirements for oral administration of Compound Ia.

[0062] Efficacy assessment: In general, tumor assessments must be performed independently of changes in the study treatment administration schedule (i.e., if treatment is withheld). If tumor assessments must be performed early or late, subsequent assessments should be performed according to the original schedule based on the date of the first study treatment administration. Tumor assessments continue according to the schedule for participants who discontinue treatment for reasons other than disease progression (unless subsequent anticancer therapy is initiated). Objective response is confirmed by two consecutive assessments at least 4 weeks apart. Previously irradiated measurable lesions are not considered target lesions unless a 20% or greater increase in size is observed after completion of radiation therapy.

[0063] Extracranial Tumor and Response Assessment: Tumor assessments will be performed at predefined time points. All known sites of disease should be recorded at screening and reassessed at each subsequent tumor assessment. Extracranial tumor assessments during treatment at C2D1 (Cycle 2, Day 1) and C3D1 (Cycle 3, Day 1) must be performed in a time window of ±3 days, and thereafter in a time window of ±7 days. Response assessments will be performed for participants according to RECIST v1.1. The extent of neoplastic disease will be determined by a reproducible radiographic technique, preferably CT or MRI scan. Ultrasound and X-rays are not acceptable for target lesion monitoring. CT (or MRI) scans should include chest, abdominal, and pelvic scans, with additional testing performed as clinically indicated (e.g., cervical bone scan and CT scan). All known and suspected areas of neoplastic disease will be evaluated as deemed appropriate by the investigator. The same assessment method and techniques must be used consistently throughout the study for each participant. The use of spiral CT or MRI is required to screen for lesions smaller than 20 mm, must be documented in the medical record, and must be used consistently throughout the study. The use of oral and IV contrast should be maintained consistently as long as clinically feasible. MRI of the abdomen and pelvis with a non-contrast CT scan of the chest may be used for participants for whom contrast-enhanced CT scanning is contraindicated (i.e., participants with contrast allergy or impaired renal clearance). If CT scans for tumor assessment are performed using a PET / CT scanner, the CT scans must be of the same diagnostic quality as full contrast-enhanced diagnostic CT scans. Assessments should be performed by the same assessor, if possible, to ensure internal consistency across visits. At the investigator's discretion, other methods of assessing measurable disease according to RECIST v1.1 may be used. For clinically measurable superficial (e.g., skin) lesions, repeat photographs should be used to document tumor response. These photographs must include a ruler for documentation purposes. Participants with known or suspected bone metastases should undergo a radionuclide bone scan.At the investigator's discretion, CT scans may be repeated whenever progressive disease is suspected.

[0064] Tumor and response assessment for intracranial lesions: Brain imaging will be performed at predefined time points. All known sites of disease should be recorded at screening and reassessed at each subsequent tumor assessment. Intracranial tumor assessments during treatment with C2D1 and C3D1 must be performed in a time window of ±3 days, with a time window of ±7 days thereafter. Response assessments of brain metastases will be performed according to the mRECIST-BM criteria, which allows for a modified measurability definition for intracranial lesions (≥0.5 cm by MRI) and up to five intracranial target lesions (in addition to any extracranial target lesions). Brain imaging must be performed using MRI with the following image acquisition requirements:

[0065] Minimum required array: · Precontrast T1, T2 / FLAIR. ·Post-contrast T1 where two orthogonal planes (or volume acquisition) are recommended. The recommended slice thickness is 5mm or less with no gaps.

[0066] If extracranial progressive disease is detected, a brain MRI scan must also be completed within 1 week of the extracranial PD determination. In addition to tumor and response assessments for both extracranial and intracranial disease, further analysis of CT and MRI scans can be performed to further elucidate drug effects.

[0067] [18F]FDG-PET imaging: [18F]-FDG-PET is performed at predetermined time points to determine drug effects on tumors. Imaging acquisition guidelines should be followed as described in the imaging manual. Participants must fast for 4–6 hours before the [18F]-FDG-PET examination. Participants should rest in the waiting room after tracer administration and prepare for scanning, which begins 60 ± 10 minutes after administration. Participants will be examined in a sufficient number of bed positions to ensure coverage from the lower brain (inclusive) to the mid-thigh. It is also essential that participants are examined under the same conditions for screening and follow-up scans, particularly with regard to acquisition and scan duration. It is recommended that the same model of scanner be used, or at least that the same spatial resolution be ensured. [18F]-FDG-PET / CT is performed at screening. For investigational FDG-PET, this assessment must be performed before administration of compound Ia at the designated time points. On-treatment assessments at C1D15 and C2D1 must be performed within the -3-day time window. Participants without evidence of FDG uptake on the screening PET scan are not required to undergo follow-up studies. For participants whose follow-up FDG PET evaluation suggests progressive disease, a confirmatory CT / MRI evaluation is strongly recommended. Response assessment using FDG-PET is performed by an independent reviewer, both locally and centrally. Transient unilateral axillary lymphadenopathy has been observed after mRNA-based SARS-CoV-2 vaccination, which may confound interpretation in oncology patients using CT, MRI, or PET / CT. While COVID-19 vaccination should not be delayed in study participants, consideration should be given to administering the vaccine in a location that avoids potentially confounding imaging findings, for example, in the arm or thigh contralateral to the localized cancer. Furthermore, details 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.

[0068] Safety rating: Safety assessments consist of monitoring and recording of AEs, including serious AEs (SAEs) and non-SAEs of special interest (NSAESIs); measurement of protocol-specified safety laboratory assessments; measurement of protocol-specified vital signs, ECGs; and other protocol-specified tests considered important to the safety assessment of the study.

[0069] A complete physical examination will be performed at screening and at the 28-day safety follow-up visit and will include, at a minimum, evaluation of the head, eyes, ears, nose, throat, neck, and lymph nodes, as well as cardiovascular, respiratory, gastrointestinal, skin, and musculoskeletal systems. A complete physical examination will include weight and height. A complete neurological examination at screening, including assessment of mental status, cranial nerves, strength, sensation, and coordination and gait, must be performed and recorded in the participant chart. At the investigator's discretion, examination of other body systems may be performed if suggestive symptoms are present. 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. Abnormalities identified at screening should be recorded. Targeted physical examinations should be performed at other visits. The targeted physical examination should be limited to primarily relevant systems (i.e., cardiovascular, respiratory, neurological, and any systems potentially relevant to the tumor evaluation [e.g., those systems related to symptoms] or potential drug-related toxicity). The targeted neurological examination should include an assessment of attention and orientation to person, place, and time. This examination should also include symptom-driven focused testing of other cranial nerves, strength, sensation, coordination, and psychiatry, as clinically warranted. Of note, the targeted physical examination may encompass a targeted neurological examination 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 from baseline abnormalities should be recorded in the participant's notes. New or worsening clinically significant abnormalities should be recorded as AEs. The investigator should pay particular attention to clinical signs associated with previous serious illness.

[0070] Vital signs include measurements of systolic and diastolic blood pressure, respiratory rate, pulse rate, and temperature while the participant is in a seated or semi-supine position. Every effort should be made to ensure that vital signs are obtained from participants in a consistent manner / position. Blood pressure and pulse measurements must be taken for at least 5 minutes in a seated or supine position in a quiet environment without distractions (e.g., television, cell phone; consistency should be maintained for each individual participant). Blood pressure and pulse measurements can be assessed using fully automated equipment. Manual techniques are used only if automated equipment is unavailable. If possible, use the same arm for all blood pressure measurements. When measuring blood pressure, the participant's arm should not be constrained by clothing or other materials, the participant should be comfortably seated with their legs apart and their back and arms supported, so that the center of the cuff on the upper arm is at the level of the right atrium (mid-sternum), and an "ideal" cuff should be 80% the length of the bladder and at least 40% the width of the arm circumference (a length-to-width ratio of 2:1).

[0071] electro-cardiogram: Triplicate 12-Lead ECG: Triplicate 12-lead ECGs are obtained using ECG equipment that automatically calculates heart rate and measures pulse rate, QRS, QT, and QT corrected for cardiac (QTc) intervals. It is important that participants remain in a stationary position for at least 10 minutes before each ECG assessment to minimize variability. Positioning must be consistently maintained for each ECG assessment to prevent changes in heart rate. Distracting environments (e.g., television, radio, conversation) should be avoided during the rest period before the ECG and during ECG recording. ECGs should be performed 2 hours after administration of study treatment and after PK / PD sample collection at the 2-hour time point. In the case of an absolute QTc of >500 ms and an increase from baseline QTc of >60 ms, another triplicate ECG should be recorded within the next 30 minutes. In the case of an abnormal ECG, repeating may be appropriate to rule out improper lead placement, which may contribute to the ECG abnormality. In the event of QTc shortening (a decrease of ≤340 ms or >15% from baseline), another triplicate ECG should be recorded within the next 30 minutes. Record ECG characteristics, including heart rate, QRS duration, pulse rate, and QT interval. QTcF (Fridericia's correction) and RR interval are automatically calculated and recorded. Record changes in T and U wave morphology and overall ECG interpretation. T wave information is captured as normal or abnormal, and U wave information is captured in two categories: absent / normal or abnormal. If clinically significant changes in ECHO or MUGA findings are identified, additional PK samples should also be obtained.

[0072] Continuous digital Holter recording (Holter) electrocardiogram monitoring to extract 12-lead ECG tracings is performed at predetermined time points. The optimal intra-treatment time point of the Holter ECG may be reevaluated using newly emerging data, shifted if deemed necessary for clinical evaluation, or additional evaluations may be added. Participants wear a digital Holter monitoring device for continuous recording of 12-lead ECG tracings over 24 hours. Holter recordings are sent to a central ECG analysis laboratory for potential retrospective expert review with ECG extraction and ECG interval estimation. At predefined time points during the 24-hour recording period, repeat ECG recordings are extracted from the continuous recording during a 5-minute time window coinciding with the scheduled ECG time point where 1-minute heart rate stability has been verified. At these specific time points, participants should remain supine and rest for at least 10 minutes before the designated ECG extraction time point and for at least another 5 minutes after the designated ECG extraction time point. Repeated estimates of the uncorrected QT interval and QTcF are derived from the ECG tracing at each scheduled time point, along with information on other intervals (PR, RR, and QRS) and T- and U-wave morphology, as appropriate. While participants undergo Holter ECG monitoring, it must be emphasized that there are no distracting environments (e.g., television, radio, conversation, or phone calls) during the rest periods before and after ECG and at the designated ECG time points. In particular, activities known to cause heart rate changes should be avoided. If PK samples need to be collected at C1D8 pre-dose and 2 hours post-dose, the following sequence of events should be followed: Pre-dose (up to 2 hours before scheduled drug administration) Collect pre-dose PK samples and record sampling times Wearing a Holter device Allow the patient to rest for 10 minutes Start the halter Allow the patient to rest for an additional 5-10 minutes The central ECG laboratory will retrospectively extract ECG tracings from the Holter in a 5-minute time window after the Holter is initiated. For PK samples taken 2 hours after administration, Allow the patient to rest for 10 minutes before the 2-hour time point and 5 minutes after this time point. ECG Then, take the actual PK blood sample. The central ECG laboratory retrospectively extracts ECG tracings from the Holter during a 5-minute window around a scheduled time point (when the patient is at rest).

[0073] The timing of assessments may be modified or the number of assessments may be increased during the conduct of the study based on emerging data to allow optimal characterization of the effect profile.

[0074] Assessment of left ventricular function: Participants will undergo assessment of left ventricular ejection fraction (LVEF) by either echocardiogram or MUGA, and as clinically indicated for new or worsening symptoms. Participants who develop clinical signs or symptoms suggestive of heart failure should undergo LVEF reassessment and further cardiovascular consultation as needed. If clinically significant changes in ECHO or MUGA findings are identified, additional PK samples should also be obtained. Assessment of left ventricular function must be performed using the same method for each participant.

[0075] Ophthalmological examination: For compound Ia monotherapy, participants will be monitored for signs and symptoms of uveitis. Examinations include visual acuity testing, intraocular pressure measurement with tonometry, slit-lamp ophthalmoscopy, specular microscopy, and direct or indirect ophthalmoscopy. Ophthalmic examinations must be performed by medical professionals skilled in these evaluations; otherwise, participants must be referred to a licensed ophthalmologist. For compound Ia and cobimetinib combination therapy, participants will be monitored for signs and symptoms of ocular toxicity, including uveitis, serous retinopathy, and retinal vein occlusion. Ophthalmic examinations must be performed by medical professionals trained in these evaluations or with a referral to a licensed ophthalmologist. Examinations include visual acuity testing, intraocular pressure measurement with tonometry, slit-lamp ophthalmoscopy, direct or indirect ophthalmoscopy as needed, and spectral-domain optical coherence tomography (OCT). If spectral-domain OCT is unavailable, time-domain OCT may be performed instead. Fluorescein angiography may also be performed if necessary.

[0076] Dermatological examination: A skin evaluation will be performed by a qualified medical professional. Unscheduled dermatological examinations may be performed during treatment to investigate any new skin lesions, as clinically indicated. New participants with skin lesions should be referred to a dermatologist for further evaluation, diagnosis, and treatment.

[0077] Clinical Safety Laboratory Evaluation: Clinical laboratory tests must be performed in accordance with local laboratory processes. The investigator must review the laboratory reports, document this review, and note any clinically relevant changes that occurred during the study. Laboratory reports must be submitted with source documentation. A clinically significant abnormal laboratory finding is one that is not related to an underlying disease, unless the investigator determines that the finding is more severe than expected for the participant's condition. In the case of unexplained abnormal clinically significant laboratory values, the tests should be repeated immediately and followed up until they return to normal ranges and / or a satisfactory explanation for the abnormality is found. If test values ​​from laboratory evaluations performed in a local laboratory not specified in the protocol require a change in the participant's management or are deemed clinically significant by the investigator (e.g., SAE or AE or dose modification), these results must be recorded in the eCRF.

[0078] Laboratory test results are recorded on eCRFs or received as electronically generated laboratory reports submitted directly from local or central laboratories. Additional blood or urine samples may be collected at the investigator's discretion if test results are outside the reference range or if clinical symptoms warrant additional testing to monitor participant safety. If the clinical significance of abnormal laboratory test results at screening is considered uncertain, screening laboratory tests may be repeated before the first dose of study treatment to confirm eligibility. Based on serial analysis of data in this and other studies, any sample type not considered important to safety may be discontinued at any time if data from the collected samples do not generate useful information.

[0079] ECOG performance status: ECOG performance status will be assessed at screening, at the discontinuation visit, and at predefined safety follow-up visits. If possible, it is recommended that participant performance status be assessed by the same individual throughout the study. If ECOG performance status is performed 72 hours prior to the scheduled dose, it does not need to be repeated on the scheduled dose date for that cycle. If it is performed on the scheduled dose date, it must be performed before administration of study treatment.

[0080] Adverse events and serious adverse events: Duration and frequency of collection of adverse event and serious adverse event information. The investigator will request information about AEs from each participant contact. All AEs will be recorded, whether reported by the participant or recorded by the investigator.

[0081] Methods for detecting adverse events and serious adverse events: Be careful not to introduce bias when detecting AEs and / or SAEs. Open-ended, non-directed verbal questioning of participants is the preferred method for inquiring about the occurrence of AEs. A consistent method of non-directed questioning should be employed to elicit AE information at all participant assessment time points.

[0082] Pharmaceuticals: Blood samples will be collected to assess concentrations of Compound Ia and cobimetinib (and its metabolites, if necessary). The date and time of each sample collection will be recorded. Compound Ia and cobimetinib levels will be analyzed using a validated LC-MS / MS assay. PK samples will be collected as outlined in Table 13. Dedicated PK samples will be collected for the pilot PK cohort and food cohort at predefined time points. During the course of the study, PK sampling time points may be modified based on new data to ensure that the PK of Compound Ia and cobimetinib can be adequately characterized. Additional PK samples will be collected at the following events: ·When treatment is discontinued. - Report of an AE grade ≥ 3 resulting in a dose reduction or delay of Compound Ia and / or cobimetinib administration. · Clinically significant changes in ECG / echocardiogram or MUGA scan. · In the case of DLT. · At the first occurrence of objective response (i.e., PR or CR). ·During disease progression.

[0083] CSF samples for assessing concentrations of Compound Ia (and its metabolites, if applicable) will be collected from a dedicated set of participants. The date and time of each sample collection will be recorded on the eCRF. Compound Ia levels in CSF will be analyzed by using a validated LC-MS / MS assay. CSF samples will be collected as outlined in Table 13. Metabolites may be measured by specific validated LC-MS / MS assays, or other adapted methods for the purpose as needed. Residual PK and CSF samples remaining after a particular analysis may also be used for additional validation experiments (e.g., metabolite identification).

[0084] If necessary, remaining PK and CSF samples may also be used for assay development / validation experiments. PK and CSF blood samples will be destroyed within 2 years after the date of the Clinical Study Report (CSR), unless the participant agrees otherwise.

[0085] Pharmacokinetic and biomarker analysis: Archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue will be collected from all study participants for NGS using F1CDx (a qualitative NGS FDA-approved tissue-based broad-sense companion diagnostic (CDx)). Analytical techniques may include, but are not limited to, BRAF-V600 mutation status, microsatellite instability (MSI), and tumor mutation burden (TMB) in the tumor. Blood and CSF samples for PD will be collected as specified in Table 13. The date and time of each sample collection should be recorded in the eCRF. Details regarding the process for collection and transport of these samples can be found in the laboratory flow diagram. These samples will be tested for DNA or blood- and CSF-derived biomarkers related to PD and the mechanism of action of compound Ia and cobimetinib. Samples will include, but are not limited to, assessment of 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 Natera's Signatera (a personalized multiplex PCR that leverages the power of F1CDx to define a set of tumor-specific variants), followed by subsequent monitoring using the Signatera ctDNA Monitoring Assessment and F1LCDx (a qualitative NGS FDA-approved test for liquid biopsies). PD assessments may be revised over the course of the trial depending on assay availability, emerging data, and the results of initial analyses. Samples may also be used for research purposes to identify biomarkers useful for predicting and monitoring response to compound Ia and cobimetinib treatment, to identify biomarkers useful for predicting and monitoring safety of compound Ia and cobimetinib, to assess the PD effects of compound Ia and cobimetinib treatment, and to investigate mechanisms of treatment resistance. Additional biomarkers may be measured if strong scientific evidence arises. Over the course of the study, sampling time points may be modified based on emerging data to ensure that the PD of compound Ia can be adequately characterized (but without increasing the total blood draw).If a participant withdraws from the study, samples collected before the withdrawal date may still be analyzed unless the participant specifically requests that the samples be destroyed or local law requires the samples to be destroyed. However, if samples are tested before collection, those test results will remain part of the overall study data. Data resulting from all biosamples, including samples for analysis of inherited DNA, will be subject to the study's confidentiality standards.

[0086] Endogenous CYP3A activity marker assay: Mandatory blood samples for measuring 4βHC, TC, and / or 4αHC concentrations will be collected to assess CYP3A activity during Compound Ia treatment. The date and time of each sample collection will be recorded on the eCRF. 4βHC, TC, and / or 4αHC levels 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, sampling time points may be revised based on emerging data to ensure that CYP3A activity during Compound Ia treatment can be adequately characterized. Blood samples will be destroyed after the date of the final clinical study report, or after approval by the study management team, or earlier depending on local regulations. Details regarding sampling procedures, sample storage, and transportation are provided in the sample documentation.

[0087] Genetic and genomic analysis: Archival FFPE tumor tissue for DNA analysis will be collected prior to study treatment administration. DNA may be used for, but is not limited to, BRAF-V600 mutation detection and genetic biomarker discovery studies using F1CDx. Whole blood samples for DNA analysis will be collected at baseline or prior to study treatment administration, and at discontinuation in Part 2. DNA may be used for, but is not limited to, BRAF-V600 mutation status and genetic biomarker discovery studies using F1LCDx. For F1CDx and F1LCDx testing, samples and / or their derivatives may be sent to one or more laboratories for analysis of germline or somatic mutations by next-generation sequencing (NGS) or other genomic analysis methods, which form the basis of F1CDx and F1LCDx. Exploratory studies of genetic biomarkers may include, but are not limited to, cancer-associated genes, biomarkers related to common molecular pathways, MSI status, and TMB. Whole blood samples for ctDNA analysis will be collected during study treatment. Analysis of cell-free DNA (cfDNA) extracted from whole blood samples may include, but is not limited to, mutations in genes associated with cancer progression, tumor molecules / mL, and the number of positive mutations defined by F1-Tracker, which may affect PK, PD, clinical activity, or safety of the study treatment. To this end, 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 facilitating investigators' understanding of disease pathobiology. Targeted DNA analysis provides comprehensive characterization of the genome, which, together with the clinical data collected in this study, may increase opportunities to develop new therapeutic approaches. Data will be analyzed in conjunction with this study but may also be explored together with data from other studies. The availability of larger datasets will aid in the identification of important pathways and guide the development of new targeted agents. Given the complexity and exploratory nature of these analyses, data and analyses will not be shared with investigators or study participants unless required by law. Participants will not be identified by name or other personally identifying information.Data generated from all biospecimens, including samples for analysis of inherited DNA, will be subject to confidentiality standards described in the sample documentation. Participants will not be identified by name or other personally identifying information. Data generated from all biospecimens, including samples for analysis of inherited DNA, will be subject to confidentiality standards described in the sample documentation.

[0088] Pharmacokinetic and biomarker samples: Blood, CSF, and archival biopsy samples will be collected. The date and time of each sample collection should be recorded. Additionally, any residual material from the blood may be used for retrospective and longitudinal testing for bacterial or viral infections by serological methods. This testing may be performed on each participant. In addition to serving as an important safety measure, these analyses will inform about the relevance of bacterial or viral infections and response to treatment. Any residual material from blood and tumor tissue samples may also be used for other exploratory analyses and studies to discover new biomarkers or to develop these clinical tests for this or similar drugs after their intended use. Unless otherwise specified below, samples (including blood, slides, extracts, etc.) will be destroyed within five years of the final clinical trial report, unless the participant specifically consents to the remaining material being stored for any exploratory studies.

[0089] Blood Sample Sampling: The following blood samples for plasma isolation will be collected for PD and exploratory biomarker evaluation: All participants will have blood collected for BRAF V600 mutation assessment for DNA extraction and clinical genotyping (BRAF V600 mutation confirmation). Samples should be collected prior to the start of treatment, as specified in the SoA. If samples are not collected prior to C1D1 administration, they can be collected at another scheduled clinic visit as soon as possible. · ctDNA blood will be collected from all participants at screening, treatment, and at progressive disease as specified in the SoA for DNA extraction and ctDNA assessment. Collect blood samples to measure 4βHC, TC, and / or 4αHC concentrations to assess CYP3A activity during Compound Ia treatment.

[0090] Tissue Sampling: Archival tumor tissue should be obtained, preferably from the primary tumor or, if unavailable, from a previous metastasis. Archival specimens can be of any age and must contain sufficient viable tumor tissue to establish BRAF V600 mutation status by a central laboratory. Additionally, these samples will be used to extract DNA for genetic biomarker, MSI, and TMB discovery studies.

[0091] Optional Sample for ctDNA CSF Sample: CSF is optional for all study participants and will be collected for PD and exploratory biomarker assessment. CSF collection can be performed via Ommaya reservoir or lumbar puncture. CSF will be used to assess the PD effect of Compound Ia in combination with cobimetinib in brain lesions by examining changes in ctDNA.

[0092] Statistical considerations: (a) Sample Size Determination: The exact number of participants will depend on the occurrence of DLTs and the number of dose levels required to determine the MTD and / or RP2D. The study will enroll up to 120 participants in the dose escalation phase (60 participants each for Part 1a and Part 1b) and up to approximately 40 participants in up to four expansions in Part 2. For FE, additional cohorts of 6-12 participants will be enrolled, resulting in an overall maximum number of 292 participants.

[0093] Validation of the Dose Expansion Part 2 Sample Size: A sample size of 40 response-evaluable participants per cohort in Part 2 allows for an 80% probability of declaring futility, assuming a true objective response rate (ORR) of 10%, based on the posterior probability that the ORR is less than 20% at a 70% confidence level. The 20% futility level is based on the response rate achieved by vemuratinib in melanoma patients with brain metastases (McArthur et al. 2017). Futility will be assessed after mature data are obtained for 10, 20, 30, and 40 participants, respectively. Futility will be concluded if ≤1 of 10 participants, ≤2 of 20 participants, ≤4 of 30 participants, or ≤6 of 40 participants have a CR or PR.

[0094] Adequacy of sample size for food cohorts: Sample size was determined by practical considerations and not based on statistical power calculations.

[0095] (b) Analytical Set: For the purposes of analysis, the following populations are defined in Table 1: [Table 1]

[0096] (c) Statistical Analysis: Where appropriate, data will be summarized by cohort, dose level, and / or dosing schedule within each portion of the study. Subjects with leptomeningeal disease may be analyzed separately in each portion if sufficient numbers of patients are available. Demographic and baseline characteristics (including, but not limited to, age, sex, biomarker status, previous treatment, and medical history) will be analyzed using descriptive statistics. Exposure to study drug will be summarized by total duration of study drug administration, number of cycles initiated, and cumulative dose using descriptive statistics. Dose interruptions and reasons for them will be presented by schedule and dose level. Efficacy Analysis: Participants will be assessed for response by the investigator based on RECIST v1.1 criteria for extracranial lesions and mRECIST-BM for intracranial lesions. Participants with missing or no response assessments will be classified as "unevaluable." Responses must be confirmed by a second assessment 4 weeks after the first assessment indicating a response. Only confirmed responses will be analyzed and used for futility analyses. Participants are considered "responders" if their best response to treatment is equivalent to a "complete response" (CR) or "partial response" (PR). ORR is defined as the proportion of responders among response-evaluable participants. Disease control rate (DCR) is defined as the proportion of participants who are either responders or have "stable disease" (SD) at least once at the first post-baseline tumor assessment. Duration of response (i.e., best [confirmed] overall response rate of CR or PR) is calculated for "responder" participants and is defined as the time from the first occurrence of a documented response to the time of documented disease progression or death from any cause, whichever occurs first. Progression-free survival (PFS) is defined as the time from the first dose of study treatment to the first occurrence of documented disease progression or death from any cause, whichever occurs first (Table 2). For participants who did not demonstrate progressive disease or death by the last response assessment during the study, PFS is censored at the last date of study tumor assessment. Participants with no post-baseline assessments or with all post-baseline assessments who have unknown outcome / response but are known to be alive at the clinical cutoff for analysis will be censored at study treatment start date +1 day.Response and PFS analyses are based on the response-evaluable population. [Table 2]

[0097] Safety Analysis: All safety parameters listed in Table 3 will be analyzed using descriptive statistics presented in tables and / or graphics. Safety will be assessed through a summary of DLTs (for Part 1), AEs, changes in clinical laboratory results, changes in vital signs, ECG and LVEF, and their respective relationships to study treatment exposure. [Table 3] TIFF2025537786000011.tif196170

[0098] Pharmacokinetic analysis: PK parameters for Compound Ia administered alone and in combination with cobimetinib were derived from plasma concentrations and are listed and summarized using descriptive statistics (e.g., mean, standard deviation, coefficient of variation, median, minimum, and maximum values, etc.). 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 ), the time to maximum observed concentration (T max ) and apparent oral clearance (CL / F), steady-state volume of distribution ( ss PK parameters may include the pharmacokinetic (pharmacokinetic) time (t / F) and terminal half-life (t1 / 2). Estimation of PK parameters may be performed using standard non-compartmental methods and / or population PK modeling. If the data permits, other methods may be used for data analysis, for example, PK and PD data may be used to develop a population PK / PD model. Individual and mean plasma Compound Ia concentration versus time data are tabulated and plotted by dose level. Graphical displays of PK data may also be provided. PK linearity (AUC and C maxTo evaluate the FE for the PK of Compound Ia, Compound Ia was orally administered to at least six participants, followed by feeding (high-fat meal) or fasting, to measure PK parameters (e.g., AUC, C max , T max and t 1 / 2 ) are analyzed. Estimation of PK parameters may be performed using standard non-compartmental methods and / or population PK modeling. Additionally, CSF concentrations of compound Ia (if applicable) may be presented by list and descriptive summary statistics (e.g., mean, standard deviation, coefficient of variation, median, minimum, and maximum, etc.). If the data permits, other methods may be used for data analysis, for example, PK and PD data may be used to develop a population PK / PD model. For participants receiving cobimetinib, PK parameters of cobimetinib (e.g., but not limited to, AUC, C max , T max and t 1 / 2 ) will be listed and compared to the exposure history observed in previous studies with cobimetinib to assess the induction potential of compound Ia. PK parameter estimation may be performed using standard non-compartmental methods and / or population PK modeling. Furthermore, the relationship between drug exposure (compound Ia or cobimetinib), safety, PD, and efficacy endpoints will be examined to establish exposure-response relationships. Further PK analysis of compound Ia (and compound Ia metabolite(s), if available and appropriate) or cobimetinib will be performed as appropriate based on available data. PK and / or any exposure-response relationship results may be reported outside of clinical study reports.

[0099] Pharmacodynamic analysis: All PD parameters will be presented by list and descriptive summary statistics separately for each group or cohort. Descriptive statistics will be used to summarize peripheral blood and tumor PD markers. Absolute and percentage changes from baseline will be calculated for PD markers. Graphical techniques will be used to better understand the relationship between PD markers and dose and time.

[0100] Pharmacokinetic / pharmacodynamic relationships: Correlations between PK parameters, PD markers, and clinical response are assessed by data tables and graphical techniques. If the data permits, other methods may be used for data analysis, for example, PK and PD data may be used to develop population PK / PD models.

[0101] Other analysis: Endogenous CYP3A activity marker analysis: For analysis of CYP3A activity during Compound Ia administration, determine plasma concentrations of 4βHC, TC, and / or 4αHC and derive percent change from baseline in 4βHC with or without normalization by TC and 4αHC. If the data permit, other exploratory methods may be used for data analysis, for example, PK and CYP3A activity data may be used to develop population PK / CYP3A activity models. [18F]-FDG-PET imaging: For analysis of FDG-PET data, participants will be considered evaluable at baseline and at least one post-baseline scan. [18F]-FDG-PET uptake data from baseline and treatment time points will be summarized descriptively. FDG-PET parameters from baseline (e.g., SUV max , SUV mean Changes and percentage changes in blood glucose levels (e.g., total lesion glycolysis) will be described and evaluated as evidence of response to treatment.

[0102] Preliminary analysis: In Part 2, futility analyses will be performed after 10, 20, and 30 participants in each expansion cohort, respectively.

[0103] Definition of adverse event: According to the E2A ICH Good Clinical Practice guideline, an adverse event (AE) is any untoward medical occurrence in a participant administered a medicinal product or clinical trial participant, which does not necessarily have a causal relationship to this treatment. Thus, an AE can be: any untoward and unintended sign (including abnormal laboratory findings), symptom or disease temporarily associated with the use of a medicinal product, whether or not considered medicinal product-related.

[0104] Events that meet the AE definition: Deterioration in laboratory values ​​(hematology, clinical chemistry, or urinalysis) or other clinical tests (e.g., ECG, X-ray) that is associated with symptoms or leads to a change in or discontinuation from study treatment or concomitant treatment. · Chronic or intermittent worsening of existing symptoms, including an increase in the frequency and / or intensity of symptoms. · New conditions that may have been present before the start of the study but are detected or diagnosed after administration of the study treatment. AEs related to protocol-mandated interventions, including those occurring before assignment of study treatment (e.g., screening invasive procedures such as biopsies). "Lack of efficacy" or "failure of expected pharmacological action" itself is not reported as an AE or serious AE (SAE) unless progression is unexpectedly accelerated and inconsistent with the natural history of the disease. When "lack of efficacy" does not require safety reporting, such cases are captured in efficacy evaluations. However, signs, symptoms, and / or clinical sequelae attributable to lack of efficacy will be reported as AEs or SAEs if they meet the definition of an AE or SAE.

[0105] Events that do not meet the AE definition: Clinically significant abnormal laboratory findings or other abnormal safety assessments related to the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. - The expected progression, signs, or symptoms of the disease / disorder being studied or the disease / disorder being tested, unless it is more severe than expected for the participant's condition. Medical or surgical procedures (e.g., endoscopy, appendectomy): Symptoms that result in a procedure are AEs. · Situations in which no untoward medical incidents occurred (social and / or convenient admission to hospital). · Expected day-to-day fluctuations in pre-existing disease(s) or condition(s) are present or detected at the start of the study and do not worsen.

[0106] Definition of serious adverse events If the event is not an AE according to the above definition, it cannot be an SAE even if the serious condition is met (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression). SAEs at any dose: Brings death, *Defined as any adverse medical event that is life-threatening. The term "life-threatening" in the definition of "serious" refers to an event in which the participant was at risk of death at the time of the event, not an event that could hypothetically have caused death if it had been more severe. o Requires inpatient hospitalization or extension of existing hospitalization. Generally, hospitalization means that the participant is kept in a hospital or emergency room for observation and / or treatment that was not appropriate in a physician's office or outpatient setting (usually including at least an overnight stay). A complication that occurs during hospitalization is an AE. If the complication prolongs hospitalization or meets some other significant criterion, the event is serious. If there is any doubt as to whether a "hospitalization" occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. o Resulting in persistent or significant impairment / incapacity o Impairment means a substantial disruption of the participant's ability to perform normal life functions. This definition is not intended to include experiences of relatively minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, flu, and accidental trauma (e.g., a sprained ankle), which interfere or have the potential to interfere with daily functioning but do not constitute a substantial disruption. *Congenital anomaly / birth defect. Other Significant Events: Medical or scientific judgment should be exercised in determining whether an SAE report is appropriate in other situations, such as significant medical events that are not immediately life-threatening or do not result in death or hospitalization, but which may endanger the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above. These events should generally be considered serious. Examples of such events include invasive or malignant cancer, allergic bronchospasm, blood disorders or seizures that do not result in hospitalization, or intensive emergency room or home-based treatment for the development of drug dependence or abuse.

[0107] Safety rating: The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the AE (assessed as mild, moderate, or severe, or according to predetermined grading criteria [e.g., National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) criteria]). The event itself may be relatively medically insignificant (e.g., a severe headache without further findings). Severity and seriousness should be assessed independently for each recorded AE. The NCI CTCAE (v5.0) AE Severity Grading Scale is used to assess AE severity. Table 4 is used to assess the severity of AEs not specifically listed in the NCI CTCAE. [Table 4]

[0108] Causality assessment: The investigator should use their knowledge of the participant, the circumstances surrounding the event, and an 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: ·Temporal relationship of event onset to initiation of study treatment. · The course of events, particularly considering the effect of dose reduction, discontinuation of study treatment, or reintroduction of study treatment. · Known association of the event with the study treatment or similar treatment. · Known association of the event with the disease under study. The participant has risk factors or is using concomitant medications known to increase the occurrence of the event. The presence of factors other than treatment known to be associated with the occurrence of the event.

[0109] For participants receiving concomitant therapy, causality will be assessed separately for each protocol-defined treatment.

[0110] Tumor measurability at baseline Definitions: At baseline, tumor lesions / lymph nodes are classified as measurable or non-measurable as described below. Measurable Tumor Lesion - Tumor Lesion: The tumor lesion must be accurately measured in at least one dimension (the longest diameter in the measurement plane is recorded) at its smallest size as follows: Computed tomography (CT) or magnetic resonance imaging (MRI) scans of 10 mm (CT / MRI scan slice thickness / interval of 5 mm or less) Clinical examination with 10mm caliper measurement (lesions that cannot be accurately measured with a caliper are recorded as non-measurable) Chest X-ray 20mm

[0111] Measurable Tumor Lesion - Malignant Lymph Nodes To be considered pathologically enlarged and measurable, lymph nodes must measure 15 mm or greater in the short axis when assessed by CT scan (a CT scan slice thickness of 5 mm or less is recommended). At baseline and follow-up, only the short axis is measured and tracked. See also the note below regarding "Baseline Documentation of Target and Non-Target Lesions" for information regarding lymph node measurement.

[0112] Nonmeasurable tumor lesions: Nonmeasurable tumor lesions include small lesions (pathological lymph nodes with a longest diameter less than 10 mm or a short axis of 10 to 15 mm) as well as truly nonmeasurable lesions. Lesions considered truly nonmeasurable include leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, cutaneous or pulmonary lymphatic lesions, peritoneal spread, and abdominal masses / organomegaly identified by physical examination that are not measurable by reproducible imaging techniques.

[0113] Special Considerations Regarding Lesion Measurability: Bone lesions, cystic lesions, and lesions previously treated with local therapy require specific comments, as outlined below.

[0114] Bone lesions: Bone scans, positron emission tomography (PET) scans, or plain films are not considered appropriate imaging techniques for measuring bone lesions. However, these techniques can be used to confirm the presence or absence of bone lesions. Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that can be assessed by cross-sectional imaging techniques such as CT or MRI can be considered measurable lesions if the soft tissue component meets the definition of measurability above. Blastic bone lesions are not measurable.

[0115] Cystic Lesions: Lesions that meet the criteria for radiographically defined simple cysts should not be considered malignant lesions (neither measurable nor nonmeasurable) because they are, by definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered measurable lesions if they meet the definition of measurability above. However, if noncystic lesions are present in the same patient, these are preferred for selection as target lesions.

[0116] Lesions with Prior Local Treatment: Tumor lesions located in areas that have previously been irradiated or have received other locoregional therapy are generally not considered measurable unless progression in the lesion has been documented. The study protocol should detail the conditions under which such lesions are considered measurable.

[0117] Areas of interest: Specifications by method of measurement: Lesion measurements: All measurements, when clinically assessed, should be recorded in metric notation using calipers. All baseline assessments should be as close as possible to the start of treatment and no more than 4 weeks prior to the start of treatment.

[0118] Assessment methods: The same assessment method and the same techniques should be used to characterize each lesion identified and reported at baseline and during the study. Imaging-based assessment should always be the preferred option.

[0119] Clinical Lesions: Clinical lesions are considered measurable only if they are superficial and ≥10 mm in diameter, as assessed using calipers (e.g., skin nodules). Clinical lesions require documentation by color photographs, including a ruler to estimate the size of the lesion.

[0120] Chest X-ray: Chest CT is preferred over chest X-ray because CT is more sensitive than X-ray in identifying new lesions, especially when progression is the key endpoint. However, lesions on chest X-ray may be considered measurable if they are well-defined and surrounded by aerated lung.

[0121] CT, MRI: CT is the best currently available and reproducible method for measuring lesions selected for response assessment. This guideline defines lesion measurability on CT scans based on the assumption that the CT slice thickness is 5 mm or less. If the CT scan has a slice thickness greater than 5 mm, the minimum size of a measurable lesion must be twice the slice thickness. MRI is also acceptable. If it is known prior to enrollment that a patient cannot undergo CT scanning with intravenous (IV) contrast due to allergy or renal insufficiency, the decision to use non-contrast CT or MRI (without IV contrast) to evaluate the patient at baseline and during the study should be guided by the tumor type and anatomical location of the disease under investigation. For patients who develop a contraindication to contrast after baseline contrast CT has been performed, the decision to perform non-contrast CT or MRI (enhanced or non-enhanced) should also be based on the tumor type and anatomical location of the disease and, if possible, optimized to allow comparison with previous studies. Each case should be discussed with a radiologist to determine whether these other approaches are feasible; if not, the patient should be considered non-evaluable from that point on. Care must be taken in measuring target lesions with different modalities and interpreting non-target or new lesions, as the same lesion may appear to have a different size when using a new modality.

[0122] Ultrasound: Ultrasound is not useful for assessing lesion size and should not be used as a measurement method.

[0123] Endoscopy, laparoscopy, tumor markers, cytology, histology: The use of these techniques for objective tumor evaluation cannot generally be recommended.

[0124] Tumor Response Assessment - Assessment of overall tumor burn and measurable disease: To assess objective response or future progression, it is necessary to estimate overall tumor burden at baseline and use this as a comparator for subsequent measurements. Measurable disease is defined by the presence of at least one measurable lesion, as detailed above.

[0125] Tumor Response Assessment - Baseline Literature for Target and Non-Target Lesions: If two or more measurable lesions are present at baseline, all lesions, up to a total of five lesions and a maximum of two lesions per organ, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. This means that if a patient has only one or two organ sites involved, a maximum of two lesions (one site) and four lesions (two sites) are recorded, respectively. Other lesions (although measurable) in those organs are recorded as non-measurable lesions (even if their size on CT scan is >10 mm). Target lesions should be selected based on their size (lesions with the longest diameter) and should represent all involved organs. Furthermore, the lesions should lend themselves to reproducible repeated measurements. In some cases, the largest lesion may not be suitable for reproducible measurement; in that situation, the next largest reproducibly measurable lesion should be selected. Lymph nodes are worth special mention, as they are normal anatomical structures that may be visible by imaging even if not involved by tumor. As mentioned above, pathological nodules that can be defined as measurable and identified as target lesions must meet the criterion of a short axis of 15 mm or greater on a CT scan. Only the short axis of these nodules contributes to the baseline sum. The short axis of a nodule is the diameter typically used by radiologists to determine whether a nodule is involved in a solid tumor. Nodule size is typically reported as two dimensions within the plane in which the image is acquired (for CT, this is almost always the axial plane; for MRI, the acquisition plane may be axial, sagittal, or coronal). The smaller of these measurements is the short axis. For example, an abdominal nodule reported as 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable nodule. In this example, 20 mm should be recorded as the nodule measurement. All other pathological nodules (those with a short axis greater than 10 mm but less than 15 mm) should be considered non-target lesions. Nodules with a short axis of 10 mm or less are considered non-pathological and should not be recorded or tracked. The sum of the diameters of all target lesions (longest axis for non-nodular lesions and short axis for nodular lesions) will be calculated and reported as the baseline sum of diameters.When lymph nodes are included in the total, only the short axis is added to the total, as described above. The baseline sum of diameters is used as a reference to further characterize any objective tumor regression in measurable dimensions of disease. All other lesions or disease sites, including pathological lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required, and these lesions should be tracked as "present," "absent," or, rarely, "definite progression." Additionally, multiple non-target lesions involving the same organ can be recorded as a single item on the eCRF (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

[0126] Response Criteria - Target Lesion Assessment: This section provides definitions of the criteria used to determine objective tumor response to target lesions. CR (complete response): Disappearance of all target lesions Any pathological lymph nodes (whether target or non-target) must have a short axis reduction to less than 10 mm. PR (partial response): At least a 30% reduction in the sum of the diameters of the target lesions, using the baseline sum of the diameters as reference. Progressive disease: At least a 20% increase in the sum of the diameters of target lesions, using the smallest sum (nadir) on the study as reference, including baseline. In addition to the 20% relative increase, the total must show an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. SD (Stable Disease): Taking the smallest sum during the study as reference, there was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.

[0127] Special note regarding target lesion evaluation: Lymph nodes identified as target lesions should always have their actual short-axis measurement (measured in the same anatomical plane as the baseline examination) recorded, even if the node regresses to less than 10 mm during the study. This means that if lymph nodes are included as target lesions, the total lesion may not be zero even if CR criteria are met, since normal lymph nodes are defined as having a short axis of <10 mm.

[0128] Target Lesions Too Small to Measure: During the study, all lesions (nodular and nonnodular) recorded at baseline should have their actual measurements recorded at each subsequent assessment, even if they are very small (e.g., 2 mm). However, lesions or lymph nodes recorded as target lesions at baseline may be very faint on the CT scan, and the radiologist may not feel comfortable assigning an accurate measurement and report them as too small to measure. When this occurs, it is important that the values ​​are recorded in the eCRF as follows: If it is the radiologist's opinion that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If a lesion is thought 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 checked. (Note: This rule is unlikely to be used for lymph nodes because they typically have a definable size and are frequently surrounded by fat, such as the retroperitoneum. However, if a lymph node is thought to be present and is faintly visible but too small to measure, a default value of 5 mm should be assigned and the BML should also be checked.) Repeat in the following cases: If the radiologist can provide an actual measurement, this measurement should be recorded, even if it is less than 5 mm, and the BML should not be checked. Lesions that Split or Coalesce During Treatment: If a non-nodal lesion fragments, the longest diameters of the fragmented segments should be added together to calculate the total target lesion. Similarly, as lesions coalesce, a plane between them can be maintained to help obtain the maximum diameter measurement of each individual lesion. If the lesions are truly coalesced and can no longer be separated, the longest diameter vector in this case should be the maximum longest diameter of the fused lesions.

[0129] Non-target Lesion Assessment: This section provides definitions of the criteria used to determine tumor response for the group of non-target lesions. While some non-target lesions may actually be measurable, they do not need to be measured and instead should only be assessed qualitatively at the time points specified in the protocol. CR: Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (short axis <10 mm). · Non-CR / non-progressive disease: persistence of one or more non-target lesions. Progressive disease: A clear progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.

[0130] Special notes regarding assessment of non-target disease progression: If the patient also has measurable disease: In this setting, to achieve definite progression based on non-target disease, there must be an overall level of substantial worsening of non-target disease, such that the overall tumor burden has increased sufficiently to merit discontinuation of treatment, even in the presence of SD or PR in target disease. A modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for definite progression status. Therefore, the designation of overall progression based solely on changes in non-target disease in the face of SD or PR in target disease is extremely rare. Patients with only nonmeasurable disease: This situation arises in some Phase III clinical trials when measurable disease is not a criterion for study entry. The same general concepts apply here as above. However, in this example, there is no measurable disease assessment to consider when interpreting an increase in nonmeasurable disease burden. Because worsening nontarget disease cannot be easily quantified (by definition, when all lesions are truly nonmeasurable), a useful test that can be applied when evaluating patients for definite progression is to consider whether the increase in overall disease burden based on nonmeasurable disease change is comparable to the increase required for declaring progressive disease for measurable disease, i.e., an increase in tumor burden representing an additional 73% increase in volume (corresponding to a 20% increase in diameter in measurable lesions). Examples include an increase in pleural effusion from "trace" to "massive" or an increase in lymphatic disease from focal to extensive. An example might be described in the clinical trial protocol as "sufficient to require a change in treatment." If definite progression is observed, the patient should be considered to have had overall progressive disease at that time. While it would be ideal to have objective criteria to apply to non-measurable diseases, the very nature of the disease makes this impossible, so increases must be substantial. New Lesions: The appearance of new malignant lesions indicates disease progression. Therefore, some opinions regarding the detection of new lesions are important. There are no specific criteria for identifying new radiological lesions; however, the detection of new lesions should be unambiguous, i.e., not attributable to differences in scanning technique, changes in imaging modality, or findings thought to represent something other than tumor (e.g., some "new" bone lesions may simply be healing or recurrence of existing lesions). This is particularly important when a patient's baseline lesions show a partial response or complete response (e.g., necrosis of a liver lesion may be reported on a CT scan report as a "new" cystic lesion, but this is not a new lesion). Lesions identified during a study in an anatomical location not scanned at baseline are considered new lesions and indicate disease progression. If a new lesion is unclear (e.g., due to its small size), continued treatment and follow-up evaluations will reveal whether it truly represents new disease. If a new lesion is reliably identified by repeat scans, the date of the initial scan should be used to declare progression.

[0131] Response evaluation: Time Point Response (Overall Response Rate): It is assumed that response assessments occur at each protocol-specified time point. Table 5 provides a summary of overall response status calculations at each time point for patients with measurable disease at baseline. If patients have only non-measurable (and therefore non-target) disease, Table 6 should be used. [Table 5] [Table 6]

[0132] Missing Assessments and Non-Evaluable Designations: If no imaging / measurements are performed at a particular time point, the patient is not evaluable at that time point. If only a subset of lesion measurements are performed at the time of evaluation, the case is typically also considered non-evaluable at that time point unless a compelling argument can be made that the contribution of the individual missing lesion(s) would not alter the assigned time point response. This is most likely to occur in cases of progressive disease (e.g., if a patient had a baseline total of 50 mm with three measured lesions, and only two lesions were evaluated during the study, but they totaled 80 mm, the patient has achieved progressive disease status regardless of the contribution of the missing lesions). If one or more target lesions were not evaluated because a scan was not performed or because the scan could not be evaluated due to poor image quality or field of view obstruction, the patient is not evaluable, and therefore the response to the target lesions should be "non-evaluable." Similarly, if one or more non-target lesions are not evaluated, the response to the non-target lesions should be "non-evaluable" unless there is clear progression. If either the target response or the non-target response is "unevaluable," the overall response rate is "unevaluable," as this is equivalent to being unevaluable at that time, unless this is clear evidence of progression. [Table 7]

[0133] Special note regarding response assessment: If nodal disease is included in the target lesion totals and nodules decrease to a "normal" size (<10 mm), they may still have a measurement reported on the scan. If this measurement is based on an increase in nodule size, it should be recorded even if the nodules are normal, to avoid exaggerating progression. As mentioned previously, this means that patients with a CR may not have a total score of "0" on the eCRF. Patients with a global deterioration in health status necessitating discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptomatic worsening." Every effort should be made to document objective progression even after treatment discontinuation. Symptomatic worsening is not a descriptor of objective response; it is a reason to discontinue study therapy. The objective response status of such patients should be determined by assessment of target and non-target disease, as shown in Tables 5–7. For findings of unclear progression (e.g., very small, 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 in which patients with progressive disease are eligible (i.e., primary disease is still or partially present), the primary tumor should also be captured as a target or non-target lesion, as appropriate. This is to avoid erroneous assessment of complete response when the primary tumor is still present but is not evaluated as a target or non-target lesion.

[0134] Modified Response Evaluation in Neuro-Oncology (mRECIST-BM) for Brain Metastases: The RANO-BM criteria are referred to as mRECIST-BM criteria in this protocol. mRECIST-BM CRITERIA: Similar to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, the definition of radiographic response is based on unidimensional measurements.

[0135] Definition: Measurable disease is defined as a contrast-enhancing lesion that can be accurately measured in at least one dimension, has a minimum size of 10 mm, and is visible on two or more axial slices, preferably separated by 5 mm or less with a 0-mm skip (and ideally separated by 1.5 mm or less with a 0-mm skip). Furthermore, the longest diameter within the measurement plane should be recorded, but the diameter perpendicular to the longest diameter within the measurement plane should be at least 5 mm for the lesion to be considered measurable. If magnetic resonance imaging (MRI) is performed with thicker slices, the size of the measurable lesion at baseline should be at least twice the slice thickness. Interslice gaps, if present, should also be considered in determining the minimum size of the measurable lesion at baseline. Measuring tumors surrounding cysts or surgical cavities presents a particularly challenging challenge. In general, such lesions should be considered nonmeasurable unless there is a nodular component with a longest diameter of 10 mm or more and a diameter of 5 mm or more in the perpendicular plane. Cystic or surgical cavities should not be measured to determine response. Nonmeasurable disease includes lesions with a longest dimension less than 10 mm, lesions with borders that cannot be reproducibly measured, dural metastases, bony skull metastases, cyst-only lesions, and all other lesions, including leptomeningeal disease. Patients with nonmeasurable disease can still be included in clinical trials where 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 a 10 mm cutoff to limit studies to measurable disease. For investigators who choose to lower the minimum size limit for measurable disease to 5 mm, we strongly recommend MRI imaging with a slice thickness of 1.5 mm or less. Complete responses and definite progressive disease can likely be interpreted even in lesions as small as 5 mm. However, measuring small changes, such as a minimum 20% increase in the longest diameter to define progressive disease or a minimum 30% decrease in the longest diameter to define partial response, may not be robust or reproducible.Due to the inherent uncertainty in measuring small lesions, lesions with a longest diameter less than 10 mm should be considered unchanged from baseline unless there is a minimum 3 mm change in the measured longest diameter. If objective response is the primary endpoint, the decision to include patients with multiple lesions with a combined diameter of 10 mm or greater but with a maximum lesion size less than 10 mm should be made carefully. If such patients are included, response should be assessed using the sum of the longest diameters of the lesions, and response criteria should be clearly delineated in the clinical trial protocol. This setting requires thin-section MRI imaging with a slice thickness of 1.5 mm or thinner.

[0136] Measurement method: The same assessment method and technique should be used to characterize each lesion identified and reported at baseline and during follow-up. Consistent use of imaging techniques across all imaging time points is important to ensure that assessment of segment appearance, lesion resolution, or size change is not affected by scan parameters such as slice thickness. The use of thin-section imaging is particularly important for assessing lesions less than 10 mm in longest diameter, small changes in lesion size, 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). MRI is strongly recommended as the default standard imaging technique, although CT with or without contrast may be considered in certain circumstances (e.g., countries with limited medical resources or contraindications to MRI).

[0137] Tumor response assessment: Only patients with measurable CNS disease at baseline should be included in protocols in which an objective CNS tumor response is the primary endpoint. For studies in which objective response is not the primary endpoint, the protocol must prospectively specify whether participation is limited to patients with measurable disease or whether patients with nonmeasurable disease are also eligible. CNS response assignment is independent of systemic disease response. CNS lesions should be evaluated according to mRECIST-BM criteria, whereas non-CNS lesions are most typically evaluated according to RECIST 1.1 criteria. Generally, CNS lesions should be initially reassessed by MRI at protocol-specified intervals of 6–12 weeks apart, although there may be specific circumstances in which longer (or shorter) intervals are desirable. Longer intervals between scans may be appropriate for patients who remain stable for extended periods. All baseline assessments should be performed as close as possible to treatment initiation and within 4 weeks of treatment initiation. For previously treated lesions, we recommend documentation of how each lesion was previously treated (e.g., stereotactic radiosurgery, whole-brain radiotherapy, surgical resection). If two or more measurable lesions are present 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 their size (longest diameter) as those that can be reproducibly measured. For patients with recurrent disease with multiple lesions, only one or two of which are increasing in size, the enlarging lesions should be prioritized as target lesions for response assessment. Lesions with prior local treatment (i.e., stereotactic radiosurgery or surgical resection) can be considered measurable if progression has occurred since the time of local treatment. However, careful consideration is needed for lesions previously treated with stereotactic radiosurgery, given the potential for therapeutic benefit. Whether such lesions can be considered measured should be prospectively identified in the clinical trial protocol. If lesions are present that have not been previously treated with local therapy, these are preferred for selection as target lesions.The sum of the diameters of all target lesions is calculated and reported as the baseline sum of the longest diameter. All other CNS lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required; these lesions should be classified as present, absent, or definite progression and followed up.

[0138] Definition of Best Overall CNS Response: Best overall CNS response is a composite of radiographic CNS target and non-target lesion responses (Table 8). In non-randomized trials where CNS response is the primary endpoint, confirmation of a partial or complete response after at least 4 weeks is required for either to be considered a best overall response. [Table 8]

[0139] Response assessments should be performed at each protocol-specified time point, and CNS assessments should be consistent with non-CNS assessments. Table 9 shows the requirements for a partial or complete response. [Table 9]

[0140] Assessment of target and non-target CNS lesions: During the study, all CNS target lesions should have their actual measurements recorded, even if they are very small (e.g., 2 mm). If the lesion disappears, the value should be recorded as 0 mm. However, if the lesion is small enough to assign an accurate scale (but is still present), a default value of 5 mm should be recorded on the eCRF. Lesions may coalesce during treatment. As lesions coalesce, a plane between them can be maintained, which helps obtain the maximum longest diameter of each individual lesion. If the lesions are truly coalesced so that they can no longer be separated, the vector of the longest diameter in this case should be the maximum longest diameter of the fused lesions. New lesions may appear during treatment. The finding of a new CNS lesion should be clear and not due to technical or slice variation. A new lesion is one that was not present on previous scans. If MRI is obtained with a slice thickness of 1.5 mm or less, new lesions should also be visible in axial, coronal, and sagittal reconstructions of 1.5 mm or less projections. For example, if a new lesion is not evident because of its small size (i.e., ≤5 mm), continued treatment can be considered, and follow-up evaluations will clarify whether it truly represents new disease. If a new lesion is identified on repeat scans, progression should be declared using the date of the first scan showing the new lesion. However, in the case of immunotherapy, new lesions alone do not constitute progressive disease. Clear progression of non-target lesions may merit discontinuation of treatment. If a patient also has measurable disease, to be considered to have clear progression based on non-target disease alone, there must also be overall substantial worsening of non-target disease, thereby superficially increasing the overall tumor burden to merit discontinuation of treatment, even in the presence of stable disease or partial response in target disease. If a patient only has non-measurable disease, there must be an overall level of substantial worsening that merits discontinuation of treatment. The mRECIST-BM group acknowledges cases of patients treated with stereotactic radiosurgery- or immunotherapy-based approaches who had radiological evidence of enlargement of target and non-target lesions that does not necessarily represent tumor progression.When radiographic evidence of progression is present but clinical evidence indicates that the radiographic changes are due to a treatment effect (rather than cancer progression), additional evidence is needed to distinguish true progression from a treatment effect; in this case, standard MRI alone is insufficient. The method used to distinguish true progression from a treatment effect should be prospectively identified in the clinical protocol. Patients may continue protocol therapy pending further investigation using one or more of the following options: Scans may be repeated at or before the next protocol-scheduled evaluation, generally within approximately 6 weeks. The investigator may choose a shorter time interval if progressive symptoms or other clinical concerns arise. Continued tumor growth may be consistent with radiographic progression, in which case the patient should be discontinued from the study. Lesion stabilization and shrinkage may be consistent with a treatment effect, in which case the patient may remain in the study. For patients in whom the next restaging scan does not provide clear results, surgery or the use of advanced imaging modalities (in the case of stereotactic radiosurgery), or both, is strongly recommended, although the scan can be repeated again at or before the subsequent protocol-scheduled evaluation. Surgical pathology can be obtained by biopsy or excision.

[0141] For lesions treated with stereotactic radiosurgery, further evidence of tumor progression or treatment response (radionecrosis) can be obtained with advanced imaging modalities such as perfusion MRI, magnetic resonance spectroscopy, or 18FLT or 18FDG PET. If subsequent testing indicates that progression has occurred, the progression date should be recorded as the date of the scan on which this issue was first raised. Patients can also have unequivocal findings on the scan (e.g., small lesions that are not clearly new). Continuing treatment until the next protocol-scheduled evaluation is acceptable. If subsequent evaluation indicates that progression has indeed occurred, the progression date should be recorded as the date of the first scan on which progression was suspected.

[0142] In patients receiving immunotherapy-based therapy, an initial increase in the number and size of metastases can be followed by radiographic stabilization or regression. This pattern may be related to the mechanism of action of immunotherapy, including immune infiltrates, and the time to mount an effective immune response. Therefore, progressive disease should not be defined solely by the appearance of new lesions, but rather by a minimum 20% increase in the combined longest diameter of CNS target and new lesions, clear progression of existing enhancing non-target CNS lesions, clear progression of existing non-enhancing (T2 / FLAIR) CNS lesions, or tumor-related clinical decline. If radiographic changes related to an immune response are suspected, we recommend not changing treatment until closely spaced scans are obtained.

[0143] Volumetric criteria: First, a partial volumetric response should be defined as a 65% or greater reduction in the total volume of CNS target lesions. Second, volumetric responses should be reported as waterfall plots to provide an overall sense of potential efficacy. Third, in the absence of high-quality data across multiple studies to demonstrate a clear correlation between a lower volumetric threshold and some measure of patient benefit, such as quality of life, neurocognitive function, or overall survival, it is premature to formally define a category of small response or lower the threshold for considering a volumetric response. However, we encourage digital archiving of clinical trial images and accompanying linked clinical outcome data to enable pooling of studies to determine whether different cutpoints may be justified in the future.

[0144] Treatment of non-CNS (extracranial) disorders: Preclinical and clinical data can show differential responses between intracranial and extracranial locations, which may be related to inadequate drug penetration, differences in the tumor microenvironment, or tumor heterogeneity between organ sites, among other factors. Many systemic agents are not expected to have CNS activity, primarily due to poor drug penetration. Local CNS therapies, such as whole-brain radiation therapy, stereotactic radiosurgery, or surgery, are not expected to affect extracranial sites at all. Traditionally, RECIST has used the sum of representative target lesions across all organ sites. Historically, patients with brain metastases have been excluded from systemic treatment trials. Even when included, patients with brain metastases often had to have stable, treated CNS lesions at study enrollment, and CNS lesions were rarely selected as target lesions. The Macdonald and RANO-HGG criteria do not provide guidance for the treatment of extracranial disease, as extracranial disease is not relevant to most patients with primary brain tumors. The results were a lack of flexibility to continue protocol therapy in the setting of discordant CNS versus non-CNS response or progression, disincentives to 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 CNS and non-CNS should be evaluated as separate compartments (Table 10). Thus, CNS response is scored independently of extracranial response, and vice versa. For progression, CNS and non-CNS are scored according to mRECIST-BM and RECIST 1.1 criteria, respectively (Table 11). If progression occurs in one or both compartments, the criteria for bicompartmental progression-free survival are met. The protocol can also prospectively specify CNS progression-free survival and non-CNS progression-free survival as endpoints. The protocol should specify a plan for patients who progress in only one compartment.For example, a patient in a systemic therapy trial who develops isolated CNS progression may be given the option to treat their CNS disease with whole-brain radiation therapy, stereotactic radiosurgery, or surgery and continue protocol therapy until the time of non-CNS disease progression, unacceptable toxicity, or death. The date of non-CNS progressive disease should be recorded when it occurs. [Table 10] [Table 11] [Table 12] TIFF2025537786000021.tif104170 [Table 13] (a) "Pre-dose" refers to sample collections performed immediately prior to drug administration ("dose") of Compound Ia and cobimetinib (if applicable). Both Compound Ia and cobimetinib (if applicable) are taken at the same time in the morning. Scheduled time points refer to the time after drug administration of Compound Ia and cobimetinib (if applicable). The time of PK sample collection should be recorded and entered into the eCRF for Compound Ia and cobimetinib (if applicable). (b) If there is no drug-drug interaction between compound Ia and cobimetinib, cobimetinib PK samples and / or endogenous CYP marker samples may not be further collected in the food cohort or in Part 2. If Part 2 consists of treatment with compound Ia alone, cobimetinib PK samples will not be collected. (c) If the half-life of compound Ia evaluated in the pilot PK cohort is short, the 8-hour post-dose samples of C1D1 and C1D15 and C1D2, C1D3, C1D4, and C1D16 samples may not be further collected in the main dose escalation cohort and / or food cohort and / or expansion cohort (Part 2). (d) If there is sufficient data for the PK characterization of Compound Ia during the study, these samples may not be collected further in Part 2. (e) If a cancellation visit coincides with a scheduled outpatient visit, all planned evaluations for the cancellation visit must be performed.

[0145] Detailed Description of the Drawings Figure 1. Overview of the Phase Ia / b study plan. Part 1 is the dose-escalation phase. In Part 1a cohorts, compound Ia is used as monotherapy, and in Part 1b cohorts, compound Ia is used in combination with cobimetinib. Part 1 also includes a pilot PK cohort and a food cohort. Part 2 is an expansion phase with four cohorts. BRAFi-naive melanoma with asymptomatic brain lesions corresponds to Cohort 1 (compound Ia monotherapy) and Cohort 3 (compound Ia + cobimetinib). BRAFi-experienced melanoma with asymptomatic brain lesions corresponds to Cohort 2 (compound Ia monotherapy) and Cohort 4 (compound Ia + cobimetinib).

[0146] Figure 2 is a process flow diagram for manufacturing film-coated tablets containing compound Ia (Example A). A dry granulation process is used to manufacture the formulation. Step 1: Compound Ia, sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, and croscarmellose sodium are weighed and blended. Optionally, spray drying of Compound Ia is carried out as step 0. Step 2: Dry granulation of the blend obtained from step 1. Alternatively, instead of dry granulation, high shear mixing or fluid bed granulation can be used on the blend obtained from step 1. Step 3: Weigh out the croscarmellose sodium and magnesium stearate. Add them to the granules from step 2 and blend. Step 4: The blend obtained from step 3 is compressed into tablets and the individual weight of the tablet cores is checked (as an in-process control). Step 5: The film coating mixture is weighed and suspended in purified water. The resulting coating suspension is sprayed onto the tablet cores from step 4. The average weight of the film coated tablets is measured (as an in-process control). Step 6: The film-coated tablets are packaged and labeled for clinical use.

[0147] Figure 3: Preliminary PK data on the effect of food show that food intake significantly increased C in the fed cohort. max Although the AUC 0-∞ ) indicates no significant change.

[0148] Figure 4: Trough concentrations (C) of compound Ia (also known as RO7276389) based on a preliminary population pharmacokinetic (PopPK) model trough ) Simulations suggest coverage around the IC95 for 1200 mg TID and 1600 mg BID. Such coverage is comparable to the C of currently available BRAF inhibitors at approved doses. trough This results in substantially higher coverage, resulting in coverage near the IC80, limited by dose-limiting toxicity. Importantly, this simulation also suggests that the highest coverage can be obtained with a dosing regimen referred to herein as 1200 mg TID6, in which the first daily dose is administered in the morning with the first meal, then the second daily dose is administered 6 hours later (presumably with the second meal), and the third daily dose is administered another 6 hours later (presumably with the third meal).

[0149] Pharmaceutical Composition: One embodiment of the present invention provides pharmaceutical compositions for use in accordance with the present invention, comprising a compound of Formula (I) and one or more therapeutically inert carriers, diluents, or excipients, as well as methods for preparing such pharmaceutical compositions. In one example, a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to recipients at the dosages and concentrations used in herbal dosage forms, at an appropriate pH and desired purity, at ambient temperature. The compound of Formula (I) exhibits low pH-dependent solubility. It behaves like a weak acid over the physiological pH range, being poorly soluble at low pH and exhibiting increased solubility at neutral and alkaline pH. In other embodiments, the compound of Formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0150] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard 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 agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0151] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all substances compatible with pharmaceutical administration, including solvents, dispersion media, coatings, enteric coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions of the present invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0152] Pharmaceutical compositions can be obtained by processing the compound of formula (I) with pharmaceutically acceptable inorganic or organic carriers or additives. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used as carriers for tablets, film-coated tablets, sugar-coated tablets, and hard gelatin capsules. Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. However, depending on the nature of the active substance, soft gelatin capsules usually do not require a carrier. Suitable carrier materials for the preparation of solutions and syrups include water, polyols, glycerol, vegetable oils, etc. Suitable carriers for suppositories include natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

[0153] Pharmaceutical compositions may further contain fillers, pH adjusters, glidants, disintegrants, lubricants, preservatives, solubilizers, stabilizers, enteric coatings, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically valuable substances. Suitable fillers for tablets include, for example, microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, isomalt, and dibasic dicalcium phosphate. Suitable wetting agents for tablets include, for example, sodium lauryl sulfate, polyvinylpyrrolidone / polyvinyl alcohol (PVP / PVA) copolymer, and hypromellose. Suitable pH adjusters for tablets include, for example, magnesium oxide, calcium carbonate, calcium bicarbonate, lysine, and tromethamine. Suitable glidants for tablets include, for example, colloidal silicon dioxide. Suitable lubricants for tablets include, for example, magnesium stearate, sodium stearyl fumarate, and macrogol 6000.

[0154] Pharmaceutical compositions of Compound Ia can be prepared for storage in the form of a lyophilized formulation or aqueous solution by mixing the active ingredient, alone or in combination, having the desired degree of purity with any pharmaceutically acceptable carrier, additive, or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. (ed.) (1980)).

[0155] 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 method well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will usually be that amount of the compound of Formula (I) which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about 90 percent of the active ingredient, preferably from about 2 percent to about 70 percent, and most preferably from about 4 percent to about 40 percent. Methods of preparing these compositions include the step of bringing the compound of Formula (I) into association with the carrier and, optionally, one or more accessory ingredients. Generally, pharmaceutical compositions are prepared by uniformly and intimately bringing the compound of Formula (I) into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. Pharmaceutical compositions suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, film-coated tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, 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 troche (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of formula (I) as an active ingredient. The compound of formula (I) may also be administered as a bolus, electuary, or paste.

[0156] The active ingredient may also be incorporated into microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, prepared, for example, by coacervation techniques or interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed.) (1980).

[0157] Formulations to be used for in vivo administration must be sterile, which is readily accomplished by filtration through sterile filtration membranes.

[0158] The dosage can vary within a wide range and, of course, must be adjusted to the individual requirements in each specific case. For oral administration, the dosage for adults can vary from about 100 mg to about 4000 mg per day, preferably from about 1000 mg to about 4000 mg per day, more preferably from about 1600 mg to about 4000 mg per day of the compound of formula (I) or a corresponding amount of its pharmaceutically acceptable salt or solvate. The daily dosage can be administered in a single dose or in divided doses, and may even exceed the upper limit if it proves to be indicated.

[0159] The following examples are provided to illustrate, but are not intended to limit, the present invention. The pharmaceutical composition advantageously contains about 5 mg to about 800 mg, particularly about 10 mg to about 700 mg, and more particularly about 25 mg to about 600 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 50 mg to about 200 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 200 mg to about 400 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 400 mg to about 600 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 600 mg to about 800 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition contains about 800 mg to about 1000 mg of a 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 specific embodiment, the pharmaceutical composition comprising the compound of Formula (I) further comprises about 1 to 500 mg, particularly 5 to 100 mg, and more particularly 60 mg of a MEK inhibitor, particularly cobimetinib, in a fixed dose combination. In a specific embodiment, the pharmaceutical composition comprising the compound of Formula (I) further comprises 20 mg of a MEK inhibitor, particularly cobimetinib, in a fixed dose combination.

[0160] Non-limiting examples of pharmaceutical compositions according to the present invention are as follows:

[0161] Example A - Film-coated tablets Film-coated tablets can be prepared by conventional dry granulation, followed by tablet compression and film coating. A non-limiting example of a film-coated tablet according to the present invention can be of the following composition: [Table 14] Table 14: Possible film-coated tablet compositions; 1. The film-coating mixture consists of the following ingredients: polyvinyl alcohol, partially hydrolyzed macrogol 3350, talc, titanium dioxide, yellow iron oxide, and red iron oxide. 2. Purified water is used for aqueous film coating; it is essentially removed during processing; qs: appropriate quantity.

[0162] Manufacturing procedure for film-coated tablets The formulation can be manufactured using a dry granulation process. Step 1: Compound Ia, sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, and croscarmellose sodium are weighed and blended. Optionally, spray drying of Compound Ia is carried out as step 0. Step 2: Dry granulation of the blend obtained from step 1. Alternatively, instead of dry granulation, high shear mixing or fluid bed granulation can be used on the blend obtained from step 1. Step 3: Weigh out the croscarmellose sodium and magnesium stearate. Add them to the granules from step 2 and blend. Step 4: The blend obtained from step 3 is compressed into tablets and the individual weight of the tablet cores is checked (as an in-process control). Step 5: The film coating mixture is weighed and suspended in purified water. The resulting coating suspension is sprayed onto the tablet cores from step 4. The average weight of the film coated tablets is measured (as an in-process control). Step 6: Packaging and labeling of film-coated tablets.

[0163] The tablet core ingredients are as follows: The formulation contains a filler or a combination of at least two fillers that ensure the desired mechanical resistance of the tablet. The desired mechanical resistance is characterized by sufficient tensile strength, low friability, and low abrasion of the tablet core to withstand the stresses during coating and packaging operations. These fillers can be, for example, microcrystalline cellulose and lactose monohydrate in a ratio of approximately 2:1. The formulation contains a wetting agent, such as sodium lauryl sulfate (0.5% by weight, based on the total weight of the uncoated tablet). The formulation contains a glidant, such as colloidal silicon dioxide (0.5% by weight, based on the total weight of the uncoated tablet). The formulation contains an alkaline pH adjuster, such as magnesium oxide, in a ratio of 1:2 relative to compound Ia. The pH adjuster is intended to create a favorable in vivo micro-pH environment for the solubility of the API (active pharmaceutical ingredient). The formulation contains a disintegrant, e.g., croscarmellose sodium (3.0% by weight based on the total weight of the uncoated tablet). Half is added before granulation and half after granulation. The formulation contains magnesium stearate as a lubricant (1.0% by weight based on the total weight of the uncoated tablet).

[0164] The film coating ingredients are as follows: · A film coating mixture containing polyvinyl alcohol as a film former, macrogol 3350 as an emollient, talc as an anti-tack agent, titanium dioxide, and red and yellow iron oxides as pigments. · The film coating mixture is dispersed in purified water at 15% solids. The film coat is sprayed onto the tablet cores in a pan coater aiming for a weight gain of 3% relative to the weight of the tablet core.

[0165] Film-coated tablet description: The formulation is a pink, rectangular, film-coated tablet. The 25 mg dosage strength contains 4% Compound Ia. The 200 mg film-coated tablet contains 25% Compound Ia.

[0166] Example B - Film-coated tablets Film-coated tablets can be prepared by conventional dry granulation, followed by tablet compression and film coating. A non-limiting example of a film-coated tablet according to the present invention can be of the following composition: [Table 15] Table 15: Possible film-coated tablet compositions; 1. The film-coating mixture consists of the following ingredients: polyvinyl alcohol, partially hydrolyzed macrogol 3350, talc, titanium dioxide, yellow iron oxide, and red iron oxide. 2. Purified water is used for aqueous film coating; it is essentially removed during processing; qs: appropriate quantity.

[0167] Manufacturing procedure for film-coated tablets The formulation is manufactured using a dry granulation process. Step 1: Compound Ia, hypromellose or PVP / PVA copolymer, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, and crospovidone are weighed and blended. Step 2: Dry granulation of the blend obtained from step 1. Alternatively, instead of dry granulation, high shear mixing or fluid bed granulation can be used on the blend obtained from step 1. Step 3: Weigh out crospovidone sodium and sodium stearyl fumarate. Add them to the granules obtained from step 2 and blend. Step 4: The blend obtained from step 3 is compressed into tablets and the individual weight of the tablet cores is checked (as an in-process control). Step 5: The film coating mixture is weighed and suspended in purified water. The resulting coating suspension is sprayed onto the tablet cores from step 4. Optionally, spray drying is performed. The average weight of the film-coated tablets is measured (as an in-process control). Step 6: Packaging and labeling of film-coated tablets.

[0168] Example C - Film-coated tablets Film-coated tablets can be prepared by conventional dry granulation, followed by tablet compression and film coating. A non-limiting example of a film-coated tablet according to the present invention can be of the following composition: [Table 16] Table 16: Possible film-coated tablet compositions; 1. The film-coating mixture consists of the following ingredients: polyvinyl alcohol, partially hydrolyzed macrogol 3350, talc, titanium dioxide, yellow iron oxide, and red iron oxide. 2. Purified water is used for aqueous film coating; it is essentially removed during processing; qs: appropriate quantity.

[0169] Manufacturing procedure for film-coated tablets The formulation is manufactured using a dry granulation process. Step 1: Compound Ia, sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, calcium carbonate, colloidal silicon dioxide, and croscarmellose sodium are weighed and blended. Optionally, spray drying of Compound Ia is carried out as step 0. Step 2: Dry granulation of the blend obtained from step 1. Alternatively, instead of dry granulation, high shear mixing or fluid bed granulation can be used on the blend obtained from step 1. Step 3: Weigh out the croscarmellose sodium and magnesium stearate. Add them to the granules from step 2 and blend. Step 4: The blend obtained from step 3 is compressed into tablets and the individual weight of the tablet cores is checked (as an in-process control). Step 5: The film coating mixture is weighed and suspended in purified water. The resulting coating suspension is sprayed onto the tablet cores from step 4. The average weight of the film coated tablets is measured (as an in-process control). Step 6: Packaging and labeling of film-coated tablets. [Table 17]

[0170] The present invention further relates to the following: Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases; A particular 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 adjuster, thereby improving the dissolution properties of compound Ia; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor and a BRAF inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor and a BRAF inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the melanoma has been previously treated with a checkpoint inhibitor and a BRAF inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the tumor has been previously treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the tumor has been previously treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a BRAF mutant metastatic or locally advanced solid tumor, wherein the tumor has been previously treated with a checkpoint inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the tumor has been previously treated with a checkpoint inhibitor and a BRAF inhibitor; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally, with or without food; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally with water; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally with food, in particular after a high-fat meal; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is administered orally without food, in particular after a 10 hour fast; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally three times daily with about six hours between the administration of each dose, and particularly each dose is administered with food; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the compound of formula (I) is administered orally, with or without food; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the compound of formula (I) is administered orally with food, in particular after a high-fat meal; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the compound of formula (I) is administered orally without food, in particular after a 10 hour fast; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein the compound of formula (I) is orally administered in a dose of 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; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors, wherein the compound of formula (I) is orally administered in a dose of 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; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of non-small cell lung cancer, wherein 200 mg / day to 2000 mg / day, particularly 600 mg / day to 2000 mg / day, more particularly 1000 mg / day to 2000 mg / day of the compound of formula (I) is orally administered; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of non-small cell lung cancer, wherein the compound of formula (I) is orally administered in a dose of about 1600 mg / day to about 4000 mg / day, particularly about 2000 mg / day to 4000 mg / day, and more particularly about 3000 mg / day to about 4000 mg / day; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of non-small cell lung cancer, wherein 1200 mg / day to 2000 mg / day, particularly 1400 mg / day to 2000 mg / day, more particularly 1600 mg / day to 2000 mg / day of the compound of formula (I) is orally administered; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of non-small cell lung cancer, wherein 800 mg / day to 1600 mg / day, particularly 800 mg / day to 1400 mg / day, more particularly 1000 mg / day to 1400 mg / day of the compound of formula (I) is orally administered; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein 50 mg / day to 800 mg / day of the compound of formula (I) is administered orally during every day of a 28-day cycle, while cobimetinib is administered on days 1 to 21 of the 28-day cycle; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein 800 mg / day to 2000 mg / day of the compound of formula (I) is administered orally during every day of a 28-day cycle, while cobimetinib is administered on days 1 to 21 of the 28-day cycle; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein about 2000 mg / day to about 4000 mg / day of the compound of formula (I) is administered orally every day of a 28-day cycle, while cobimetinib is administered on days 1-21 of the 28-day cycle; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein about 3000 mg / day to about 4000 mg / day, particularly about 3200 mg / day, of the compound of formula (I) is administered orally every day of a 28-day cycle, while cobimetinib is administered on days 1 to 21 of the 28-day cycle; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein 1200 mg / day to 2000 mg / day, in particular 1600 mg / day, of the compound of formula (I) is administered orally every day of a 28-day cycle, while cobimetinib is administered on days 1 to 21 of the 28-day cycle; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein 800 mg / day to 1200 mg / day of the compound of formula (I) is administered orally during every day of a 28-day cycle, while cobimetinib is administered on days 1 to 21 of the 28-day cycle; A particular embodiment of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant metastatic melanoma with brain metastases, wherein 50 mg / day to 800 mg / day, in particular 200 mg / day to 600 mg / day, of the compound of formula (I) is administered orally every day of a 28-day cycle, while 60 mg / day of cobimetinib is administered on days 1 to 21 of the 28-day cycle; Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the uses described herein, wherein administration is twice daily (BID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 800 mg of the compound of formula (I) is administered twice a day (BID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 1200 mg of the compound of formula (I) is administered twice a day (BID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 1600 mg of the compound of formula (I) is administered twice a day (BID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 2000 mg of the compound of formula (I) is administered twice a day (BID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 800 mg of the compound of formula (I) is administered three times a day (TID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses 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 and second doses, and between the second and third doses, respectively; Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 1200 mg of the compound of formula (I) is administered three times a day (TID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses 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 and second doses, and between the second and third doses, respectively; Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), for the uses described herein, wherein 1600 mg of the compound of formula (I) is administered three times a day (TID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the uses described herein, wherein administration is three times daily (TID); Certain embodiments of the present invention relate to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the uses described herein, wherein the administration is three times daily (TID), with a 6-hour interval between the first and second administrations, and between the second and third administrations, respectively; Certain embodiments of the present invention relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of BRAF mutant cutaneous melanoma with asymptomatic brain metastases; and Certain embodiments of the present invention relate to the compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with cobimetinib, for use in the treatment of BRAF mutant cutaneous melanoma with radiologically confirmed asymptomatic brain metastases.

[0171] Specific numbered embodiments: 1. A compound of formula (I) for use in the treatment of melanoma with brain metastases. TIFF2025537786000027.tif43170 or a pharmaceutically acceptable salt thereof.

[0172] 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to embodiment 1, wherein the brain metastases are asymptomatic.

[0173] 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to embodiment 1 or 2, wherein the melanoma is cutaneous melanoma.

[0174] 4. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 3, wherein the melanoma has previously been treated with a BRAF inhibitor.

[0175] 5. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to embodiment 4, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib.

[0176] 6. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 3, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0177] 7. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 6, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0178] 8. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 7, wherein the compound of formula (I) is in combination with cobimetinib.

[0179] 9. A method for treating or preventing melanoma with brain metastasis, the method comprising administering an effective amount of a compound of formula (I) TIFF2025537786000028.tif43170 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0180] 10. The method of embodiment 9, wherein the brain metastases are asymptomatic.

[0181] 11. The method of embodiment 9 or 10, wherein the melanoma is cutaneous melanoma.

[0182] 12. The method of any one of embodiments 9-11, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0183] 13. The method of embodiment 12, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, and encorafenib.

[0184] 14. The method of any one of embodiments 9-11, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0185] 15. The method of any one of embodiments 9 to 14, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0186] 16. The method of any one of embodiments 9-14, wherein the compound of formula (I) is combined with cobimetinib.

[0187] 17. A compound of formula (I) for the treatment of melanoma with brain metastases Use of a compound of TIFF2025537786000029.tif43170 or a pharmaceutically acceptable salt thereof.

[0188] 18. The use of embodiment 17, wherein the brain metastases are asymptomatic.

[0189] 19. The use according to embodiment 17 or 18, wherein the melanoma is cutaneous.

[0190] 20. The use according to any one of embodiments 17 to 19, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0191] 21. The use according to embodiment 20, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib.

[0192] 22. The use according to any one of embodiments 17 to 19, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0193] 23. The use according to any one of embodiments 17 to 22, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0194] 24. The use according to any one of embodiments 17 to 23, wherein the compound of formula (I) is combined with cobimetinib.

[0195] 25. A compound of formula (I) for use in the treatment of melanoma with brain metastases A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier.

[0196] 26. The pharmaceutical composition of embodiment 25, wherein the brain metastases are asymptomatic.

[0197] 27. The pharmaceutical composition for use according to embodiment 25 or 26, wherein the melanoma is cutaneous melanoma.

[0198] 28. The pharmaceutical composition of any one of embodiments 25 to 27, wherein the melanoma has been previously treated with a BRAF inhibitor.

[0199] 29. The pharmaceutical composition for use according to any one of embodiments 25 to 28, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib.

[0200] 30. The pharmaceutical composition of any one of embodiments 25-27, wherein the melanoma has not been previously treated with a BRAF inhibitor.

[0201] 31. The pharmaceutical composition for use according to any one of embodiments 25 to 30, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a MEK inhibitor.

[0202] 32. The pharmaceutical composition for use according to any one of embodiments 25 to 31, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with cobimetinib.

[0203] 33. Formula (I) A pharmaceutical composition comprising a compound of TIFF2025537786000031.tif43170 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 adjusters, lubricants and wetting agents.

[0204] 34. The pharmaceutical composition according to embodiment 33, wherein the pharmaceutical composition comprises a film coat.

[0205] 35. The pharmaceutical composition of embodiment 34, wherein the film coat comprises one or more ingredients selected from polyvinyl alcohol, macrogol 3350, polyethylene glycol 4000, talc, titanium dioxide, yellow iron oxide, and red iron oxide.

[0206] 36. The pharmaceutical composition according to any one of embodiments 33-35, wherein the filler is selected from microcrystalline cellulose, lactose monohydrate, anhydrous lactose, mannitol, isomalt and dibasic dicalcium phosphate.

[0207] 37. The pharmaceutical composition according to any one of embodiments 33-36, wherein the filler is selected from microcrystalline cellulose and lactose monohydrate.

[0208] 38. The pharmaceutical composition of any one of embodiments 33-37, wherein the filler is microcrystalline cellulose and lactose monohydrate in a ratio of about 2:1 (microcrystalline cellulose:lactose monohydrate) weight percent.

[0209] 39. The pharmaceutical composition of any one of embodiments 33-38, wherein the weight percentage of the filler or the total weight percentage of the fillers is between about 30 weight percent and about 90 weight percent of the pharmaceutical composition.

[0210] 40. The pharmaceutical composition of any one of embodiments 33-39, wherein the wetting agent is selected from sodium lauryl sulfate, PVP / PVA copolymer, and hypromellose in a weight percentage range of about 0.1 weight percent to about 5.0 weight percent of the pharmaceutical composition.

[0211] 41. The pharmaceutical composition of any one of embodiments 33-40, wherein the wetting agent is sodium lauryl sulfate in a weight percentage of about 0.1 weight percent of the pharmaceutical composition.

[0212] 42. The pharmaceutical composition according to any one of embodiments 33-40, wherein the weight percentage of the glidant is about 0.5 weight percent of the pharmaceutical composition.

[0213] 43. The pharmaceutical composition according to any one of embodiments 33-42, wherein the glidant is colloidal silicon dioxide.

[0214] 44. The pharmaceutical composition of any one of embodiments 33-43, wherein the pH adjuster is an alkaline pH adjuster.

[0215] 45. The pharmaceutical composition of any one of embodiments 33-44, wherein the pH adjuster is selected from magnesium oxide, calcium carbonate, calcium bicarbonate, lysine and tromethamine.

[0216] 46. ​​The pharmaceutical composition of any one of embodiments 33-45, wherein the pH adjuster is magnesium oxide.

[0217] 47. The pharmaceutical composition according to any one of embodiments 33-46, wherein the weight percentage ratio of pH adjuster to compound of formula (I) is between about 3:1 and about 1:5.

[0218] 48. The pharmaceutical composition according to any one of embodiments 33-47, wherein the weight percentage ratio of the pH adjuster to the compound of formula (I) is about 1:2.

[0219] 49. The pharmaceutical composition of any one of embodiments 33-48, wherein the disintegrant is selected from crospovidone, sodium starch glycolate, L-HPC and croscarmellose sodium.

[0220] 50. The pharmaceutical composition of any one of embodiments 33-49, wherein the disintegrant is sodium croscarmellose.

[0221] 51. The pharmaceutical composition of any one of embodiments 33-50, wherein the weight percentage of the disintegrant is about 2 weight percent to 5 weight percent of the pharmaceutical composition.

[0222] 52. The pharmaceutical composition of any one of embodiments 33-51, wherein the weight percentage of the disintegrant is about 3 weight percent of the pharmaceutical composition.

[0223] 53. The pharmaceutical composition according to any one of embodiments 33-52, wherein part of the disintegrant is added before dry granulation and part of the disintegrant is added after dry granulation.

[0224] 54. The pharmaceutical composition according to any one of embodiments 33-53, wherein the disintegrant contains at least one suspending agent selected from HPMC, HPMC-AS, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG), PVP / PVA copolymer, in a weight percentage range of 5 weight percent to 10 weight percent of the disintegrant.

[0225] 55. The pharmaceutical composition according to any one of embodiments 33-54, wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate and macrogol 6000.

[0226] 56. The pharmaceutical composition of any one of embodiments 33-55, wherein the lubricant is magnesium stearate.

[0227] 57. The pharmaceutical composition of any one of embodiments 33-56, wherein the weight percentage of the lubricant is from about 0.5 weight percent to about 3.0 weight percent of the pharmaceutical composition.

[0228] 58. The pharmaceutical composition of any one of embodiments 33-57, wherein the weight percentage of the lubricant is from about 0.5 weight percent to about 1.0 weight percent of the pharmaceutical composition.

[0229] 59. The pharmaceutical composition of any one of embodiments 34 to 58, wherein the film coat contains HPMC.

[0230] 60. The pharmaceutical composition of any one of embodiments 34-59, wherein the weight percentage of the film coat is from about 2.0 weight percent to about 5.0 weight percent of the pharmaceutical composition.

[0231] 61. The pharmaceutical composition of any one of embodiments 34-60, wherein the weight percentage of the film coat is about 3.0 weight percent of the pharmaceutical composition.

[0232] 62. The pharmaceutical composition according to any one of embodiments 25-61, wherein the pharmaceutical composition comprises sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate, magnesium oxide, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.

[0233] 63. The pharmaceutical composition according to any one of embodiments 25-62, wherein the pharmaceutical composition comprises an enteric coating.

[0234] 64. The pharmaceutical composition of any one of embodiments 25-62, wherein the pharmaceutical composition comprises an enteric coating comprising 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 (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methyl acrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate, and zein.

[0235] 65. The compound, pharmaceutical composition, method or use for use according to any one of embodiments 7, 15, 23 or 31, wherein the MEK inhibitor is selected from binimetinib, trametinib and cobimetinib.

[0236] 66. The compound, pharmaceutical composition, method or use for use according to any one of embodiments 4-5, 12-13, 20-21 or 28-29, in which relapse has occurred under previous treatment with a BRAF inhibitor.

[0237] 67. Melanoma, BRAF V600 The compound, pharmaceutical composition, method or use for use according to any one of embodiments 1 to 32 or 65 to 66, relating to mutations.

[0238] 68. A compound of formula (I) for use in treating locally advanced solid tumors and / or cancer metastases The compound of TIFF2025537786000032.tif43170 or a pharmaceutically acceptable salt thereof.

[0239] 69. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to embodiment 68, wherein the metastatic cancer has at least one metastatic site in the brain.

[0240] 70. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to embodiment 68 or 69, wherein cancer metastasis is asymptomatic.

[0241] 71. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 68 to 70, wherein the locally advanced solid tumor is selected from melanoma, non-small cell lung cancer (NSCLC), thyroid cancer, colorectal cancer (CRC), in particular non-small cell lung cancer (NSCLC).

[0242] 72. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 68-71, wherein the metastatic or locally advanced solid tumor has previously been treated with a BRAF inhibitor.

[0243] 73. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to embodiment 72, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib.

[0244] 74. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 68 to 71, wherein the solid tumor has not been previously treated with a BRAF inhibitor.

[0245] 75. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 68-74, wherein the compound of formula (I) is combined with a MEK inhibitor.

[0246] 76. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 68-75, wherein the compound of formula (I) is combined with cobimetinib.

[0247] 77. A pharmaceutical composition having an approximate weight to weight ratio (relative to the mass of the total composition) according to any one of Examples A, B or C, wherein the weight to weight ratio may deviate from the examples by no more than 20%, preferably no more than 10%.

[0248] 78. A pharmaceutical composition according to any one of Examples A, B or C.

Claims

1. A compound of formula (I) for use in the treatment of melanoma with brain metastases or a pharmaceutically acceptable salt thereof.

2. 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the melanoma has not been previously treated with a BRAF inhibitor.

3. 3. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to claim 1 or 2, wherein said compound of formula (I) is combined with a MEK inhibitor.

4. 4. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein said compound of formula (I) is in combination with cobimetinib.

5. A compound of formula (I) for use in the treatment of melanoma with brain metastases or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert carrier.

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

7. 7. The pharmaceutical composition for use according to claim 5 or 6, wherein the melanoma has not been previously treated with a BRAF inhibitor.

8. Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises one or more fillers, glidants, disintegrants, pH adjusters, lubricants, and wetting agents.

9. 9. The pharmaceutical composition of 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. 10. The pharmaceutical composition of claim 8 or 9, wherein the pharmaceutical composition comprises a film coat.

11. 1. A compound of formula (I) for use in the treatment of BRAF mutant metastatic melanoma with brain metastases or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein about 3000 mg / day to about 4000 mg / day, in particular about 3200 mg / day, of said compound of formula (I) is administered orally daily for 28 day cycles, and cobimetinib is administered on days 1 to 21 of said 28 day cycles.

12. A compound of formula (I) for use in treating locally advanced solid tumors and / or cancer metastasis or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein administration is three times daily (TID).

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

14. A compound of formula (I) for use in treating locally advanced solid tumors and / or cancer metastasis or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein 1200 mg of said compound of formula (I) is administered three times a day (TID) with a 6-hour interval between the first and second doses and between the second and third doses, respectively.

15. 1. A compound of formula (I) for use in the treatment of BRAF mutant metastatic or locally advanced solid tumors or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert carrier, wherein said compound of formula (I) is administered orally with food, in particular after a high-fat meal.

Images