CN116981462A - Soto-raschib dosing regimen - Google Patents

Abstract

Provided herein are methods of administering a total daily dose of 240mg of sotoracicb to a patient having a cancer with a KRAS G12C mutation. Also provided herein are methods of treating KRAS G12C-mutated cancers in a patient comprising administering to the patient a total daily dose of 960mg of sotoracicmide and reducing the total daily dose of sotoracicmide to 480mg in a patient experiencing an adverse event of a dose of 960mg of sotoracicmide.

Description

Soto-raschib dosing regimen

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application Ser. No. 63/162,273, filed on 3 months of 2021, 6 months of 2021, U.S. provisional application Ser. No. 63/185,054, filed on 5 months of 2021, 18 days of 2021, and U.S. provisional application Ser. No. 63/190,096, all of which are incorporated herein by reference in their entirety.

Background

Rat sarcoma (RAS) proto-oncogenes have been identified as oncogenic drivers of tumorigenesis in cancers such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). The RAS family consists of 3 closely related genes that express Guanosine Triphosphate (GTP) enzymes responsible for regulating cell proliferation and survival. RAS proteins, kirsten rat sarcoma viral oncogene homologs (KRAS), harvey rat sarcoma viral oncogene Homologs (HRAS), and neuroblastoma RAS viral oncogene homologs (NRAS) may be mutationally activated at codons 12, 13, or 61, resulting in human cancer. Different tumor types are associated with mutations of certain subtypes of the RAS, with KRAS being the most common mutant subtype in most cancers. Although the role of KRAS mutations in human cancers has been known for decades, until recently, no anti-cancer therapies have been successfully developed that specifically target KRAS mutations, primarily because the protein is considered difficult to inhibit by small molecules.

Disclosure of Invention

Provided herein are methods of treating cancer in a patient, the methods comprising administering to the patient a total daily dose of 240mg of sotorasiibd (motorasib), wherein the cancer is a KRAS G12C mutant cancer.

Also provided herein are methods of treating cancer in a patient, the methods comprising administering to the patient a total initial daily dose of 960mg of sotoraciclovir, and administering a total daily dose of sotoraciclovir reduced to 480mg when the patient experiences an adverse event of the initial total daily dose, wherein the cancer is a KRAS G12C mutant cancer. In some embodiments, the methods further comprise administering 240mg of the second reduced total daily dose of sotoracicada when the patient experiences adverse events of the reduced total daily dose.

In various embodiments, the sotoracicada is administered once a day. In various embodiments, the sotorubin is administered orally. In various embodiments, the subject is administered sotoracicada for at least one month. In various embodiments, the subject is administered sotoracicada for at least three months. In various embodiments, the subject is administered sotoracicada for at least six months.

In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, and in some cases, metastatic or locally advanced and unresectable. In various embodiments, the cancer is colorectal cancer. In various embodiments, the cancer is pancreatic cancer. In various embodiments, the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasm, head and neck cancer, esophageal gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

In various embodiments, the patient has undergone at least one other systemic cancer therapy prior to initiation of the sotoprazole therapy. In various embodiments, the patient has undergone at least two other systemic cancer therapies. In various embodiments, the at least one systemic cancer therapy is selected from anti-PD 1 immunotherapy, anti-PDL 1 immunotherapy, and platinum-based chemotherapy. In various embodiments, the patient has previously undergone (i) anti-PD 1 therapy or anti-PDL 1 therapy unless contraindicated, or (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy, if the cancer also exhibits mutations in EGFR, ALK, or ROS 1. In various embodiments, the patient has previously undergone (i) anti-PD 1 therapy or anti-PDL 1 therapy unless contraindicated, and (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy, if the cancer also exhibits mutations in EGFR, ALK, or ROS 1.

In various embodiments, the patient has no active brain metastasis within four weeks of initiation of the sotoraciclovir therapy. In various embodiments, the patient exhibits an eastern tumor collaboration group (ECOG) physical state of 0, 1, or 2.

In various embodiments, the patient exhibits at least disease Stabilization (SD) after 1, 3, or 6 months of sotoraciclovir therapy, as measured by RECIST 1.1 regimen. In various embodiments, the disease stability is neither sufficiently reduced to conform to the Partial Response (PR) nor sufficiently increased to conform to the disease Progression (PD).

In various embodiments, the patient exhibits at least a Partial Response (PR) after 1, 3, or 6 months of sotoraciclovir therapy, as measured by RECIST 1.1 regimen. In various embodiments, the partial response is at least a 30% reduction in the sum of the diameters of the target lesions.

In various embodiments, the patient exhibits a Progression Free Survival (PFS) of at least 3 months. In various embodiments, the patient exhibits PFS for at least 6 months.

In various embodiments, the cancer exhibits a PDL1 tumor proportion score (tumor proportion score, TPS) of 1% -49%. In various embodiments, the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of less than 1%. In various embodiments, the cancer exhibits a PDL1 Tumor Proportion Score (TPS) of 50% -100%. In various embodiments, the cancer further comprises a STK11 mutation. In various embodiments, the cancer further comprises a KEAP1 mutation. In various embodiments, the cancer further comprises a STK11 wild type. In various embodiments, the cancer further comprises KEAP1 wild type.

Drawings

Figure 1 shows the mean plasma concentration time profile after oral administration of 180, 360, 720 or 960mg of sotoracicmide once daily on day 1, where N represents the number of observations between data points.

Figure 2 shows the mean plasma concentration time profile after oral administration of 180, 360, 720 or 960mg of sotoracicmide once daily on day 8, where N represents the number of observations between data points.

Fig. 3 shows a box plot of optimal tumor shrinkage for non-small cell lung cancer patients given sotoraciclovir 180mg QD, 360mg QD, 720mg QD, or 960mg QD, where n is the number of patients and the percent change in diameter sum from baseline only considers tumor assessments prior to and including the first assessment, where the time point response is disease progression.

Detailed Description

Provided herein are methods of administering sotoraciclovir to a patient suffering from a cancer having a KRAS G12C mutation. Sotolacib is an irreversible inhibitor of KRAS ^G12C Small molecules of muteins. Soto-traxib is also known as AMG 510 or 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) - (1M) -1- [ 4-methyl-2- (propan-2-yl) pyridin-3-yl]-4- [ (2S) -2-methyl-4- (prop-2-enyl) piperazin-1-yl]Pyrido [2,3-d ]]Pyrimidin-2 (1H) -one and has the following structure:

the sotoracicb binds to the P2 pocket and the nucleotide binding pocket of KRAS adjacent to the mutated cysteine at position 12. The inhibitors contain a thiol-reactive moiety which covalently modifies a cysteine residue and binds KRAS ^G12C Locked in an inactive Guanosine Diphosphate (GDP) binding conformation. This blocks the interaction of KRAS with effectors such as Rapidly Accelerated Fibrosarcoma (RAF), thereby preventing downstream signaling, including phosphorylation of extracellular signal regulated kinases (ERKs) (Cully and Downward,2008; ostrem et al, 2013; simanshu et al, 2017). Inactivation of KRAS by RNA interference (RNAi) or small molecule inhibition has previously been demonstratedInhibition of cell growth and induction of apoptosis in tumor cell lines and xenografts containing KRAS mutations (including KRAS G12C mutations) is described (Janes et al, 2018; mcdonald et al, 2017; xie et al, 2017; ostrem and Shokat,2016; patricelli et al, 2016). Studies of sotorubin confirmed these in vitro findings and also demonstrated inhibition of growth and regression of cells and tumors harboring KRAS G12C mutations (Canon et al, 2019).

In various embodiments of the present disclosure, the patient is administered a total daily dose of 240mg of sotoracicada. In some embodiments, the sotoracicada is administered once daily. In various embodiments, the sotorubin is administered orally. In various embodiments, the sotoracicada is administered with the food. In various embodiments, the sotoracicada is administered without food.

In various embodiments, the patient is further in need of treatment with an acid reducing agent. Acid reducing agents include, but are not limited to, proton Pump Inhibitors (PPIs), H2 receptor antagonists (H2 RA), and locally acting antacids. In one embodiment, the patient is further in need of treatment with PPI or H2 RA. Exemplary PPIs include, but are not limited to, esomeprazole, lansoprazole, rabeprazole, and dexlansoprazole. Exemplary PPIs include, but are not limited to, omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, or dexlansoprazole. Exemplary H2 RAs include, but are not limited to, famotidine, ranitidine, cimetidine, nizatidine, roxatidine, and lafutidine. Exemplary topically acting antacids include, but are not limited to, sodium bicarbonate, calcium carbonate, aluminum hydroxide, and magnesium hydroxide. In some embodiments, the patient is not administered a proton pump inhibitor or a combination of an H2 receptor antagonist and sotoprazole. In some embodiments, the sotorubin is administered about 4 hours before or about 10 hours after the topically acting antacid if the patient further requires treatment with an acid reducing agent.

In various embodiments, the patient is further in need of treatment with a CYP3A4 inducer. In some embodiments, the patient is not administered a combination of a CYP3A4 inducer and sotoraciclovir. Exemplary CYP3A4 inducers include, but are not limited to, barbiturates, bugatinib, carbamazepine, clobazane, darafenib, efavirenz, oxagolide, enzalutamide, eslicarbazepine, glucocorticoids, latifolia, latifinib, modafinil, nevirapine, olanzapine, oxcarbazepine, pirapamide, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, tetroxat, and traglione. See, e.g., flockhart DA, drug Interactions: cytocochrome P450 Drug Interaction Table [ drug interactions: cytochrome P450 drug interaction table ]. University of indiana medical college (2007), www.drug-interactions. In some embodiments, the patient is not administered a combination of a strong CYP3A4 inducer and sotoraciclovir. Exemplary strong CYP3A4 inducers include, but are not limited to, phenytoin and rifampin. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-subsystems-inhibitors-and-inhibitors, 2021, month 5 access.

In various embodiments, the patient is further in need of treatment with a CYP3A4 substrate. In some embodiments, the patient is not administered a combination of a CYP3A4 substrate and sotoraciclovir. Exemplary CYP3A4 substrates include, but are not limited to, arbutin, acartinib, aletinib, alfentanil, alprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, bocatinib, epipiprazole, buntinib, buspirone, gefebukudze, caffeine, carbamazepine, carbolazine, carboplatin, and ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobratinib, cocaine, codeine, colchicine, copanil, crizotinib, cyclosporine, dabrafenib, dacarbazine, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, rituximab, dititaconil, ciclovir, and the like domperidone, doxepin, oxarogridone, elbavir/granzopivir, ibrutinib, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, glifebrile, haloperidol, hydrocortisone, ibrutinib, idazocine, indacavir, indinavir, irinotecan, isaconazole, ivabradine, lansoprazole, rivaroxazole, lercanidipine, lenvatica, lidocaine, linagliptin, lovastatin, macitentan, methadone, idazopranlde, nadimide, naloxonol, nateglinide, nelfinavir, lenatinib, nepitalopirox, prazocine, netizene, netide, ondaripipradon, nifedipine, nitrodipine, oxidazole, omeprazole, ondansamitraz, ondansetron, ospemifene, pamidronib, panobinostat, pantoprazole, pirenzpane, pimecrolin, pemirolazine, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, rebamiphene, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, topiramate, romidepsin, lu Suoti, salmeterol, saquinavir, celecoxib, sildenafil, semepivir, simvastatin, sirolimus, sonidegide sorafenib, sunitinib, suvorexant, tacrolimus (fk 506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, toliter, tramadol, trazodone, valphenazine, vandetanib, vitamin E, venlafaxine, verapamil, verazodone, vincristine, valvapamil, voriconazole, zaleplon and ziprasidone. See, e.g., flockhart DA, drug Interactions: cytocochrome P450 Drug Interaction Table [ drug interactions: cytochrome P450 drug interaction Table ]. Ind university of Indiana medical institute (2007), https:// drug-interactions.

In some embodiments, the patient is not administered a combination of a CYP3A4 substrate and sotoraciclovir, wherein the CYP3A4 substrate is a CYP3A4 substrate with a narrow therapeutic index. Exemplary CYP3A4 substrates with narrow therapeutic indices include, but are not limited to, alfentanil, fentanyl, cyclosporine, pimozide, dihydroergotamine, quinidine, ergotamine, sirolimus, everolimus, and tacrolimus.

In various embodiments, the patient is further in need of treatment with a P-glycoprotein (P-gp) substrate. In some embodiments, the patient is not administered a combination of P-gp substrate and sotoraciclovir. Exemplary P-gp substrates include, but are not limited to, dabigatran etexilate, digoxin, and fexofenadine. See, e.g., www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-subsystems-inhibitors-and-inhibitors, 2021, month 5 access. In some embodiments, the patient is not administered a combination of a P-gp substrate and sotoracicb, wherein the P-gp substrate is a P-gp substrate with a narrow therapeutic index. Exemplary P-gp substrates with narrow therapeutic indices include, but are not limited to, digoxin, everolimus, cyclosporine, sirolimus, tacrolimus, and vincristine. P-gp substrates with narrow therapeutic indices are compounds whose minimal concentration changes may result in severe toxicity.

In various embodiments, prior to administration of sotoprazole as disclosed herein, the patient has a composition determined to have one or more expression KRAS ^G12C Cancer of cells of the mutein. KRAS ^G12C The assay for muteins can be evaluated as described elsewhere in the disclosure.

Patients administered 240mg of sotoracicle in the methods disclosed herein may have been previously treated with systemic cancer therapies (e.g., at least one (e.g., one, two, or three) other systemic cancer therapies). In some embodiments, the patient administered the sotoprazole in the methods described herein has not been previously treated with systemic cancer therapy. In some embodiments, the patient has been previously treated with one other systemic cancer therapy, so that the sotoprazole therapy is a two-wire therapy. In some embodiments, the patient has been previously treated with two other systemic cancer therapies, so that the sotoprazole therapy is trilinear therapy.

In some embodiments, the prior systemic cancer therapy is with KRAS ^G12C Treatment with inhibitors. In some embodiments, the prior systemic cancer therapy is not an exerciseBy KRAS ^G12C Treatment with inhibitors. In certain embodiments, the patient exhibits a response to the use of KRAS ^G12C The sensitivity of the inhibitor therapy is reduced. In some embodiments, the patient pair uses KRAS ^G12C The inhibitor is resistant to therapy. In some embodiments, KRAS ^G12C The inhibitor is Sotolacca, adaglazeb, GDC-6036, D-1553, JDQ443, LY3537982, BI1823911, JAB-21822, RMC-6291 or APG-1842. In certain embodiments, KRAS ^G12C The inhibitor is sotoracicada. In certain embodiments, KRAS ^G12C The inhibitor is adaglazeb. In some embodiments, the therapy is monotherapy. In one embodiment, KRAS is used ^G12C The inhibitor therapy is sotoraciclovir monotherapy. In another embodiment, KRAS is used ^G12C The inhibitor therapy is monotherapy with adaglazeb.

As used herein, "sensitivity" refers to the manner in which a cancer responds to a drug (e.g., sotoraciclovir). In an exemplary aspect, "sensitivity" means "responsive to treatment" and the concepts of "sensitivity" and "responsiveness" are positively correlated in the following manner: cancers or tumors that are responsive to drug treatment are said to be sensitive to drugs. In an exemplary case, "sensitivity" is defined as the ability of a population, individual or tissue to respond to a particular drug dose in a qualitatively normal manner relative to other populations, individuals or tissues, according to Pelikan, edward, glossary of Terms and Symbols used in Pharmacology [ compilation of pharmacological terms and symbols ] (dictionary of expertise of the university of boston medical college pharmacological and experimental therapeutic). The smaller the dose required to produce an effect, the more sensitive the response system. "sensitivity" can be measured or quantitatively described in terms of the intersection between the dose-effect curve and the axis of the abscissa value or a line parallel thereto; such points correspond to the dosages just required to produce a given degree of effect. Similarly, the "sensitivity" of a measurement system is defined as the lowest input (minimum dose) required to produce a given degree of output (effect). In an exemplary aspect, "sensitivity" is opposite to "resistance" and the concept of "resistance" is inversely related to "sensitivity". For example, cancers that are resistant to drug treatment are neither sensitive nor responsive to such drugs or are no longer sensitive after they are initially sensitive to the drug but acquired resistance; for such tumors or cancer cells, such drugs are not or no longer effective treatments.

Previous systemic cancer therapies include, but are not limited to, chemotherapy and immunotherapy. Previous systemic cancer therapies of particular concern include anti-PD 1 therapies, anti-PDL 1 therapies, platinum-based chemotherapy, and anti-EGFR therapies. Some examples of anti-PD 1 therapies and anti-PDL 1 therapies include, but are not limited to, pembrolizumab, nivolumab, cimip Li Shan antibody (cemiplimab), tirelizumab (tisielizumab), terrappriab Li Shan antibody (toripalimab), aspartalizumab, dortarlizumab (dostarlimab), refafer Li Shan antibody (retifanlimab), similimab, pimelimumab (pimelizumab), atzolizumab (atezolizumab), avistuzumab (avelumab), and Devaluzumab (durvalumab). In some embodiments, the anti-PD 1 therapy or anti-PDL 1 therapy is baterimumab, bragg Li Shan antibody, cadonilimab, carlizumab, secuti Li Shan antibody, cimetidine Li Shan antibody, rituximab, ezabenlimab, finotonlimab, nivolumab, pe An Puli mab, pembrolizumab, putirimumab, refferon Li Shan antibody, rulonilimab, sare Li Shan antibody, si Lu Lishan antibody, singdi Li Shan antibody, swadazumab, teborlizumab, tirelimumab, terlipendrin Li Shan antibody, zeluvalimab (AMG 404), and sapalimumab. In certain embodiments, the anti-PD 1 therapy or antibody is a cimetidine Li Shan antibody, a rituximab, a pembrolizumab, or a nivolumab therapy. Some examples of anti-PDL 1 therapies or antibodies include, but are not limited to, alemtuzumab, ke Xili mab, dewaruzumab, en Wo Lishan mab, erfonrilimab, garivulimab, lodenduzumab, eucolimumab (Shu Geli mab, first gram of annotated mab, and tagitanlimab. In some embodiments, the anti-PDL 1 therapy or antibody is alemtuzumab, avermectin, or Devaluzumab. Some examples of platinum-based chemotherapy include, but are not limited to, carboplatin, Oxaliplatin, cisplatin, nedaplatin, satraplatin, lobaplatin, triplatin tetranitrate (triplatin tetranitrate), picoplatin, proLindac ^TM (AP 5346) and alloplatin (arostatin). Some examples of anti-EGFR therapies include, but are not limited to, cetuximab and panitumumab.

In some embodiments, if the cancer is identified as having an oncogenic driving mutation in the epidermal growth factor receptor gene (EGFR), the anaplastic lymphoma kinase gene (ALK), and/or ROS proto-oncogene 1 (ROS 1), the patient has previously been administered a systemic cancer therapy as a targeted therapy. Targeted therapies for EGFR mutations include, but are not limited to, cetuximab, panitumumab, erlotinib, gefitinib, and afatinib. Targeted therapies for ALK mutations include, but are not limited to, crizotinib, emtrictinib, loratidine, lopatinib, buganinib, ocatinib, altenib, ensartinib, and ceritinib. Targeted therapies for ROS1 mutations include, but are not limited to, crizotinib, emtrictinib, ensartinib, oxcritinib, buganidine, talatinib, cabotinib, lopatinib, loratidine, and ceritinib.

In various embodiments, the patient does not exhibit active brain metastases. In some embodiments, the patient does not exhibit brain metastasis within 4 weeks of initiation of the sotoprazole therapy as disclosed herein.

In various embodiments, the patient exhibits an eastern tumor collaboration group (ECOG) physical state of 0, 1, or 2 in the united states (see, e.g., zubrod et al, 1960). State 0 indicates fully active and is able to perform all activities before the disease without restriction. State 1 indicates that physical exertion is limited, but can be ambulatory and can be done in a mild or sedentary nature. State 2 indicates that the user can walk and is fully self-care but unable to perform any work activities; more than 50% of the waking time can get up and walk. State 3 indicates that only limited self-care can be performed, more than 50% of the awake time being bedridden or sitting still. State 4 indicates complete disability, failure to do any self-care, and complete restraint on a bed or chair. State 5 indicates death.

Dose modification scheme

Also provided herein are methods of treating cancer in a patient comprising administering to the patient a total initial daily dose of 960mg of sotoraciclovir, and when the patient experiences an adverse event of the total initial daily dose, administering a reduced total daily dose of 480mg of sotoraciclovir, wherein the cancer is a KRAS G12C mutant cancer. In some embodiments, the methods further comprise administering 240mg of the second reduced total daily dose of sotoracicada when the patient experiences adverse events of the reduced total daily dose.

The term "adverse event or (AE)" as used herein refers to any adverse and unexpected sign (including abnormal laboratory findings), symptom, or disease that is temporally related to the use of a medical treatment or procedure that may be considered to be related to the medical treatment or procedure.

In some embodiments, the adverse event is liver toxicity (e.g., elevated liver enzymes), diarrhea, and/or nausea/vomiting. In some embodiments, the adverse event is hepatotoxicity (e.g., elevated liver enzymes), interstitial lung disease/pneumonia, diarrhea, and/or nausea/vomiting.

Hepatotoxicity

In some embodiments, the adverse event is liver toxicity. The term "hepatotoxicity" as used herein refers to a patient having an abnormal laboratory value of a liver biomarker (e.g., alkaline phosphatase (ALP), aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), and/or Total Bilirubin (TBL)), when the patient has a non-abnormal laboratory value prior to administration of sotoraciclovir or a baseline level of one or more liver biomarkers below the level measured after administration of sotoraciclovir.

Alanine Aminotransferase (ALT), also known as serum glutamate pyruvate aminotransferase (SGPT) or alanine aminotransferase (ALAT), catalyzes the transfer of amino from alanine to alpha-ketoglutarate to produce pyruvate and glutamate. When the liver is damaged, ALT levels in the blood may rise due to leakage of ALT from damaged or necrotic hepatocytes into the blood.

Aspartate Aminotransferase (AST), also known as serum glutamic oxaloacetate aminotransferase (SGOT or GOT) or aspartate aminotransferase (ASAT), catalyzes the transfer of amino groups from aspartic acid to alpha-ketoglutarate to produce oxaloacetate and glutamate. AST may increase in response to liver injury. AST elevation may also be caused by injury from other sources including erythrocytes, cardiac muscle, skeletal muscle, kidney tissue and brain tissue. The ratio of AST to ALT can be used as a biomarker for liver injury.

Bilirubin is a catabolite of heme that is cleared from the body by the liver. Hepatocytes conjugate bilirubin with glucuronic acid to produce direct bilirubin, a water-soluble product that is readily cleared from the body. Indirect bilirubin is unconjugated and the sum of direct and indirect bilirubin constitutes total bilirubin. Elevated total bilirubin may indicate liver damage.

Alkaline phosphatase (ALP) hydrolyzes the phosphate groups of various molecules and is present in cells lining the bile duct of the liver. ALP levels in plasma may rise in response to liver injury and are higher in growing children and elderly patients with Paget's disease. However, elevated ALP levels generally reflect biliary tract disease.

In some embodiments, the patient does not have an disorder that results in elevated liver biomarkers. Disorders associated with elevated liver biomarkers (e.g., AST/ALT and/or TBL values) include, but are not limited to, liver and biliary tract diseases; viral hepatitis (e.g., hepatitis a/b/c/t/e, epstein barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right heart failure, hypotension or any cause of hypoxia leading to liver ischemia; exposure to hepatotoxic/pharmaceutical or hepatotoxic agents, including herbal and dietary supplements, plants and mushrooms; genetic disorders that result in impaired glucuronidation (e.g., gilbert syndrome, crigler-naltrexone syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-1 antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; wilson's disease and hemochromatosis; non-alcoholic fatty liver disease including steatohepatitis; and/or non-liver causes (e.g., rhabdomyolysis, hemolysis).

Prior to receiving sotorubin, the baseline liver function of the patient may be assessed by various means known in the art, such as blood chemistry tests measuring liver function biomarkers. In some embodiments, the methods described herein comprise monitoring liver biomarkers of a patient and suspending administration of sotorubin to a patient with liver dysfunction > grade 2 as assessed by AST and/or ALT levels. In such embodiments, administration of sotoraciclib is suspended until the patient's AST and/or ALT levels improve to grade 1 or better (baseline).

The adverse reaction grade of abnormal liver function is defined herein by the revised Common Toxicity Criteria (CTCs) provided in table 1. See U.S. national cancer institute adverse events common term standard v5.0 (NCI CTCAE), published by the U.S. national cancer institute at 2017, 11, 27, which is incorporated herein by reference in its entirety.

Table 1.

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper normal value; WNL = within normal limits

Grade 0 levels are characterized by biomarker levels Within Normal Limits (WNL). As used herein, "normal" liver function refers to adverse effect grade 0. As used herein, "abnormal" liver function refers to adverse reactions of grade 1 and above.

"grade 1 liver dysfunction" includes an ALT or AST elevation greater than ULN and less than or equal to 3 times ULN under normal baseline conditions; in the event of baseline abnormalities, 1.5-3.0 x baseline. Grade 1 liver dysfunction also includes elevated bilirubin levels greater than ULN and less than or equal to 1.5 times ULN under normal baseline conditions; in case of baseline abnormalities, >1.0-1.5x baseline. Grade 1 liver dysfunction also includes ALP elevation greater than ULN and less than or equal to 2.5 times ULN under normal baseline conditions; in case of baseline abnormalities, >2.0-2.5x baseline.

"grade 2 liver dysfunction" includes an ALT or AST elevation greater than 3 times the upper limit of normal value (ULN) and less than or equal to 5 times ULN in the case of normal baseline, and >3.0-5.0 baseline in the case of abnormal baseline. Grade 2 liver dysfunction also includes elevated bilirubin levels greater than 1.5 times ULN and less than or equal to 3 times ULN under normal baseline conditions; in case of baseline abnormalities, >1.5-3.0x baseline. Grade 2 liver dysfunction also includes ALP elevations of greater than 2.5 times ULN and less than or equal to 5 times ULN under normal baseline conditions; in case of baseline abnormalities, >2.5-5.0x baseline.

"grade 3 liver dysfunction" includes an ALT, AST, or ALP elevation greater than 5 times ULN and less than or equal to 20 times ULN under normal baseline conditions; in case of baseline abnormalities, >5.0-20.0x baseline. Grade 3 liver dysfunction also includes elevated bilirubin levels greater than 3 times ULN and less than or equal to 10 times ULN under normal baseline conditions; in case of baseline abnormalities, >3.0-10x baseline.

"grade 4 liver dysfunction" includes an ALT, AST or ALP elevation greater than 20 times ULN under normal baseline conditions; in case of baseline abnormalities, >20x baseline. Grade 4 liver dysfunction also includes an increase in bilirubin levels of greater than 10-fold of ULN under normal baseline conditions; in case of baseline abnormalities, >10.0x baseline.

ULNs for various indicators of liver function depend on the assay used, the patient population, and the normal range of values for each laboratory for a particular biomarker, but can be readily determined by a skilled practitioner. Exemplary values for the normal range of healthy adult populations are listed in table 2 below. See Cecil Textbook of Medicine [ Siser internal science ], pages 2317-2341, mulberry Co., USA (W.B. Saunders & Co.) (1985).

TABLE 2 upper normal value limit (ULN) value

In any of the methods described herein, the total daily dose of sotoracicada is reduced (e.g., from 960mg to 480mg, or from 480mg to 240 mg) when the patient's AST and/or ALT level is increased, e.g., to a grade 2 or grade 3 level, wherein the patient's baseline AST and/or ALT level is below a grade 2 or grade 3 level. In some embodiments, when the patient's AST and/or ALT level increases to a grade 1 level, wherein the patient's baseline AST and/or ALT level is below grade 1 level, the total daily dose of sotoraciclovir is reduced (e.g., from 960mg to 480mg, or from 480mg to 240 mg).

Alternatively, in any of the methods disclosed herein, the total daily dose of sotorubin is reduced (e.g., from 960mg to 480mg, or from 480mg to 240 mg) when (1) the patient's AST and bilirubin levels are increased, or (2) when the patient's AST or ALP levels are increased, or (3) when the patient's ALT and ALP levels are increased, or (4) when the patient's ALT and ALP levels are increased, or (5) when the patient's bilirubin and ALP levels are increased to, for example, a level 1, a level 2, a level 3, or a level 4, wherein the patient's baseline AST, bilirubin, ALP, and/or ALT levels are below a level 1, a level 2, a level 3, or a level 4, respectively. Alternatively, in any of the methods disclosed herein, three biomarkers of liver function (e.g., ALT and AST and bilirubin, or ALT and AST and ALP) of the patient may be elevated to a level of grade 1, grade 2, grade 3, or grade 4, wherein the patient's baseline biomarker level is below a level of grade 1, grade 2, grade 3, or grade 4, respectively.

In some embodiments, the total daily dose of sotoraciclovir is reduced (e.g., from 960mg to 480mg, or from 480mg to 240 mg) when the level of ALT and/or AST is greater than about 3-fold as compared to the upper limit of normal value (ULN). In related embodiments, the abnormal level of ALT and/or AST increases by a factor of greater than about 3 to about 5, i.e., a "grade 2 abnormality", as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient having an abnormal baseline, the level 2 abnormality is an increase in the abnormal level of ALT and/or AST from about 3 to about 5 fold over the baseline. In some embodiments, the abnormal level of ALP increases by a factor of greater than about 2.5 to about 5 times, i.e. "level 2 abnormality", as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient with an abnormal baseline, the level 2 abnormality is an increase in the abnormal level of ALP from about 2.5 to about 5 times greater than the baseline. In some embodiments, the abnormal level of bilirubin increases by a factor of greater than about 1.5 to about 3, i.e., "level 2 abnormality", as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient with an abnormal baseline, the level 2 abnormality is an increase in abnormal levels of bilirubin from about 1.5-fold to about 3-fold over the baseline.

In some embodiments, the total daily dose of sotoraciclovir is reduced (e.g., from 960mg to 480mg, or from 480mg to 240 mg) when the level of ALT and/or AST is greater than about 5 times the upper limit of normal value (ULN). In some embodiments, the total daily dose is reduced when the level of ALT, AST, or ALP increases by a factor of greater than about 5 to about 20, i.e., a "grade 3 abnormality" as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient having an abnormal baseline, the level 3 abnormality is an increase in the abnormal level of ALT and/or AST from about 5 to about 20 times as compared to the baseline. In some embodiments, the abnormal level of ALP increases by a factor of greater than about 5 to about 20, i.e., a "level 3 abnormality", as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient with an abnormal baseline, the grade 3 abnormality is an increase in the abnormal level of ALP from about 5 to about 20 times greater than baseline. In some embodiments, the total daily dose is reduced when the level of bilirubin increases by a factor of greater than about 3 to about 10, i.e., "grade 3 abnormality", as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient with an abnormal baseline, the level 3 abnormality is an increase in abnormal levels of bilirubin from about 3-fold to about 10-fold over the baseline.

In some embodiments, the total daily dose of sotoraciclovir is reduced (e.g., from 960mg to 480mg, or from 480mg to 240 mg) when the level of ALT and/or AST is greater than about 20-fold (i.e., "grade 4 abnormality") as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient having an abnormal baseline, the level 4 abnormality is an increase in the abnormal level of ALT and/or AST by a factor of greater than about 20 compared to the baseline. In some embodiments, the abnormal level of ALP increases by a factor of greater than about 20 compared to the upper limit of normal value (ULN), i.e. "level 4 abnormality". In some embodiments, in the case of a patient with an abnormal baseline, the level 4 abnormality is an increase in the abnormal level of ALP by a factor of greater than about 20 compared to the baseline. In some embodiments, the total daily dose is reduced when the level of bilirubin increases by more than about 10-fold, i.e., "level 4 abnormality", as compared to the upper limit of normal value (ULN). In some embodiments, in the case of a patient with an abnormal baseline, the level 4 abnormality is an increase in abnormal levels of bilirubin by a factor of greater than about 10 times compared to the baseline.

In some embodiments, the methods described herein further comprise increasing the total dose of sotoraciclovir (e.g., from 240mg to 480mg, or from 480mg to 960 mg) when one or more liver biomarkers of the patient have improved to grade 1 or better (e.g., baseline).

Nausea/vomiting

In some embodiments, the adverse event is nausea or vomiting. In some embodiments, nausea/vomiting is present despite proper supportive care (e.g., antiemetic therapy). As used herein, "nausea" refers to a disorder characterized by regurgitation and/or vomiting impulse.

Adverse reaction grades for nausea and vomiting are defined herein by revised Common Toxicity Criteria (CTCs) provided in table 3. See U.S. national cancer institute adverse events common term standard v5.0 (NCI CTCAE), published by the U.S. national cancer institute at 2017, 11, 27, which is incorporated herein by reference in its entirety.

Table 3.

In some embodiments, the methods described herein comprise suspending administration of sotoracicada in a patient suffering from > grade 3 nausea until the patient has improved to +.1 or baseline. In some embodiments, once the patient has improved to +.1 or baseline, the methods include administering a reduced total daily dose of sotoracicada to the patient (e.g., from 960mg to 480mg, or from 480mg to 240 mg).

In some embodiments, the methods described herein comprise suspending administration of sotoracicb in a patient with > grade 3 emesis until the emesis improves to +.1 or baseline. In some embodiments, once the patient has improved to +.1 or baseline, the methods include administering a reduced total daily dose of sotoracicada to the patient (e.g., from 960mg to 480mg, or from 480mg to 240 mg).

In some embodiments, the methods described herein further comprise increasing the total dose of sotoraciclovir (e.g., from 240mg to 480mg, or from 480mg to 960 mg) when the patient's nausea or vomiting has improved to grade 1 or better (e.g., baseline).

Diarrhea (diarrhea)

In some embodiments, the adverse event is diarrhea. In some embodiments, diarrhea is present despite proper supportive care (e.g., anti-diarrhea therapy).

Adverse reaction grade for diarrhea is defined herein by the revised Common Toxicity Criteria (CTCs) provided in table 4. See U.S. national cancer institute adverse events common term standard v5.0 (NCI CTCAE), published by the U.S. national cancer institute at 2017, 11, 27, which is incorporated herein by reference in its entirety.

Table 4.

In some embodiments, the methods described herein comprise suspending administration of sotoracicada in a patient suffering from > grade 3 diarrhea until the patient has improved to +.1 or baseline. In some embodiments, once the patient has improved to +.1 or baseline, the methods include administering a reduced total daily dose of sotoracicada to the patient (e.g., from 960mg to 480mg, or from 480mg to 240 mg).

In some embodiments, the methods described herein further comprise increasing the total dose of sotoraciclovir (e.g., from 240mg to 480mg, or from 480mg to 960 mg) when the patient's diarrhea has improved to grade 1 or better (e.g., baseline).

Response to sotoprazole therapy

After the patient has been subjected to 240mg of sotoprazole therapy for a suitable length of time, the responsiveness or outcome of the patient to whom the total daily dose of 240mg of sotoprazole is administered in the methods disclosed herein can be measured in a variety of ways. In various embodiments, a total daily dose of 240mg of sotoraciclovir is administered to a patient for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, or at least 23 months, such as 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 15 months, 18 months, 21 months, or 24 months. In various embodiments, a total daily dose of 240mg of sotoracicb is administered to the patient for at least 1 month. In various embodiments, the patient is administered a total daily dose of 240mg of sotoracicada for at least 3 months. In various embodiments, the patient is administered a total daily dose of 240mg of sotoracicada for at least 6 months.

As determined by RECIST 1.1 protocol, patients may respond to sotorubin therapy as measured by at least disease Stabilization (SD) (Eisenhauer et al 2009). At least disease stabilization is a stable disease that exhibits a Partial Response (PR) or a Complete Response (CR) (i.e., "at least SD" =sd+pr+cr, commonly referred to as disease control). In various embodiments, the disease stability is neither sufficiently reduced to conform to the Partial Response (PR) nor sufficiently increased to conform to the disease Progression (PD). In various embodiments, the patient exhibits at least a partial response (i.e., "at least PR" =pr+cr, commonly referred to as an objective response).

The response may be measured by one or more of the following: reduction in tumor size, inhibition or reduction of tumor growth, reduction in target or tumor lesions, delay in progression time, absence of new tumors or lesions, reduction in new tumor formation, increase in survival or Progression Free Survival (PFS), and absence of metastasis. In various embodiments, the progression of a patient's disease can be assessed by: measuring tumor size, tumor lesions, or formation of new tumors or lesions, the patient is assessed using a Computed Tomography (CT) scan, a Positron Emission Tomography (PET) scan, a Magnetic Resonance Imaging (MRI) scan, X-rays, ultrasound, or some combination thereof.

Progression free survival can be assessed as described in RECIST 1.1 protocol. In various embodiments, the patient exhibits PFS for at least 3 months. In some embodiments, the patient exhibits PFS for at least 6 months.

Additional methods for evaluating responses are described in detail in the examples below and may be generally applied to the methods disclosed herein.

KRAS G12C cancer

Without wishing to be bound by any particular theory, attention is paid to the following: sotorubin is a small molecule that specifically and irreversibly inhibits KRAS ^G12C (Hong et al 2020). Hong et al report "preclinical studies indicate that [ sotoracicb ]]Almost all detectable phosphorylation of extracellular signal-regulated kinase (ERK), which is a key downstream effector of KRAS, was inhibited, leading to persistent complete tumor regression in KRAS p.g12c tumor-bearing mice. "(see also Canon et al, 2019 and Lanman et al, 2020, supra). Thus, in various embodiments, a total daily dose of 240mg of sotoracicb is disclosed for use in treating cancer, wherein one or more cells express a KRAS G12C mutein.

Sotorubin was evaluated in phase 1 dose escalation and expansion experiments in which 129 subjects had a histologically confirmed, locally advanced or metastatic cancer with KRAS G12C mutations (identified by local molecular detection of tumor tissue), including 59 subjects with non-small cell lung cancer, 42 colorectal cancer subjects, and 28 subjects of other tumor types (Hong et al 2020, pages 1208-1209). Hong et al reported a disease control rate of non-small cell lung cancer (95% ci) of 88.1%, colorectal cancer of 73.8% and other tumor types of 75.0% (Hong et al 2020, page 1213, table 3). The types of cancers that show disease Stabilization (SD) or Partial Response (PR) as reported by Hong et al are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, unknown primary cancer, ampulla cancer, gastric cancer, small intestine cancer, sinus cancer, cholangiocarcinoma, or melanoma (Hong et al 2020, page 1212 (panel a) and supplementary appendixes (page 59 (S5) and page 63 (S6)).

The frequency of changes in KRAS G12C mutations is shown in the following table (Cerami et al 2012; gao et al 2013). For example, the table shows that 11.6% of non-small cell lung cancer subjects have cancer in which one or more cells express KRAS G12C muteins. Thus, specifically and irreversibly bind KRAS ^G12C Is useful for treating a subject having cancer, including but not limited to the cancers listed in table 5 below.

Table 5.

In various embodiments, the cancer is a solid tumor. In various embodiments, the cancer is non-small cell lung cancer, small intestine cancer, appendiceal cancer, colorectal cancer, unknown primary cancer, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasm, head and neck cancer, esophageal gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In some embodiments, the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasm, head and neck cancer, esophageal gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma. In various embodiments, the cancer is non-small cell lung cancer, and in some embodiments, metastatic or locally advanced and unresectable non-small cell lung cancer. In various embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer.

Method for detecting mutation status of KRAS, STK11, KEAP1 EGFR, ALK and/or ROS1

The presence or absence of G12C, STK, KEAP1, EGFR, ALK, and/or ROS1 mutations in cancers as described herein can be determined using methods known in the art. Determining whether a tumor or cancer comprises a mutation may be performed, for example, by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of a putative mutant protein or any other suitable method known in the art. The nucleotide and amino acid sequences of wild-type human KRAS (nucleotide sequence set forth in Genbank accession number BC 010502; amino acid sequence set forth in Genbank accession number AGC 09594), STK11 (Gene ID:6794; available at https:// www.ncbi.nlm.nih.gov/gene/6794; accessed at 1 st 2020), KEAP1 (Gene ID:9817; available at www.ncbi.nlm.nih.gov/gene/9817; accessed at 1 st 2020), EGFR (Gene ID:1956; available at www.ncbi.nlm.nih.gov/gene/1956; accessed at 3 rd 2021), ALK (Gene ID:238; available at htps:// www.ncbi.nlm.nih.gov/gene/238; accessed at 3 rd 2021), and ROS1 (Gene ID:6098; available at htps:// www.ncbi.nlm.nih.gov/gene/6098; accessed at 3 rd 2021) are known in the art.

Methods for detecting mutations include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct and/or next generation based sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, taqMan assays, SNP genotyping assays, high resolution melting assays, and microarray analysis. In some embodiments, the sample is assessed for mutations (e.g., KRAS G12C mutations) by real-time PCR. In real-time PCR, a fluorescent probe specific for a certain mutation (e.g., KRAS G12C mutation) is used. In the presence of the mutation, the probe binds and fluorescence is detected. In some embodiments, mutations are identified using direct sequencing methods of specific regions in the gene. This technique identifies all possible mutations in the sequenced region. In some embodiments, gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays may be used to detect the presence or absence of insertion mutations. In some embodiments, these methods include, but are not limited to, detection of mutants using binding agents (e.g., antibodies) specific for mutant proteins, protein electrophoresis and western blotting, and direct peptide sequencing.

In some embodiments, multiplex PCR-based sequencing is used for mutation detection and may include a number of amplicons that provide increased sensitivity for detection of one or more genetic biomarkers. For example, multiplex PCR-based sequencing can include about 60 amplicons (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 amplicons). In some embodiments, multiplex PCR-based sequencing may include 61 amplicons. Amplicons generated using multiplex PCR-based sequencing may include nucleic acids that are about 15bp to about 1000bp (e.g., about 25bp to about 1000bp, about 35bp to about 1000bp, about 50bp to about 1000bp, about 100bp to about 1000bp, about 250bp to about 1000bp, about 500bp to about 1000bp, about 750bp to about 1000bp, about 15bp to about 750bp, about 15bp to about 500bp, about 15bp to about 300bp, about 15bp to about 200bp, about 15bp to about 100bp, about 15bp to about 80bp, about 15bp to about 75bp, about 15bp to about 50bp, about 15bp to about 40bp, about 15bp to about 30bp, about 15bp to about 20bp, about 20bp to about 100bp, about 25bp to about 50bp, or about 30bp to about 40 bp) in length. For example, an amplicon generated using multiplex PCR-based sequencing may include a nucleic acid that is about 33bp in length.

In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using a sequencing technique (e.g., a next generation sequencing technique). A variety of sequencing techniques are known in the art. For example, methods of detecting and characterizing circulating tumor DNA in cell-free DNA can be described elsewhere (see, e.g., haber and Velculescu, 2014). Non-limiting examples of such techniques include SafeSeqs (see, e.g., kinde et al, 2011), onTarget (see, e.g., forshew et al, 2012), and TamSeq (see, e.g., thompson et al, 2012).

In some embodiments, the presence of one or more mutations in a sample obtained from a patient is detected using drop digital PCR (ddPCR), a method known to be highly sensitive to mutation detection. In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using other sequencing techniques, including but not limited to chain termination techniques, shotgun techniques, synthetic sequencing methods, methods utilizing microfluidics, other capture techniques, or any other sequencing technique known in the art that can be used to detect small amounts of DNA in a sample (e.g., ctDNA in a cell-free DNA sample).

In some embodiments, the presence of one or more mutations present in a sample obtained from a patient is detected using an array-based method. For example, a step of detecting a genetic alteration (e.g., one or more genetic alterations) in cell-free DNA is performed using a DNA microarray. In some embodiments, the DNA microarray can detect one or more of a variety of cancer cell mutations. In some embodiments, the cell-free DNA is amplified prior to detecting the genetic change. Non-limiting examples of array-based methods that can be used with any of the methods described herein include: complementary DNA (cDNA) microarrays (see, e.g., kumar et al 2012; laere et al 2009; mackay et al 2003; alizadeh et al 1996), oligonucleotide microarrays (see, e.g., kim et al 2006; lodes et al 2009), bacterial Artificial Chromosome (BAC) cloning chips (see, e.g., chung et al 2004; thomas et al 2005), single Nucleotide Polymorphism (SNP) microarrays (see, e.g., mao et al 2007; jasmine et al 2012), microarray-based comparative genomic hybridization arrays (array-CGH) (see, e.g., bees and Nederlof,2006; pinkel et al 2005; michels et al 2007), molecular Inversion Probe (MIP) assays (see, e.g., wang., 2012; lin et al 2010). In some embodiments, the cDNA microarray is an Affymetrix microarray (see, e.g., irizarry 2003; dalma-Weiszhausz et al 2006), a NimbleGen microarray (see, e.g., wei et al 2008; albert et al 2007), an Agilent microarray (see, e.g., hughes et al 2001), or a BeadArray array (see, e.g., liu et al 2017). In some embodiments, the oligonucleotide microarray is a DNA tiling array (see, e.g., mockler and Ecker,2005; bertone et al 2006). Other suitable array-based methods are known in the art

Methods for determining whether a tumor or cancer contains a mutation can use a variety of samples. In some embodiments, the sample is taken from a patient having a tumor or cancer. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a Formalin Fixed Paraffin Embedded (FFPE) sample. In some embodiments, the sample is a circulating cell-free DNA and/or Circulating Tumor Cell (CTC) sample. In some embodiments, the sample is treated to form a cell lysate. In some embodiments, the sample is processed into DNA or RNA. In certain embodiments, the sample is obtained by excision, hollow needle aspiration biopsy (CNB), fine Needle Aspiration (FNA), urine collection, or hair follicle collection. In some embodiments, a liquid biopsy test using whole blood or cerebrospinal fluid may be used to assess mutation status.

In various embodiments, a test approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA), is used to determine whether a patient has a mutation (e.g., KRAS) ^G12C Mutant cancers) or whether a tumor or tissue sample obtained from such a patient contains cells with mutations. In some embodiments, the test for KRAS mutations used is KRAS RGQ PCR kit (Qiagen).KRAS RGQ PCR the kit is a real-time quantitative PCR assay for detecting 7 somatic mutations in codons 12 and 13 of the human KRAS oncogene (G12A, G12D, G12R, G12C, G12S, G V and G13D) using a Rotor-Gene Q MDx 5plex HRM instrument. The kit is intended for DNA extracted from FFPE samples of NSCLC samples obtained from excision, CNB or FNA. STK11, KEAP1, EGFR, ALK and/or ROS1 mutation assays can be performed using commercially available assays, such as the resolution biological science company (Resolution Bioscience) resolution ctDx Lung (Resolution ctDx LungTM assay) assay comprising 24 genes, including those available in NSCLC. Tissue samples can be tested using the Tempus xT 648 set.

In some embodiments, the cancer has been identified as having a KRAS G12C mutation. In some embodiments, the cancer has been identified as having a mutation, e.g., a loss of function mutation, of STK11. In some embodiments, the cancer has been identified as having a mutation, e.g., a loss of function mutation, of KEAP1. In some embodiments, the cancer has been identified as having a wild-type STK11. In some embodiments, the cancer has been identified as having wild-type KEAP1.

In various embodiments, cancers have been identified as having a loss-of-function mutation of STK11 and wild-type KEAP1. In some embodiments, the cancer has been identified as having a loss-of-function mutation of STK11 and a loss-of-function mutation of KEAP1. In some embodiments, the cancer has been identified as wild-type and wild-type KEAP1 with STK 11. In some embodiments, the cancer has been identified as having a wild type for STK11 and a loss of function mutation for KEAP1.

The term "loss of function mutation" as used herein refers to a mutation (e.g., substitution, deletion, truncation, or frame shift mutation) that results in the expression of a mutant protein that no longer exhibits wild-type activity (e.g., reduced or eliminated wild-type biological or enzymatic activity), results in the expression of a protein fragment alone that no longer exhibits wild-type activity, or results in the non-expression of the wild-type protein. For example, a loss of function mutation affecting the STK11 gene in a cell may result in a loss of expression of the STK11 protein, a loss of expression of only a fragment of the STK11 protein, or a loss of expression of the STK11 protein that exhibits reduced or no enzymatic activity (e.g., no serine/threonine kinase enzyme activity) in a cancer cell. Similarly, loss of function mutations affecting the KEAP1 gene in a cell may result in loss of expression of the KEAP1 protein, loss of expression of only a KEAP1 protein fragment, or loss of expression of a KEAP1 protein that exhibits reduced or no activity, e.g., fails to interact with nuclear factor erythrocyte 2 associated factor 2 (NRF 2) or fails to activate nuclear factor erythrocyte 2 associated factor 2 (NRF 2).

Method for detecting expression of PDL1 protein

PDL1 expression can be determined by methods known in the art. For example, PDL1 expression can be detected using PDL1 IHC 22C3 pharmDx (developed by dactyl (Dako) and bezier's precious corporation (Bristol-Meyers Squibb)) as an accompanying test for therapy with pembrolizumab, an FDA-approved in vitro diagnostic Immunohistochemical (IHC) test. This is a qualitative assay using the EnVision FLEX visualization system on monoclonal mouse anti-PD-L1, clone 22c3 PDL1 and autostainer Lin 48 to detect PDL1 in FFPE samples (e.g., human non-small cell lung cancer tissue). Expression levels can be measured using a tumor ratio score (TPS) that measures the percentage of viable tumor cells that show partial or complete membrane staining at any intensity. Staining may show 0% to 100% PDL1 expression.

PDL1 expression can also be detected using PDL1 IHC 28-8pharmDx (an FDA approved in vitro diagnostic Immunohistochemistry (IHC) test developed by daceae and Merck, as a concomitant test for treatment with nivolumab). The qualitative assay used a monoclonal rabbit anti-PDL 1, clone 28-8, and an EnVision FLEX visualization system on an autostainer Lin 48 to detect PDL1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue.

Other commercially available tests for PDL1 detection include the Ventana SP263 assay (developed by pantanana (Ventana) in concert with the aslican company (AstraZeneca)) using monoclonal rabbit anti-PD-Ll, clone SP263 and the Ventana SP142 assay (developed by pantanana in concert with the gene tec/Roche company (Genentech/Roche)) using rabbit monoclonal anti-PDL 1 clone SP 142.

In some embodiments, the test is approved by a regulatory agency, such as the U.S. Food and Drug Administration (FDA), for PDL1TPS for determining cancer as disclosed herein. In various embodiments, PDL1TPS is determined using an Immunohistochemical (IHC) test. In some embodiments, the IHC test is a PDL1 IHC 22C3 pharmDx test. In various embodiments, IHC testing is performed using samples obtained by, for example, excision, CNB, or FNA.

In various embodiments, the patient has a PDL1TPS less than: 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In various embodiments, the patient has less than 50% or less than 1% PDL1TPS. In various embodiments, the patient has a PDL1TPS greater than or equal to: 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In various embodiments, the patient has a PDL1TPS less than or equal to: 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In various embodiments, the patient has less than or equal to 50%, or less than or equal to 1% PDL1TPS. In various embodiments, the patient has a PDL1TPS greater than: 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 50%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In various embodiments, the patient has a PDL1TPS score within a range defined by any of the values cited in the previous embodiments. For example, a patient has a PDL1TPS score in the following range: less than 50% and greater than or equal to 1%, less than or equal to 50% and greater than or equal to 1%, or less than 50% and greater than 1%.

In various embodiments, the patient has a PDL1 TPS score in the range of less than 50% and greater than or equal to 1%. In some embodiments, the patient has a PDL1 TPS score in the range of greater than or equal to 0% and less than 1%. In some embodiments, the patient has a PDL1 TPS score in the range of greater than 50% and less than or equal to 100%. In some embodiments, the patient has a PDL1 TPS score of less than 1%. In some embodiments, the patient has a PDL1 TPS score of 1% -49%. In some embodiments, the patient has a PDL1 TPS score of 50% or greater (i.e., 50% -100%).

Examples

1. A method of treating cancer in a patient comprising administering to the patient a total daily dose of 240mg of sotoracicb, wherein the cancer is a KRAS p G12C mutant cancer.

2. A method of treating cancer in a patient comprising administering to the patient a total initial daily dose of 960mg of sotoracicb, and when the patient experiences an adverse event of the total initial daily dose, administering a reduced total daily dose of 480mg of sotoracicb, wherein the cancer is a KRAS p G12C mutant cancer.

3. The method of embodiment 2, further comprising administering 240mg of a second reduced total daily dose of sotoracicada when the patient experiences adverse events of reduced total daily dose.

4. The method of embodiment 2 or 3, wherein the adverse event is an elevation of one or more liver enzymes in the patient, wherein the liver enzyme is alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST).

5. The method of example 4, wherein the elevated level of ALT and/or AST is >3xULN.

6. The method of any one of embodiments 2-5, further comprising suspending the treatment of the patient with sotoprazole until the patient's ALT and/or AST levels improve to grade 1 or baseline prior to administering the reduced total daily dose of sotoprazole or the second reduced total daily dose of sotoprazole.

7. The method of any one of embodiments 2-6, comprising stopping the sotoraciclovir treatment when AST or ALT levels >3x ULN and total bilirubin >2x ULN in the absence of an alternative cause.

8. The method of any one of embodiments 2-7, wherein the adverse event is diarrhea.

9. The method of embodiment 8, further comprising suspending the treatment of the patient with sotoprazole until the patient's diarrhea improves to grade 1 or baseline prior to administering the reduced total daily dose of sotoprazole or the second reduced total daily dose of sotoprazole.

10. The method of any one of embodiments 2-9, wherein the adverse event is nausea/vomiting.

11. The method of embodiment 10, further comprising suspending the treatment of the patient with sotoprazole until the patient's nausea/vomiting improves to grade 1 or baseline prior to administration of the reduced total daily dose of sotoprazole or the second reduced total daily dose of sotoprazole.

12. The method of any one of embodiments 1-11, wherein the sotoracicada is administered once daily.

13. The method of any one of embodiments 1-12, wherein the sotoracicada is administered orally.

14. The method of any one of embodiments 1-13, wherein the cancer is a solid tumor.

15. The method of any one of embodiments 1-14, wherein the cancer is non-small cell lung cancer.

16. The method of embodiment 15, wherein the cancer is metastatic non-small cell lung cancer.

17. The method of embodiment 16, wherein the cancer is locally advanced and unresectable.

18. The method of any one of embodiments 1-13, wherein the cancer is colorectal cancer.

19. The method of any one of embodiments 1-13, wherein the cancer is pancreatic cancer.

20. The method of any one of embodiments 1-13, wherein the cancer is small intestine cancer, appendix cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasm, head and neck cancer, esophageal gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

21. The method of any one of embodiments 1-20, wherein the patient has undergone at least one other systemic cancer therapy prior to initiation of sotoprazole therapy.

22. The method of embodiment 21, wherein the patient has undergone at least two other systemic cancer therapies.

23. The method of embodiment 21 or 22, wherein at least one systemic cancer therapy is selected from the group consisting of anti-PD 1 immunotherapy, anti-PDL 1 immunotherapy, and platinum-based chemotherapy.

24. The method of example 23, wherein the patient has previously undergone (i) anti-PD 1 therapy or anti-PDL 1 therapy unless contraindicated, or (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS 1.

25. The method of example 23, wherein the patient has previously undergone (i) anti-PD 1 therapy or anti-PDL 1 therapy unless contraindicated, and (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS 1.

26. The method of any one of embodiments 1-25, wherein the patient has no brain metastasis within four weeks of initiating sotoraciclovir therapy.

27. The method of any one of embodiments 1-26, wherein the patient exhibits an eastern tumor collaboration group (ECOG) physical status of 0, 1, or 2.

28. The method of any one of embodiments 1-27, wherein the patient is administered sotoracicada for at least one month.

29. The method of any one of embodiments 1-27, wherein the patient is administered sotoracicada for at least three months.

30. The method of any one of embodiments 1-27, wherein the patient is administered sotoracicada for at least six months.

31. The method of any one of embodiments 28-30, wherein the patient exhibits at least disease Stabilization (SD) after 1, 3, or 6 months of sotoraciclovir therapy as measured by RECIST 1.1 regimen.

32. The method of embodiment 31, wherein the disease stability is neither sufficiently reduced to conform to Partial Response (PR) nor sufficiently increased to conform to disease Progression (PD).

33. The method of any one of embodiments 28-31, wherein the patient exhibits at least a Partial Response (PR) after 1, 3, or 6 months of sotoraciclovir therapy as measured by RECIST 1.1 regimen.

34. The method of embodiment 33, wherein the partial response is at least a 30% reduction in the sum of target lesion diameters.

35. The method of any one of embodiments 1-34, wherein the patient exhibits a Progression Free Survival (PFS) of at least 3 months.

36. The method of embodiment 35, wherein the patient exhibits PFS for at least 6 months.

37. The method of any one of embodiments 1-36, wherein the cancer exhibits a PDL1 tumor ratio score (TPS) of 1% -49%.

38. The method of any one of embodiments 1-36, wherein the cancer exhibits a PDL1 tumor ratio score (TPS) of less than 1%.

39. The method of any one of embodiments 1-36, wherein the cancer exhibits a PDL1 tumor ratio score (TPS) of 50% -100%.

40. The method of any one of embodiments 1-39, wherein the cancer further comprises a STK11 mutation.

41. The method of any one of embodiments 1-40, wherein the cancer further comprises a KEAP1 mutation.

42. The method of any one of embodiments 1-39 and 41, wherein the cancer further comprises STK11 wild-type.

43. The method of any one of embodiments 1-40 and 42, wherein the cancer further comprises KEAP1 wild type.

44. The method of any one of embodiments 1-43, wherein the patient exhibits liver toxicity and the method further comprises administering a steroid to the patient.

45. The method of example 44, wherein the steroid is prednisone at a dose of 0.25 to 1.0 mg/kg/day.

46. The method of any one of embodiments 1-45, wherein the patient is further in need of treatment with an acid reducing agent.

47. The method of embodiment 46, wherein the acid reducing agent is a Proton Pump Inhibitor (PPI), an H2 receptor antagonist (H2 RA), or a topically acting antacid.

48. The method of example 46 or example 47, wherein the topical antacid is administered about 4 hours before or about 10 hours after the topical antacid if the patient further requires treatment with an acid reducing agent.

49. The method of any of embodiments 46-48, wherein the topically acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide.

50. The method of any one of embodiments 1-45, wherein the patient is further in need of treatment with a Proton Pump Inhibitor (PPI) or an H2 receptor antagonist (H2 RA).

51. The method of embodiment 47, wherein the patient is not administered PPI or a combination of H2RA and sotoprazole.

52. The method of any one of embodiments 47 or 50-51, wherein the PPI is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole or dexlansoprazole.

53. The method of any one of embodiments 47 or 50-51, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine.

54. The method of any one of embodiments 1-53, wherein the patient is further in need of treatment with a CYP3A4 inducer.

55. The method of example 54, wherein the patient is not administered a combination of a CYP3A4 inducer and sotoracicmide.

56. The method of example 54 or 55, wherein the CYP3A4 inducer is barbiturates, buganib, carbamazepine, clobazam, dabrafenib, efavirenz, oxagolide, enzalutamide, eslicarbazepine, glucocorticoids, letrovir, lalatinib, modafinil, nevirapine, olanzapine, oxcarbazepine, pirapamide, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, tetroxat, and traglione.

57. The method of example 54, wherein the patient is not administered a combination of a strong CYP3A4 inducer and sotoraciclovir.

58. The method of example 57, wherein the strong CYP3A4 inducer is phenytoin or rifampin.

59. The method of any one of embodiments 1-58, wherein the patient is further in need of treatment with a CYP3A4 substrate.

60. The method of example 59, wherein the patient is not administered a combination of a CYP3A4 substrate and sotoracicb.

61. The method of example 59 or 60, wherein the CYP3A4 substrate is Abeli, abiraterone, alcalitinib, alatinib, alfentanil, apprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, acitenib, boceprevir, boscalid, eppiprazole, buntinib, buspirone, gatifuge, caffeine, carbamazepine, carilazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobratinib, cocaine, codeine, colchicine, copanil, crizotinib, cyclosporine, dabrafenib, dacarbazine, daphne, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, pharmaceutical compositions Duolavir, domperidone, doxepin, oxaprozin, ebavir/Grazopicvir, ibrutin, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, glifevidone, haloperidol, hydrocortisone, ibrutinib, edaltefrail, indacavir, irinotecan, esaconazole, ivabradine, ivaccatol, lansoprazole, lenvatipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, idazoprazol, nadimedes, duloxetine, nateglinide, nefinasteride, lenetanervone, pranopirudine, virapigenin, nifedipine, nivomide, oxideside, olanil, prazoprazode, ondansetron, octenib, ospemifene, pamycini, panobinostat, pantoprazole, pirenzeneb, pimavanserin, pemaline, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, rebamipinib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, zolpidem, romidepsin, lu Suoti, salmeterol, saquinavir, celecoxib, sildenafil, semepivir, simvastatin, sirolimus Sonid, sorafenib, sunitinib, suvorexant, tacrolimus (fk 506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, toliter, tramadol, trazodone, valphenazine, vandetanib, vitamin A, venlafaxine, verapamil, verazodone, vincristine, valvapamil, voriconazole, zaleplon and ziprasidone.

62. The method of any one of embodiments 1-61, wherein the patient is further in need of treatment with a P-glycoprotein (P-gp) substrate.

63. The method of example 62, wherein the patient is not administered a combination of P-gp substrate and sotoracicb.

64. The method of example 57 or example 58, wherein the P-gp substrate is dabigatran etexilate, digoxin, and fexofenadine.

Examples 1-960mg, 360mg, 180mg and 240mg pharmacokinetic analysis of sotoprazole

Preliminary Pharmacokinetic (PK) data for subjects with advanced solid tumors with specific KRAS p.g12c mutations are available, with doses ranging from 180 to 960mg PO QD. A relevant increase in exposure from 180 to 960mg PO QD dose was observed on day 1. On day 1, the increase in exposure was less than the dose ratio. There was no accumulation of multiple PO QD dosing within 8 days. On day 8, exposure changes from 180 to 960mg PO QDs were less than dose ratio. Rapid absorption of tmax was observed 1 to 2 hours after PO administration. Figure 1 shows the mean plasma concentration time profile after oral administration of 180, 360, 720 or 960mg of sotoracicmide on day 1. Fig. 2 shows the concentration after once daily dosing within 8 days (day 8). The following table provides pharmacokinetic parameters, where AUC _0-24h Is the area under the concentration-time curve from 0 to 24 hours after administration; c (C) _max Is the maximum drug concentration observed during the dosing interval; t is t _1/2,z Is the terminal elimination half-life; t is t _max Is up to C _max Is a time of (a) to be used. Reported data are expressed as geometric mean (arithmetic CV%), t _max And t _1/2 Except for that, they are reported as median (range) and arithmetic mean (SD), respectively. Numerical values are reported as three significant digits, CV% and t _max Except that they are reported as 0-bit decimal and 2-bit significant digits, respectively.

Table 6.

^a N＝5； ^b N＝6； ^c N＝17； ^d N＝19； ^e N＝8； ^f N＝9； ^g N＝18； ^h N＝24； ⁱ N＝16；

Examples 2-180mg, 360mg and 720mg QD efficacy in non-small cell lung cancer

To a patient diagnosed with non-small cell lung cancer or other solid tumor and identified as having KRAS ^G12C The mutated patients were orally administered 180mg, 360mg, 720mg and 960mg QD sotoracicada. Responses were observed at all dose levels studied (Hong et al, 2020). The box line plot of optimal tumor reduction for NSCLC patients given 180mg QD, 360mg QD, 720mg QD, and 960mg QD is shown in fig. 3.

Among 24 NSCLC patients that could be evaluated and treated at doses of 180mg, 360mg or 720mg, a response was observed in 8 patients (ORR 33.3%). Among 34 NSCLC patients treated with 960mg, a response (ORR of 35.5%) was observed in 12 subjects. In a phase 2 study of sotoracib 960mg QD, the ORR of NSCLC (n=124) was 37.1%.

The objective response of NSCLC patients is shown in table 7 below:

table 7.

Month is expressed in days x (12/365.25).

^a The exact 95% confidence interval was calculated using the Clopper Pearson method.

^b The response occurrence time and the response duration are calculated in the confirmed responder N1.

Examples 3-960mg QD and 240mg QD dose comparison study

Under the study conditions of study 20170543 (CodeBreak 100), 960mg QD's sotoracicb proved to be safe and effective. However, sotoprazole exhibits a non-linear pharmacokinetic profile in humans, with responses observed at all dose levels ranging from 180mg to 960 mg. Based on the observed pharmacokinetic profile discussed in example 1, the 240mg QD dose is expected to approximate exposure at lower doses of 180mg or 360mg QDs. Drug exposure at the 240mg QD dose was expected to be similar to the 960mg QD dose, and the 240mg QD dose was expected to be higher than the concentration associated with 90% inhibition in the in vitro 2 hour cellular pERK assay (see, e.g., hong et al 2020, supplement appendix, figure S3).

A multicenter, randomized, open-label study was established to assess the safety and efficacy of sotoprazole as monotherapy in subjects previously treated locally advanced and unresectable or metastatic KRAS G12C mutant advanced NSCLC. Approximately 200 subjects were enrolled and received either 960mg QD or 240mg QD of sotoracicb at 1:1 randomization. Tumor response was assessed using RECIST 1.1 based on contrast-enhanced CT/MRI, with assessment performed by a separate radiology center laboratory. The subject continues treatment until disease progression, treatment intolerance results in cessation of treatment, initiation of another anti-cancer therapy, or withdrawal of consent. The scan of the subject underwent independent central confirmation of progression (COP) upon first disease Progression (PD). After focused confirmation of progression, both groups of subjects may choose to continue with the sotope therapy at their current dose if tolerability is available and the investigator considers that no reasonable alternative treatment options are available. Subjects undergoing post-progression treatment continue to receive scans after confirmation of the first PD.

Subject inclusion criteria included the following:

the subject had provided informed consent before any study-specific activities/procedures began

Men or women at least 18 years old.

A pathologically proven, locally advanced or metastatic malignancy having a KRAS G12C mutation identified by molecular testing.

For NSCLC: if actionable oncogenic driving mutations (i.e., EGFR, ALK, and ROS 1) are identified, the subject must have progressed after receiving anti-PD 1 or anti-PDL 1 immunotherapy (unless contraindicated) and/or platinum-based combination chemotherapy and targeted therapies.

For all NSCLC subjects, the following guidelines should be used: (1) If the subject has progressed at or within 6 months of the adjuvant therapy administration, the adjuvant therapy is counted as 1 treatment normal. (2) In locally advanced and unresectable NSCLC, disease progression at or within 6 months of the end of multimode therapy for previous cure purposes was counted as 1 treatment normal. If there is no recorded progress between chemo-radiation and systemic therapy following planned systemic therapy, the overall treatment course is counted as 1 treatment normal. (3) Maintenance therapy after platinum-based duplex chemotherapy is not considered a separate therapy line.

For CRC: the subject must progress after receiving fluoropyrimidine and oxaliplatin and irinotecan. For those CRC subjects with MSI-H tumors, if they are clinically able to receive inhibitors, and 1 of these agents is approved for this indication in that region or country, at least 1 of the previous systemic regimens must include anti-PD 1 therapy.

For advanced solid tumor types other than NSCLC or CRC, the subject must have received at least 1 previous systemic therapy that is intolerant or that does not conform to available therapies known to provide clinical benefit. Subjects with advanced solid tumor types other than NSCLC or CRC can be recruited and treated at stage 1 or stage 2 without central confirmation of KRAS p.g12c mutation.

Subjects were willing to provide archived tumor tissue samples (formalin-fixed, paraffin-embedded [ FFPE ] samples collected over 5 years) or to undergo pretreatment tumor biopsies. If tumor biopsy is not feasible, subjects with tumor types other than NSCLC or CRC without available archived tissue and with KRAS p.g12c mutations previously molecular confirmed may be allowed to be recruited without undergoing tumor biopsy after agreement with the investigator and medical supervisor.

Subjects with biopsieable lesions will be required to undergo an optional biopsy as the tumor progresses.

Diseases measurable according to RECIST 1.1 criteria.

The state of physical performance of the eastern tumor cooperative group (ECOG) in the United states is less than or equal to 2.

Adequate kidney laboratory assessment was as follows: based on MDRD (diet adjustment for renal disease) calculation, the estimated glomerular filtration rate is not less than 45ml/min/1.73m ² 。

Exclusion criteria included the following:

active brain metastases from non-brain tumors. Subjects who had resected brain metastases prior to study day 1 or who had received radiation therapy ending for at least 4 weeks were eligible if the subjects met all of the following criteria: a) The grade of the residual neurological symptoms is less than or equal to 2; b) A steady dose of dexamethasone (if applicable) is being received; and c) follow-up MRI performed within 30 days showed no new lesions to appear.

History of hematological malignancy or presence of hematological malignancy, unless there is no evidence of disease, curative treatment is no less than 2 years.

Myocardial infarction (within 6 months from study day 1), symptomatic congestive heart failure (new york heart association > grade II), unstable angina, or cardiac arrhythmias requiring drug therapy.

Resulting in Gastrointestinal (GI) tract diseases that cannot be orally administered, malabsorption syndrome, inflammatory GI diseases that require intravenous high energy nutrition that are uncontrolled (e.g., crohn's disease, ulcerative colitis).

Active infection requires IV antibiotics within 1 week of study enrollment (day 1).

Hepatitis virus infection is excluded based on the following results and/or criteria: hepatitis b surface antigen (HepBsAg) positive (indicative of chronic hepatitis b or recent acute hepatitis b); negative HepBsAg positive for hepatitis b core antibody (hepatitis b core antibody test is not required for screening, however if the test is performed and positive, hepatitis b surface antibody [ anti-HB ] test is required). Failure to detect anti-HB in this case would indicate that the infection is ambiguous and likely, and need to be excluded; hepatitis c virus antibody positive: PCR of hepatitis C virus RNA is necessary. The detectable hepatitis C virus RNA indicates chronic hepatitis C.

Known HIV positive tests.

Non-regressive toxicity of prior anti-tumor therapies, defined as having not regressed to grade 0 or grade 1 in the adverse event common term standard (CTCAE) version 5.0, or having not regressed to a level specified in the qualifying standard (except for alopecia) (if the exclusion standard is not otherwise described for toxicity and both the investigator and the sponsor agree to permit, then grade 2 or grade 3 toxicity (such as ifosfamide-related proteinuria) that was considered irreversible [ defined as having been present and stable for >6 months ] in prior anti-tumor therapies) may be permitted.

Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [ subjects with breast cancer excluded ] or study agents) within 28 days from study day 1; allowing the concurrent use of hormone deprivation therapy for hormone refractory prostate or breast cancer.

Therapeutic or palliative radiation therapy within 2 weeks from day 1 was studied. The subject must recover from all radiation therapy-related toxicities.

Another research device or drug study has been engaged in or less than 28 days from the end of another research device or drug study or receipt of other study drug or drugs. Except for the following cases: subjects who have participated in another study device or long-term follow-up portion of the drug study, but did not employ the corresponding study drug or device.

Other study procedures were excluded.

Large surgery within 28 days from study day 1.

Monotherapy using AMG 510: men and women with fertility (WOCBP) who are reluctant to perform an acceptable method of birth control during treatment and at least 7 days (women) or 7 days (men) after receiving the last dose of AMG 510. For females, acceptable effective methods of birth control include sexual abstinence (avoidance of anisotropic intercourse); vasectomy (women with a single male sexual partner), tests indicate that semen is devoid of sperm; ligature or occlusion of bilateral fallopian tubes; or an intrauterine device. For men, acceptable methods of birth control include sexual abstinence (avoidance of anisotropic intercourse); vasectomy, testing showed no sperm in semen; ligature or block the parietal oviduct; or a condom (the way in which a female partner should also consider birth control). And (3) injection: women are considered to have fertility (WOCBP), i.e. to be able to give birth after menstrual beginner until it becomes postmenopausal, unless permanently sterile. Permanent sterilization procedures include hysterectomy, bilateral tubectomy, and bilateral ovariectomy. Postmenopausal status is defined as no menstruation for 12 months, no alternative medical reasons. High follicle stimulating hormone levels in the postmenopausal range can be used to confirm postmenopausal status in women who do not use hormonal contraception or hormone replacement therapy. However, in the absence of 12 month amenorrhea, a single follicle stimulating hormone measurement was insufficient.

Women who are lactating/nursing or are scheduled to nursing during the study until 7 days after receiving the last dose of study medication.

Women who are positive for pregnancy test.

Pregnant women were planned during the study period until 7 days after receiving the last dose of study medication.

The subject has known sensitivity to any product to be administered during the administration period.

With the best knowledge of the subject and the researcher, the subject will not be available for study visits or procedures for which the regimen is required.

In the view of the investigator, the subject suffers from any type of disorder that may have compromised the subject's ability to write informed consent and/or to follow all required study procedures.

A medical history or evidence of any other clinically significant disorder, condition or disease (except those outlined above) that would appear to a researcher or corporate doctor to pose a risk to subject safety or interfere with research evaluation, procedure or completion.

The known P-gp sensitive substrate (with a therapeutic window) was used before study day 1, within 14 days or 5 half-lives (whichever is longer) of the drug or its primary active metabolite, without review and approval by the primary investigator.

Proton Pump Inhibitors (PPIs) of H2 receptor antagonists were used within 14 days or 5 half-lives (based on the longer) of the drug or its primary active metabolite prior to study day 1, without review and approval by the primary investigator.

The known cytochrome P450 (CYP) 3A4 sensitive substrate (with a narrow therapeutic window) was used before study day 1, within 14 days or 5 half-lives (whichever is longer) of the drug or its primary active metabolite, without review and approval by the primary investigator and the corporate medical supervisor.

The use of strong inducers of CYP3A4 (including herbal supplements such as san jose grass) was not reviewed and approved by major researchers and corporate medical supervisors within 14 days or 5 half-lives (whichever is longer) prior to study day 1.

History of other malignancies over the last 2 years, with the following exceptions: malignant tumors treated for curative purposes and for which no known active disease exists for > 2 years prior to recruitment, and the risk of recurrence is considered low by the treating physician; no evidence of disease, fully treated non-melanoma skin cancer or malignant nevus of small mole; no evidence of disease, fully treated cervical carcinoma in situ; no evidence of disease, fully treated ductal carcinoma in situ; prostate intraepithelial neoplasia without evidence of prostate cancer; fully treated papillary non-invasive carcinoma or carcinoma in situ of the urothelium.

Previous use of direct KRAS ^G12C Inhibitor treatment.

Randomization of subjects

After meeting all recruitment requirements, subjects were randomly assigned to either grotroxib 960mg QD or 240mg QD at a partition ratio of 1:1 in an open label fashion. Randomization is stratified by the number of previous normals to metastatic disease (1 to 2 or > 2), history of CNS metastasis (yes or no), performance status (< 2 or 2), and race (asian versus non-asian).

Dosage and administration

Sotolacca is administered orally once daily. No drug holidays are allowed. The subject should take a dose of sotoraciclovir with or without food at about the same time per day (all tablets taken simultaneously). The dose should be taken within a 2 hour window of the predetermined time. If emesis occurs within 15 minutes of administration, all tablets administered have been counted (e.g., 4 tablets must be collected if 4 tablets are administered), and are intact (uncracked, partially dissolved, chewed or crushed) by visual inspection, one dose of sotoracle can be replaced in the event of emesis. If 6 hours have elapsed since the scheduled dosing time, the subject should skip the sotoracicada dose.

Dose interruption

Subjects randomly assigned to the 960mg QD group were allowed to reach 2 dose interruptions, followed by dose reduction to 480mg QD (1 dose lower) or 240mg QD (2 doses lower), as summarized in table 8 below. Subjects who need to drop the dose below 240mg should permanently stop treatment, as the 240mg QD dose is most likely to be near the exposure at the lower dose with the observed clinical response. Subjects randomly assigned to the 240mg QD group allowed 2 dose interruptions to be reached, but if deemed medically safe and appropriate according to the opinion of the investigator, the dose was not reduced upon reuse of sotoracicada. Subjects in the 960mg QD group who need to have more than 2 doses reduced due to toxicity management associated with sotoracicb, and subjects in the 240mg QD group who need to have more than 2 doses discontinued due to toxicity management associated with sotoracicb should permanently discontinue treatment.

Table 8.

^* For subjects in the 240mg QD group, the subjects were allowed to resume dosing without a decrease in dose level for toxicity

^a For utensilSubjects with hepatotoxicity, see below

Guidelines for hepatotoxicity of sotoracicb: guidelines for management and monitoring of AST, ALT or alkaline phosphatase (ALP) increased subjects are presented in table 9 below.

Table 9.

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = adverse event generic term criteria; INR = international normalized ratio; LFT = liver function test; TBL = total bilirubin; ULN = upper normal value limit ^a If an increase in AST/ALT may be associated with an alternative drug, the pathogenic drug is stopped and the Soto is reused after waiting to revert to baseline or grade 1.

^b For example: prednisone 0.25 to 1.0 mg/kg/day or equivalent dose followed by a gradual decrement.

^c Close monitoring at restart (e.g., daily LFT x 2, then weekly x 4). The sotoracicmide dose may be increased after discussion with the medical supervisor.

^d There is no limit to the number of times that sotorubin is re-excited with respect to the alkaline phosphatase alone rise to return to baseline or grade 1.

^e Dose reduction below 240mg is not allowed. The subject may restart at the same dose without dose reduction.

Hepatotoxic response: subjects with abnormal liver laboratory values (i.e., alkaline phosphatase (ALP), aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), total Bilirubin (TBL)) and/or International Normalized Ratio (INR) and/or signs/symptoms of hepatitis (described below) may meet the criteria for halting or permanently halting sottorsemib.

The following shutdown and/or suspension rules apply to subjects who have not yet been identified for other reasons of liver biomarker (TBL, INR, and transaminase) changes. Important alternative reasons for elevated AST/ALT and/or TBL values include, but are not limited to: liver and gall tract diseases; viral hepatitis (e.g., hepatitis a/b/c/t/e, epstein barr virus, cytomegalovirus, herpes simplex virus, varicella, toxoplasmosis, and parvovirus); right heart failure, hypotension or any cause of hypoxia leading to liver ischemia; exposure to hepatotoxic/pharmaceutical or hepatotoxic agents, including herbal and dietary supplements, plants and mushrooms; genetic disorders that result in impaired glucuronidation (e.g., gilbert syndrome, crigler-naltrexone syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, atazanavir); alpha-1 antitrypsin deficiency; alcoholic hepatitis; autoimmune hepatitis; wilson's disease and hemochromatosis; non-alcoholic fatty liver disease including steatohepatitis; and/or non-liver causes (e.g., rhabdomyolysis, hemolysis).

As described in table 10 below, re-excitation may be considered if an alternative cause of impaired liver testing (ALT, AST, ALP) and/or TBL elevation and/or a return of laboratory abnormalities to normal or baseline is found.

Table 10.

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; TBL = total bilirubin; ULN = upper normal value limit

Radiological imaging assessment

The extent of disease was assessed by contrast-enhanced MRI/CT according to RECIST 1.1, as follows. In order to reduce the radiation exposure of the subject, a low dose CT should be used as much as possible.

Screening scans must be performed within 28 days prior to recruitment and used as a baseline. All subsequent scans are performed in the same manner as in the screening with the same contrast, preferably on the same scanner. Radiological assessment must include MRI/CT of chest, abdomen and pelvis, as well as assessment of all other known disease sites. If signs or symptoms occur that indicate central nervous system metastasis, magnetic Resonance Imaging (MRI) of the brain should be performed.

The same imaging modality, MRI field strength, and intravenous and oral contrast agents that should be used at the time of screening should be used for all subsequent evaluations. Liver-specific MRI contrast agents should not be used. To reduce potential safety issues, according to the national institutes of health guidelines, it is recommended to use macrocyclic gadolinium contrast agents or, in more stringent cases, to follow local standards.

During treatment and follow-up, radiological imaging of the chest, abdomen, pelvis, and all other known disease sites was performed every 6±1 weeks independently of the treatment cycle for the first 8 response assessments, with the first post-baseline scan occurring 6±1 weeks after C1D 1. Radiological imaging and tumor assessment were performed every 12±1 weeks after eight 6 week response assessments. Radiological imaging and tumor assessment are performed until disease progression or end of study product, whichever is later. Imaging may also be performed more frequently, as determined by the attending physician, if clinically desired. Radiographic responses (full response, partial response) require confirmation by repeated scans at least 4 weeks after the first recording of the response, and may be delayed until the next scheduled scan to avoid unnecessary procedures. The minimum time interval for confirming the stabilization of the disease is more than or equal to 5 weeks.

All subjects with brain metastases must undergo brain MRI within 28 days prior to the first dose of AMG 510. Subsequently, if the attending physician determines that there is a clinical indication, a brain scan may be performed at any time. All brain scans in the protocol require MRI unless MRI is contraindicated, then CT plus contrast is acceptable.

According to RECIST 1.1 guidelines, radiological imaging assessment during EOT visits is only applicable to subjects who have stopped treatment for reasons other than disease progression.

Disease response assays for clinical management of subjects were evaluated at the clinical center according to RECIST 1.1.

Independent central validation of progress (COP)

When the researcher identifies radiographic progress from RECIST v1.1, the current imaging plus all images so far must be sent immediately to a central imaging provider. Once any critical issues are resolved, the central imaging provider will execute an independent COP and will provide a second independent opinion to the research center and sponsor as to whether the participants have reached disease progression according to RECIST v 1.1. This is performed by a single radiologist of the central radiologist group independent of the reading of the images to understand the efficacy. The results of the independent COPs are not discussed with the central efficacy inspector and therefore will not affect the determination of response or progress by the central efficacy inspector. The independent COP is only used to provide a second opinion to the field PI as to whether there is disease progression at the current point in time according to RECIST v1.1 and no discussion of clinical subject data is required.

If the assessment of radiological disease progression via the central imaging provider does not confirm disease progression at that point in time, the central imaging provider may organize a conference held between individual radiologists and live radiologists to review the images of the participants for determining confirmation of radiological disease progression. The on-site PI makes final treatment and subject management decisions.

The progression of the radiological disease should be intensively verified before stopping the study drug, performing a local intervention, starting a new anticancer therapy or after-progression treatment. If there are no safety issues and the study participants are clinically stable, the participants should continue to take study medication while continuing to centrally confirm that progress is underway until confirmation of radiological disease progression is completed.

Testing for KRAS G12C, PD1 and various mutations

From QIAGENKRAS RGQ PCR kit is a real-time quantitative PCR assay performed on a Rotor-Gene Q MDx instrument for the purpose of makingThe DNA extracted from FFPE tissue was used to detect 7 somatic mutations in the human KRAS oncogene. The mutations detected were: G12A, G12D, G12R, G12C, G12S, G12V, G D.KRAS RGQ PCR the kit is a research in vitro diagnostic device useful for testing a subject suffering from NSCLC and CRC for KRAS p.g12c mutations. Qiagen->KRAS RGQ PCR kits may be approved in certain areas.

PDL1 testing was performed in a central laboratory using the PharmDx 22C3 immunohistochemical FDA approved kit from daceae, according to the instructions for use.

Solid tumor response evaluation Standard version 1.1 (RECIST 1.1)

Definition of the definition

Measurable lesions

Measurable tumor lesions-a well-defined non-nodular lesion, which can be accurately measured in at least 1 dimension in a CT/MRI scan, with a longest diameter of ≡10mm, while the slice thickness is no more than 5mm. When the slice thickness is greater than 5mm, the smallest dimension of the measurable lesion should be twice the slice thickness.

Nodular lesions-lymph nodes are considered pathologically enlarged and measurable, and the short axis of the lymph node must be 15mm or more (scan slice thickness of 5mm or less is recommended) when assessed by CT/MRI. At baseline and at follow-up, only the short axis was measured and tracked. The nodule size is typically reported as two dimensions in the axial plane. Smaller of these metrics is the short axis (perpendicular to the longest axis).

Irradiation lesions-tumor lesions located in previously irradiated areas or areas subjected to other local therapies are not measurable unless progression in lesions has been demonstrated prior to recruitment.

Non-measurable lesions: all other lesions, including small lesions (longest diameter<10mm or having a diameter of ≡10mm<Short axis of 15mmPathological lymph nodes, with CT scan slice thickness no greater than 5 mm) are considered to be unmeasurable and characterized as non-target lesions.

Other examples of non-measurable lesions include: lesions with previous local treatment: tumor lesions located in previously irradiated areas or areas subject to other local therapies may not be considered measurable unless progression in the lesions has been demonstrated; biopsy lesions; clustered small lesions, bone lesions, inflammatory breast disease and leptomeningeal disease are not measurable in classification.

Measurement method

Measurement of lesions-the maximum diameter of the selected lesions should be measured on the plane (axial plane) where the image was taken. All measurements should be made and recorded in metric notation. All baseline evaluations should be performed as close as possible to the beginning of treatment and not more than 4 weeks prior to study day 1.

Evaluation methods-the same evaluation methods and the same techniques should be used to characterize each identified and reported lesion throughout the trial.

CT/MRI-contrast enhanced CT or MRI should be used to assess all lesions. Optimal visualization and measurement of solid tumor metastasis requires consistent IV contrast agent administration (dose and rate) and scan time. CT and MRI should be performed with serial sections of 5mm or less thick.

Baseline recordings of "target" and "non-target" lesions

Target lesions-all measurable lesions (up to two (2) lesions per organ and five (5) lesions total, representing all affected organs) should be identified as target lesions and recorded and measured at baseline.

The target lesions should be selected based on their size (lesions with longest diameter) and suitability for accurate repeated measurements.

Pathological lymph nodes (minor axis. Gtoreq.15 mm) can be identified as target lesions. All other pathological nodules (with a minor axis of ≡10mm but <15 mm) should be considered non-target lesions.

The sum of the diameters of all target lesions (longest diameter of non-nodular lesions, short axis of nodular lesions) was calculated and reported as the baseline sum of the diameters. The baseline sum of diameters was used as a reference to characterize objective tumor responses.

Non-target lesions-all other lesions (or disease sites), including pathological lymph nodes, should be identified as non-target lesions and should also be recorded at baseline. These lesions need not be measured and should be tracked as "present", "absent" or "clear progression" throughout the course of the study. In addition, multiple non-target lesions involving the same organ may be recorded as a single item on a case report table (e.g., "multiple enlarged pelvic lymph nodes" or "multiple liver metastases").

Response criteria

TABLE 11 evaluation of target lesions

TABLE 12 evaluation of non-target lesions

¹ In order to achieve a "clear progression" on the basis of non-target disease, there must be a substantial worsening overall level in the non-target disease, such that the overall tumor burden has increased sufficiently to be worth stopping therapy even if SD or PR is present in the target disease. A modest "increase" in the size of 1 or more non-target lesions is generally insufficient to meet a well-defined progression state.

Assessment of overall response

The best overall response is the best response recorded from the beginning of study treatment until the end of treatment or disease progression/recurrence (minimum measured value recorded since the beginning of treatment was taken as reference for PD).

In general, the optimal response distribution of a subject depends on the findings of both target and non-target diseases, and also considers the appearance of new lesions.

Table 13a. Time point response: subjects with target (+/-non-target) disease

Ne=unable to evaluate

Table 13b. Time point response: subjects with non-target disease only

¹ For non-target diseases, "non-CR/non-PD" is more preferred than "SD" because SD is increasingly used as an endpoint for efficacy assessment in some trials, and therefore it is not recommended to assign this class when lesions cannot be measured.

Table 14. Overall response: it is necessary to confirm the Complete Response (CR) and the Partial Response (PR)

¹ If CR is indeed met at a first time point, any disease at a later time point, even if the disease meets PR criteria relative to baseline, will make the disease PD at that point (since the disease must reappear after CR). The optimal response will depend on whether it is fullThe shortest duration of foot SD. However, a "CR" may sometimes be declared when a subsequent scan shows that a small lesion may still be present, and in fact the subject has PR at a first point in time, rather than CR. In these cases, the original CR should be changed to PR and the best response is PR.

Specific description about response assessment

Lesion of noduleThe lymph nodes identified as target lesions should always record actual short axis measurements even if the nodules subside below 10mm in the study. To meet CR, each nodule must achieve a short axis<10mm, rather than completely disappearing. The nodular target lesion short axis measurement is added to the target lesion longest diameter measurement to get the target lesion diameter sum for the particular assessment (time point).

Target lesions become "too small to measure"In the study, all lesions (nodules and non-nodules) recorded at baseline should have their measurements recorded at each subsequent evaluation. If the lesion becomes smaller than 5mm, the accuracy of measurement is lowered. Therefore, lesions smaller than 5mm are considered "too small to measure" and no measurement is made. With this reference, they are assigned a default measurement of 5 mm. Lesion measurements less than 5mm should not be recorded unless the lesions completely disappear, and the measurements can be recorded as "0".

New lesionsThe term "new lesions" always refers to the appearance of new findings that are indeed tumors. New findings that may be only tumors, but may also be benign (infection, inflammation, etc.) are not selected as new lesions until examination determines that they represent a tumor.

If a new lesion is suspicious, for example because of its small size, continued therapy and follow-up assessment will clarify whether it represents a truly new disease. If repeated scans confirm that a new lesion does exist, the date of the initial scan should be used to announce progress.

Lesions of anatomical location identified in the follow-up study (not scanned at baseline) are considered new lesions and will indicate disease progression regardless of any response that may be seen from target or non-target lesions present at baseline.

Subjects who have overall worsening of health status, need to stop treatment, and then have no objective evidence of disease progression should be categorized as "worsening of symptoms. Even after stopping the treatment, all efforts should be made to record objective progression through additional imaging evaluations.

In some cases, it may be difficult to distinguish residual disease from scar or normal tissue. When the assessment of Complete Response (CR) depends on this determination, it is suggested to further investigate residual lesions by fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET/computed tomography (PET/CT) or possibly fine needle aspiration/biopsy to confirm CR status.

Validating measurement/response duration

Response confirmation-in non-random experiments with response as the primary endpoint, PR and CR need to be confirmed to ensure that the identified response is not the result of measurement error.

Duration of the overall response-duration of the overall response is measured from the first meeting the measurement criteria for CR/PR (based on the first record) until the first day (based on the earlier) of objective record of recurrence or disease progression or death.

Duration of disease stabilization-SD is measured from the beginning of treatment until the criteria for disease progression are met, referenced to the minimum measured value recorded since the beginning of treatment or death (whichever is earlier).

Preliminary data (2022, 21 days 2 month):

the table provided below summarizes the Pharmacokinetic (PK) data following administration of sotoraciclovir (240 mg or 960 mg) on days 1 and 8.

Table 15.

^a N＝33； ^b N＝19； ^c N＝27； ^d N＝18； ^e N＝36； ^f N＝15； ^g N＝29； ^h N＝16；

Except t, which is expressed as median (range) _max Data for all PK parameters are also shown as geometric mean (GeoMean) (mean, CV%). Except for t, which are represented as two significant digits and the nearest integer _max And CV%, values are reported as 3 significant digits.

t _max =reach C _max Time of (2); c (C) _max =maximum drug concentration observed; AUC (AUC) _0-24h Area under concentration-time curve from 0 to 24 hours post-dose; t is t _1/2,z Half-life =

Briefly, a higher number of average exposures (C) were observed on days 1 and 8 after 960mg compared to 240mg _max And AUC _0-24h ). 960mg PK was consistent with the expected exposure range and elimination half-life. For both 240mg and 960 doses, the exposure on day 8 was 30% -40% lower than on day 1, consistent with the expected steady state profile.

In addition, preliminary data from two NSCLC adenocarcinoma (stage IV) patients treated with 240mg of sotoracicada once daily were reviewed. One patient showed disease Stabilization (SD) after the 3 rd and 5 th cycles and Partial Response (PR) after the 7 th and 9 th cycles after 9 cycles of treatment with 240mg of sotoracicada. One patient showed Partial Response (PR) after 9 cycles of treatment, after 3, 5 and 7 cycles, and disease Progression (PD) after 9 cycles, with new lesions.

Example 4-Soto-Racemosib dose reduction regimen

During phase 2 studies, the most common adverse events for sotoracicb treatment included laboratory abnormalities (. Gtoreq.10%), lymphopenia, hemoglobin reduction, diarrhea, musculoskeletal pain, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, decreased sodium, nausea, fatigue, decreased albumin, increased activated partial thromboplastin time, cough, vomiting, constipation, dyspnea, and abdominal pain.

Table 16.2 common adverse events during phase 2 study

* Grading defined by NCI CTCAE v.5.0; abdominal pain includes upper abdominal pain and lower abdominal pain; hepatotoxicity includes: increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, drug-induced liver injury, hepatitis, abnormal aminotransferase and increased aminotransferase

When certain adverse events (e.g., hepatotoxicity, nausea/vomiting, diarrhea, other adverse reactions) are observed, the dose is allowed to decrease (from 960mg to 480mg total daily dose, or from 480mg to 240 mg). The following table 17 summarizes the dose reduction levels.

Table 17.

Dose reduction level	Dosage of
		First dose reduction	480mg per day
Second dose reduction	240mg per day

TABLE 18 adverse reactions and related recommended actions

Of 427 subjects receiving soromide monotherapy for any tumor type and any dose, 56 subjects (13.1%) had reduced dose, most of which were due to Adverse Events (AEs) (46 subjects, 10.8%). See table 19 below.

Table 19. Soto-Laxib dose reduction summary (safety analysis set)

Of the 56 subjects with reduced dose, 39 subjects (69.6%) stopped treatment with sotoracicb (table 20), and the remaining 17 subjects continued treatment by the date of data cut-off.

Table 20. The reason for treatment and cessation of any dose reduced subjects.

Of the 39 subjects stopped in the sorafenib treatment, only 12 subjects (21.4%) stopped due to AE, confirming that most subjects receiving a modified dose of sorafenib did not need to permanently stop the sorafenib treatment due to AE. Of the 39 subjects, most subjects stopped sottorsemib after dose reduction because of disease progression (25 subjects, 44.6%). The data show that unexpectedly considering the nonlinear pharmacokinetic properties of sotoprazole as shown herein, dose reduction improves individual safety and may continue to keep the ratio of sotoprazole stopped for AE low.

Example 5-contraindications for Simultaneous administration of Sotolaccb with acid reducing agent under fasted conditions

This phase 1, open-label, fixed sequence study recruited 14 healthy subjects. Subjects received 960mg of sotoprazole on day 1, 40mg of omeprazole once daily on days 4 to 8, and 40mg of omeprazole followed by 960mg of sotoprazole on day 9. All doses were administered under fasted conditions. Blood samples of sotoraciclovir PK were collected before and up to 48 hours after sotoraciclovir administration. The non-atrioventricular method was used to estimate sotoraciclovir plasma PK parameters.

Simultaneous administration of sotoprazole with omeprazole brings the sotoprazole to a maximum plasma concentration (t _max ) Is delayed by 0.75 hours. The average terminal half-life (t _1/2 ) Similar to that after concomitant administration with omeprazole. Geometric mean Soto-plasiban AUC following Simultaneous administration of Soto-plasiban with omeprazole (17000 h ng/mL and 3100ng/mL, respectively) compared to Soto-plasiban administered alone (29300 h ng/mL and 7200ng/mL, respectively) _inf (area under curve from time 0 to infinity) and C _max (maximum plasma concentration) is low. When administered to healthy subjects either concurrently with 40mg omeprazole or separately, sotoprazole is safe and well tolerated.

The results show that co-administration of sotoprazole with omeprazole causes an AUC of sotoprazole in the fasted state compared to administration of sotoprazole alone _inf 42% lower, and C _max Reduced by 57%.

Example 6-contraindications for Simultaneous administration of Sotolaccb with acid reducing agent under fed conditions

This is a phase 1, open-label, fixed sequence, crossover, single-center study that was used to explore mitigation strategies to limit the effect of acid reducing agents on sotoraciclovir exposure. This study assessed PK in healthy men and women (total 14 subjects) under fed conditions with sotoracicmide alone and in combination with famotidine or omeprazole. The subject received a single dose of sotoprazole on day 1, a night dose of famotidine on day 3 (10 hours prior to administration of sotoprazole), a single dose of sotoprazole on day 4, followed by another dose of famotidine after 2 hours, a daily dose of omeprazole on days 6 to 10, and a single dose of both omeprazole and sotoprazole on day 11. All administration of sotoracicada occurs after ingestion of a standard caloric medium fat meal. Blood was collected at predetermined time points to characterize plasma concentrations of sotoracicb. Safety and tolerability monitoring was performed throughout the study.

A total of 15 healthy subjects (1 female and 13 men) participated in the study. 13 of the 14 subjects received all treatment and completed the study.

When the co-administration of sotoprazole and famotidine under fed conditions is compared to the sotoprazole alone, the sotoprazole AUC _inf And C _max The geometric least squares average ratio of (2) is 0.622 and 0.654, respectively. When comparing the co-administration of sotoprazole and omeprazole with the administration of sotoprazole alone, the sotoprazole AUC _inf And C _max The geometric least squares average ratio of (2) is 0.430 and 0.349, respectively. For healthy subjects, a dose of 960mg of sotoprazole is safe and well tolerated under fed conditions with a single dose of 40mg of famotidine administered simultaneously and after multiple daily administrations of 40mg of omeprazole.

In summary, administration of a single dose of famotidine (H2 receptor antagonist) administered simultaneously 10 hours before and 2 hours after a single dose of sotoprazole results in C of the sotoprazole under fed conditions _max Reduced by 35% and AUC reduced by 38%. In addition, repeated doses of omeprazole (PPI) are administered concurrently with a single dose of sotoprazole under fed conditions to cause the administration of sotoprazole C _max 65% reduction and 57% reduction in AUC.

Example 7-contraindications for Simultaneous administration of Sotolaccb with Strong CYP34A4 inducer

This phase 1, open-label, fixed sequence study recruited 14 healthy subjects. Each subject received 960mg of sotoracicada on days 1, 3 and 18 and 600mg of rifampin on days 3 and 5 to 19. Blood samples of sotoraciclovir PK were collected before and up to 48 hours after sotoraciclovir administration. The non-atrioventricular method was used to estimate sotoraciclovir plasma PK parameters.

Results:

geometric mean Soto-plasiban AUC following single dose simultaneous administration of rifampin and Soto-plasiban (19600 h ng/mL and 5340ng/mL, respectively) _inf (area under curve from time 0 to infinity) and C _max (maximum plasma concentration) was similar to that of sotorubin alone (25600 h ng/mL and 6350ng/mL, respectively). Multiple doses of rifampin in combination with sotoracib (12400 h ng/mL and 4110ng/mL, respectively) after simultaneous administration, as compared to sotoracib alone (25600 h ng/mL and 6350ng/mL, respectively), had a geometric mean sotoracib AUC _inf And C _max Lower.

When administered to healthy subjects either concurrently with 600mg rifampin or alone, sotoracicada is safe and well tolerated. Single dose rifampin had no clinically significant effect on sotoraciclovir PK, suggesting that sotoraciclovir is not a substrate for OATP1B 1. Multiple doses of rifampin enable sotoracicle AUC _inf Reduced by 51%, and C _max 35% reduction, indicating that sotoraciclovir is a CYP3A4 substrate, consistent with in vitro data.

Example 8-contraindications for Simultaneous administration of Sotolaccb with CYP34A substrate

This phase 1, open label, fixed sequence study recruited 5 subjects previously untreated NSCLC who received a single oral dose of 2mg of midazolam on day-1, 960mg of sotoraciclovir on days 1 to 14, and 2mg of midazolam on day 15 approximately at the same time as 960mg of sotoraciclovir. Blood samples of sotoraciclovir PK were collected before and up to 48 hours after sotoraciclovir administration. The non-atrioventricular method was used to estimate sotoraciclovir plasma PK parameters.

Single dose plasma midazolam PK data were obtained from 5 subjects who received midazolam alone and midazolam administered concurrently with sotoprazole after multiple daily administrations of sotoprazole for 14 days. The results show that after multiple daily administrations of sotoracib, the combination with sotoracibThe exposure to midazolam is reduced when the cloths are administered simultaneously. Simultaneous administration of sotoprazole with midazolam (a sensitive CYP3A4 substrate) causes midazolam C _max 48% reduction and 53% reduction in AUV.

Example 9-contraindications for Simultaneous administration of Sotolaccb and P-gp substrate

This phase 1, open-label, fixed sequence study recruited 14 healthy subjects. Each subject received 0.5mg of digoxin on day 1 and 960mg of sotoracicada followed by 0.5mg of digoxin on day 7. Blood samples of digoxin PK were collected before and up to 144 hours after dosing of digoxin. The samples were measured using a validated high performance liquid chromatography tandem mass spectrometry method. PK parameters were estimated using a non-atrioventricular approach. Safety and tolerability were monitored throughout the study.

After simultaneous administration of digoxin and sotobacillus, the median time to maximum plasma concentration of digoxin (t _max ) And average terminal half-life (t) _1/2 ) Similarly. Geometric mean digoxin AUC after concurrent administration of digoxin and sotobacillus (40.3 h ng/mL) _inf The area under the curve (from time 0 to infinity) is similar to digoxin alone (33.2 h ng/mL). Geometric mean digoxin C after concurrent administration of digoxin and sotoprazole (3.64 ng/mL) as compared to digoxin alone (1.90 ng/mL) _max (maximum plasma concentration) is higher. A single dose of 0.5mg digoxin is safe and well tolerated when administered alone or concurrently with 960mg of sotoraciclovir.

The results indicate that simultaneous administration of digoxin with single dose of sotoracicb results in a digoxin AUC compared to digoxin alone _inf And C _max About 21% and 91% increase, respectively.

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Claims (64)

1. A method of treating cancer in a patient, the method comprising administering to the patient a total daily dose of 240mg of sotoracicb, wherein the cancer is a KRAS G12C mutant cancer.

2. A method of treating a patient, the method comprising administering to the patient a total initial daily dose of 960mg of sotoracicb, when the patient experiences an adverse event of the total initial daily dose, 480mg of reduced total daily dose of sotoracicb, wherein the cancer is KRAS G12C mutant cancer.

3. The method of claim 2, further comprising administering 240mg of the second reduced total daily dose of sotoracicada when the patient experiences the adverse event of the reduced total daily dose.

4. The method of claim 2 or claim 3, wherein the adverse event is an elevation of one or more liver enzymes in the patient, wherein the liver enzyme is alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST).

5. The method of claim 4, wherein elevated levels of ALT and/or AST are >3x ULN in case of normal baseline, and >3.0x baseline in case of abnormal baseline.

6. The method of any one of claims 2-5, further comprising suspending the treatment of the patient with sotoprazole until the patient's ALT and/or AST levels improve to grade 1 or baseline prior to administering the reduced total daily dose of sotoprazole or the second reduced total daily dose of sotoprazole.

7. The method of any one of claims 2-6, comprising stopping the sotoraciclovir treatment when AST or ALT levels >3x ULN and total bilirubin >2x ULN in the absence of an alternative cause.

8. The method of any one of claims 2-7, wherein the adverse event is diarrhea.

9. The method of claim 8, further comprising suspending the treatment of the patient with sotoprazole until the patient's diarrhea improves to grade 1 or baseline prior to administering the reduced total daily dose of sotoprazole or the second reduced total daily dose of sotoprazole.

10. The method of any one of claims 2-9, wherein the adverse event is nausea/vomiting.

11. The method of claim 10, further comprising suspending the treatment of the patient with sotoprazole until the patient's nausea/vomiting improves to grade 1 or baseline prior to administering the reduced total daily dose of sotoprazole or the second reduced total daily dose of sotoprazole.

12. The method of any one of claims 1-11, wherein the sotoracicada is administered once daily.

13. The method of any one of claims 1-12, wherein the sotoracicada is administered orally.

14. The method of any one of claims 1-13, wherein the cancer is a solid tumor.

15. The method of any one of claims 1-14, wherein the cancer is non-small cell lung cancer.

16. The method of claim 15, wherein the cancer is metastatic non-small cell lung cancer.

17. The method of claim 16, wherein the cancer is locally advanced and unresectable.

18. The method of any one of claims 1-13, wherein the cancer is colorectal cancer.

19. The method of any one of claims 1-13, wherein the cancer is pancreatic cancer.

20. The method of any one of claims 1-13, wherein the cancer is small intestine cancer, appendiceal cancer, endometrial cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell tumor, ovarian cancer, gastrointestinal neuroendocrine tumor, bladder cancer, myelodysplastic/myeloproliferative tumor, head and neck cancer, esophageal gastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.

21. The method of any one of claims 1-20, wherein the patient has undergone at least one other systemic cancer therapy prior to initiation of sotoraciclovir therapy.

22. The method of claim 21, wherein the patient has undergone at least two other systemic cancer therapies.

23. The method of claim 21 or 22, wherein at least one systemic cancer therapy is selected from anti-PD 1 immunotherapy, anti-PDL 1 immunotherapy, and platinum-based chemotherapy.

24. The method of claim 23, wherein the patient has previously undergone (i) anti-PD 1 therapy or anti-PDL 1 therapy unless contraindicated, or (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS 1.

25. The method of claim 23, wherein the patient has previously undergone (i) anti-PD 1 therapy or anti-PDL 1 therapy unless contraindicated, and (ii) platinum-based chemotherapy, and (iii) EGFR, ALK, or ROS1 targeted therapy if the cancer also exhibits mutations in EGFR, ALK, or ROS 1.

26. The method of any one of claims 1-25, wherein the patient has no brain metastasis within four weeks of initiating sottorsemib therapy.

27. The method of any one of claims 1-26, wherein the patient exhibits an eastern tumor collaboration group (ECOG) physical status of 0, 1, or 2.

28. The method of any one of claims 1-27, wherein the patient is administered sotoracicada for at least one month.

29. The method of any one of claims 1-27, wherein the patient is administered sotoracicada for at least three months.

30. The method of any one of claims 1-27, wherein the patient is administered sotoracicada for at least six months.

31. The method of any one of claims 28-30, wherein the patient exhibits at least disease Stabilization (SD) after 1, 3, or 6 months of sotoraciclovir therapy as measured by RECIST 1.1 regimen.

32. The method of claim 31, wherein the disease stability is neither sufficiently reduced to conform to Partial Response (PR) nor sufficiently increased to conform to disease Progression (PD).

33. The method of any one of claims 28-31, wherein the patient exhibits at least a Partial Response (PR) after 1, 3, or 6 months of sotoraciclovir therapy as measured by RECIST 1.1 regimen.

34. The method of claim 33, wherein the partial response is at least a 30% reduction in the sum of target lesion diameters.

35. The method of any one of claims 1-34, wherein the patient exhibits a Progression Free Survival (PFS) of at least 3 months.

36. The method of claim 35, wherein the patient exhibits PFS for at least 6 months.

37. The method of any one of claims 1-36, wherein the cancer exhibits a PDL1 tumor ratio score (TPS) of 1% -49%.

38. The method of any one of claims 1-36, wherein the cancer exhibits a PDL1 tumor ratio score (TPS) of less than 1%.

39. The method of any one of claims 1-36, wherein the cancer exhibits a PDL1 tumor ratio score (TPS) of 50% -100%.

40. The method of any one of claims 1-39, wherein the cancer further comprises a STK11 mutation.

41. The method of any one of claims 1-40, wherein the cancer further comprises a KEAP1 mutation.

42. The method of any one of claims 1-39 and 41, wherein the cancer further comprises STK11 wild-type.

43. The method of any one of claims 1-40 and 42, wherein the cancer further comprises KEAP1 wild type.

44. The method of any one of embodiments 1-43, wherein the patient exhibits liver toxicity and the method further comprises administering a steroid to the patient.

45. The method of example 44, wherein the steroid is prednisone at a dose of 0.25 to 1.0 mg/kg/day.

46. The method of any one of claims 1-45, wherein the patient is further in need of treatment with an acid reducing agent.

47. The method of claim 46, wherein the acid reducing agent is a Proton Pump Inhibitor (PPI), an H2 receptor antagonist (H2 RA), or a topically acting antacid.

48. The method of claim 46 or claim 47, wherein the administration of the sotomimetic is about 4 hours before or about 10 hours after the topically acting antacid if the patient further requires treatment with an acid reducing agent.

49. The method of any one of claims 46-48, wherein the topically acting antacid is sodium bicarbonate, calcium carbonate, aluminum hydroxide, or magnesium hydroxide.

50. The method of any one of claims 1-45, wherein the patient is further in need of treatment with a Proton Pump Inhibitor (PPI) or an H2 receptor antagonist (H2 RA).

51. The method of claim 47, wherein the patient is not administered a proton pump inhibitor or a combination of an H2 receptor antagonist and sotoprazole.

52. The method of any one of claims 47 or 50-51, wherein the proton pump inhibitor is omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole or dexlansoprazole.

53. The method of any one of claims 47 or 50-51, wherein the H2RA is famotidine, ranitidine, cimetidine, nizatidine, roxatidine, or lafutidine.

54. The method of any one of claims 1-53, wherein the patient is further in need of treatment with a CYP3A4 inducer.

55. The method of claim 54, wherein the patient is not administered a combination of a CYP3A4 inducer and sotoracicmide.

56. The method of claim 54 or 55, wherein the CYP3A4 inducer is barbiturates, buganib, carbamazepine, clobazam, dabrafenib, efavirenz, oxagolide, enzalutamide, eslicarbazepine, glucocorticoids, letrovir, lafutinib, modafinil, nevirapine, olanzapine, oxcarbazepine, pirapamide, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, tetroxat, and traglione.

57. The method of claim 54, wherein the patient is not administered a combination of a strong CYP3A4 inducer and sotoraciclovir.

58. The method of claim 57, wherein the strong CYP3A4 inducer is phenytoin or rifampin.

59. The method of any one of claims 1-58, wherein the patient is further in need of treatment with a CYP3A4 substrate.

60. The method of claim 59, wherein the patient is not administered a combination of a CYP3A4 substrate and sotoracicb.

61. The method of claim 59 or 60, wherein the CYP3A4 substrate is Abeli, abiraterone, alcalitinib, alatinib, alfentanil, apprazolam, amitriptyline, amlodipine, apixaban, aprepitant, aripiprazole, astemizole, atorvastatin, acitenib, boceprevir, boscalid, eppiprazole, buntinib, buspirone, gatifuge, caffeine, carbamazepine, carilazine, ceritinib, cerivastatin, chlorpheniramine, cilostazol, cisapride, citalopram, clarithromycin, clobazam, clopidogrel, cobratinib, cocaine, codeine, colchicine, copanil, crizotinib, cyclosporine, dabrafenib, dacarbazine, daphne, dapsone, deflazacort, dexamethasone, dextromethorphan, diazepam, diltiazem, docetaxel, pharmaceutical compositions Duolavir, domperidone, doxepin, oxaprozin, ebavir/Grazopicvir, ibrutinib, enzalutamide, eplerenone, erythromycin, escitalopram, esomeprazole, estradiol, felodipine, fentanyl, finasteride, flibanserin, glifevidone, haloperidol, hydrocortisone, ibrutinib, edaltefrail, indacavir, irinotecan, execonazol, ivabradine, ivacaine, lansoprazole, lenvatipine, lidocaine, linagliptin, lovastatin, macitentan, methadone, idazoprazol, nadimide, nalmezomib, naloxonol, nateglinide, nefinasteride, lenetanervone, pranopirudine, virapipine, nifedipine, nivogliptine, nilapatinib, offord, prazotinib, lercanide, lercanidipine, and cilazapiride, omeprazole, ondansetron, octreotide, ospemifene, pamoxcilib, panacistat, pantoprazole, pranpentanel, pimavanserin, pemirolazine, pomalidomide, ponatinib, progesterone, propranolol, quetiapine, quinidine, quinine, regorafenib, rebamipinib, rilpivirine, risperidone, ritonavir, rivaroxaban, roflumilast, topiramate, romidepsin, lu Suoti, salmeterol, saquinavir, celecoxib, sildenafil, semepivir, simvastatin, simetryptane sirolimus, sorafenib, sunitinib, suvorexant, tacrolimus (fk 506), tamoxifen, tasimelteon, taxol, telaprevir, telithromycin, terfenadine, testosterone, ticagrelor, tofacitinib, tolvaptan, tolperisil, tramadol, trazodone, valphenazine, vandetanib, vitamin patavir, vitamin mofefil, vitamin netoolong, venlafaxine, verapamil, vincristine, valsarsasapoxazole, zaleplon and ziprasidone.

62. The method of any one of claims 1-61, wherein the patient is further in need of treatment with a P-glycoprotein (P-gp) substrate.

63. The method of claim 62, wherein the patient is not administered a combination of P-gp substrate and sotoracicb.

64. The method of claim 57 or claim 58, wherein the P-gp substrate is dabigatran etexilate, digoxin, and fexofenadine.