PI3K-Delta Inhibitors for Use in Treatment Regimens

Abstract

A compound or a pharma- ceutical acceptable salt thereof for use in a method for treating a disease or condition in which signaling through the PI3Kδ pathway is pathologically implicated in a patient, such as cancer and inflammatory or autoimmune diseases. The compound is provided at a particular dose and has been found to have a favorable safety profile in humans, particularly with respect to hepatotoxicity, diarrhea / colitis, respiratory infections, and hematological toxicity.

Description

[Technical field]

[0001] This application claims priority to GB2104416.9, filed March 29, 2021, and GB2117511.2, filed December 3, 2021, the contents and elements of which are incorporated by reference herein for all purposes.

[0002] The present invention relates to the treatment of diseases or conditions in which signaling through the PI3Kδ pathway is pathologically implicated with PI3Kδ inhibitors, including cancer and several inflammatory and autoimmune diseases. [Background technology]

[0003] PI3Ks belong to a family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring. PI3Ks are classified into three classes (class I, II, and III) according to their structure, regulation, and substrate specificity. Class I PI3Ks, including PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, are lipid kinases that catalyze the phosphorylation of phosphatidylinositol-4,5-bisphosphate to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 functions as a second messenger that controls several cellular processes, including growth, survival, adhesion, and migration.

[0004] All four class I PI3K isoforms exist as heterodimers and are composed of a catalytic subunit (p110) and closely related regulatory subunits that control expression, activation, and subcellular localization. PI3Kα, PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Jimenez, Hernandez et al. 2002), whereas PI3Kγ associates with two regulatory subunits (p101 and p84) and its activation is driven by activation of G protein-coupled receptors (Brock, Schaefer et al. 2003). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast, PI3Kγ and PI3Kδ are expressed primarily in leukocytes (Vanhaesebroeck, Ali et al. 2005).

[0005] The PI3K pathway is frequently activated in a variety of solid tumors and hematological malignancies, making PI3K an attractive therapeutic target in oncology. This has generated considerable interest in the field of developing inhibitors targeting this pathway (Buchanan 2019). Although many PI3K inhibitors have reached various stages of clinical development, few PI3K inhibitors have been approved for clinical use. Although these agents are clinically effective, their use is accompanied by drug-specific side effects as well as several severe class-related side effects. Some of these are believed to be immune-mediated and include skin reactions, severe diarrhea with or without colitis, hepatotoxicity, and pneumonitis. PI3K inhibitors also induce various metabolic abnormalities, e.g., hyperglycemia and hypertriglyceridemia.

[0006] As a result, many new PI3K inhibitors with varying degrees of target selectivity have been synthesized in the hope of improving safety and efficacy. Some of these are currently in clinical trials for use in a variety of solid tumors as well as hematological malignancies. However, evidence from early clinical trials suggests that these new agents are associated with class-related side effects as well as other serious and unexpected side effects. As a result, development of many of these new agents has been discontinued.

[0007] As a class, PI3Kδ inhibitors are associated with severe dermatological, myelosuppressive, metabolic, gastrointestinal and respiratory side effects (Curigliano 2019). Unlike the ubiquitously expressed p110α and p110β, p110δ is primarily expressed in leukocytes (e.g., T and B cells), and thus PI3Kδ inhibitors have been used to target relapsed or refractory lymphomas, including but not limited to CLL, mantle cell lymphoma and non-Hodgkin's lymphoma (Buchanan 2019). Not surprisingly, these PI3Kδ isoform-specific inhibitors have also been noted for hematologic toxicity, including anemia, thrombocytopenia, leukocytosis, hemolysis and neutropenia. Inhibition of PI3Kδ leads to activation of the immune response, which is also thought to be responsible for some of the side effects to these agents, such as the PI3Kδ selective idelalisib. Idelalisib-induced colitis, hepatitis, and pneumonitis are believed to be immune-mediated effects, and a high incidence of idelalisib-induced diarrhea, pneumonitis, and elevated liver transaminases has been observed in immunocompetent patients. The FDA-approved labeling for idelalisib includes a detailed boxed warning regarding the possibility of "fatal and serious toxicities: hepatic, severe diarrhea, colitis, pneumonitis, infection, and intestinal perforation." Thus, the safety of currently approved PI3K inhibitors is under intense scrutiny, especially when administered over long periods of time.

[0008] Adverse events (AEs) experienced by patients receiving PI3Kδ inhibitors can be clinically significant and limit their use (Phillips 2020). At this time, it is unclear whether interruptions / changes in dosing due to side effects negatively impact the efficacy of PI3Kδ inhibitors. In general, target- or class-specific toxicities associated with PI3Kδ inhibitors are thought to be hepatotoxicity, diarrhea / colitis, respiratory infections, and hematologic toxicity.

[0009] Hematologic toxicity, e.g., neutropenia, is often noted in the study outcomes as a common laboratory abnormality. Hepatotoxicity is most often assessed by elevation of blood liver transaminases and graded according to its severity (grade 1 being minimal and grade 5 being often fatal). Grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels commonly observed with PI3Kδ inhibitors often lead to interruption or modification of dosing and, less frequently, to discontinuation. Diarrhea or colitis has been reported in up to one-third of patients receiving PI3Kδ inhibitors and usually requires treatment with antidiarrheal or anti-inflammatory drugs. Respiratory infections have been observed in up to 20% of patients receiving idelalisib and anti-infective prophylaxis is usually administered to PI3Kδ inhibitor-treated patients.

[0010] In view of the above, there is a need in the art for PI3K modulators that inhibit certain PI3K isoforms, particularly PI3Kδ, with high selectivity over other isoforms, while at the same time having a favorable safety profile (particularly with respect to elevated liver enzymes, diarrhea, and neutropenia).Furthermore, there is a need in the art for improved methods of treating (and preventing) diseases involving the PI3Kδ pathway with compounds that have high selectivity and a favorable safety profile (particularly with respect to elevated liver enzymes, diarrhea, and neutropenia).

[0011] The present inventors recognized this need and embarked on the devising of the present invention.

[0012] Among numerous disclosures regarding PI3K inhibitor compounds, WO2011058149 describes tricyclic pyrazolamine derivatives that are PI3K inhibitors and their use for treating autoimmune diseases, inflammatory disorders, multiple sclerosis and other diseases such as cancer. Summary of the Invention

[0013] In a first aspect, the present invention provides a compound of formula I for use in a method for the treatment of a disease or condition in which signaling through the PI3Kδ pathway is pathologically implicated in a patient (such as, but not limited to, an imbalance in immune cell responses or expression in tumor cells). [ka] or a pharma- ceutically acceptable salt thereof, the method comprising administering a compound of formula I at a dose of 18 mg to 108 mg of the compound per day. In some embodiments, the dose is 18 mg to 72 mg per day. Preferably, the dose is about 36 mg per day. In another embodiment, preferably, the dose is about 72 mg per day.

[0014] As described and exemplified herein, the pharma- ceutically acceptable salt is preferably the hemifumarate salt, i.e. the compound is provided as a salt of formula Ia: [ka]

[0015] Thus, the present invention provides a salt of formula Ia for use in a method of treating a disease or condition in which signaling through the PI3Kδ pathway is pathologically implicated in a patient (such as, but not limited to, an imbalance in immune cell response or expression in tumor cells), the method comprising administering a salt of formula Ia at a dose of 20 mg to 120 mg of the salt per day. In some embodiments, the dose is 20 mg to 80 mg per day. Preferably, the dose is about 40 mg per day. In another embodiment, preferably, the dose is about 80 mg per day.

[0016] The dosage can be administered in a once-a-day regimen.That is, the daily dosage can be taken in one or more dosage units at a time.Thus, in some embodiments, the administration is once a day.This can be referred to as QD (quaque die).

[0017] Suitably, the administration is oral, which is sometimes referred to as PO (per os).

[0018] In other words, in some embodiments, the dose of the salt of formula Ia can be 20-120 mg, more preferably 20-80 mg, more preferably 30-60 mg, more preferably 30-50 mg, and most preferably about 40 mg, POQD. In other embodiments, the dose of the salt of formula Ia can be 20-120 mg, more preferably 20-80 mg, more preferably 30-100 mg, more preferably 30-80 mg, more preferably 40-80 mg, and most preferably about 80 mg, POQD.

[0019] Suitably, more than one solid dosage unit is used per administration.In other words, the dose is divided into multiple dosage units.For example, the administration may comprise two solid dosage units, each dosage unit comprising 20mg of the salt of formula Ia.In another example, the administration may comprise four solid dosage units, each dosage unit comprising 20mg of the salt of formula Ia.

[0020] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 20 mg of a salt of formula Ia.

[0021] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 5 mg of a salt of formula Ia.

[0022] In another embodiment, one solid dosage unit is used per administration.For example, the administration can comprise one solid dosage unit that comprises 40mg of the salt of formula Ia.In another embodiment, the administration can comprise one solid dosage unit that comprises 80mg of the salt of formula Ia.

[0023] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 80 mg of a salt of formula Ia.

[0024] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 40 mg of a salt of formula Ia.

[0025] In some embodiments, the salt of Formula Ia is formulated in a pharmaceutical composition comprising microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate, hi some embodiments, the pharmaceutical composition is provided in a shell capsule.

[0026] The method of the present invention is directed to the treatment of a disease or condition in which signal transduction through the PI3Kδ pathway is pathologically involved (for example, but not limited to, imbalance of immune cell response or expression in tumor cells). Such diseases or conditions include inflammatory diseases, autoimmune diseases and cancer. In other words, the method can be a method for treating a disease or condition selected from inflammatory diseases, autoimmune diseases and cancer.

[0027] In some embodiments, the method is a method for treating cancer.

[0028] In some embodiments, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, stomach cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including Waldenstrom's disease), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer and colorectal cancer. For example, the cancer can be melanoma, lymphoma, myelofibrosis, non-small cell lung cancer or mesothelioma. In some cases, the melanoma is advanced or metastatic melanoma or ocular / uveal melanoma. Advanced or metastatic melanoma can be histologically confirmed, unresectable stage III or stage IV melanoma. In some cases, the cancer is B-cell lymphoma. In some cases, the cancer is T-cell lymphoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma.

[0029] In some embodiments, the inflammatory disease or autoimmune disease can be activated PI3K delta syndrome (APDS), allergic disease, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS), primary Sjogren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic lupus erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and idiopathic thrombocytopenic purpura (ITP).

[0030] In some preferred embodiments, the treatment does not result in clinically significant treatment-related elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in the patient. In some preferred embodiments, the treatment does not cause treatment-related grade 3 diarrhea or colitis.

[0031] In some preferred embodiments, the treatment does not result in clinically significant treatment-related neutropenia in patients.

[0032] In some preferred embodiments, the treatment provides extended duration of treatment in the absence of serious side effects.

[0033] The present invention further provides solid dosage forms for use in these methods. Suitable solid dosage forms include tablets and hard or soft shell capsules.

[0034] The present invention includes combinations of the aspects and preferred features described herein except where such combinations are clearly unacceptable or clearly avoided.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present invention will now be described with reference to the accompanying drawings. [Brief description of the drawings]

[0036] [Figure 1] 6A and 6B show ALT levels measured in patients administered Compound 1. [Diagram 2] a and b show AST levels measured in patients administered Compound 1. [Diagram 3] a and b show neutrophils measured in patients administered Compound 1. [Figure 4] a and b show CD63 positive basophils measured in patients receiving Compound 1 after ex vivo stimulation with anti-IgE. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Aspects and embodiments of the invention are described herein. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0038] compound 1 Compound 1 is Example 339 of WO2011058149, which is incorporated herein by reference in its entirety. Its structure is according to Formula I: [ka]

[0039] In IUPAC nomenclature, the above compound 1 can be referred to as 6-fluoro-3-(morpholin-4-ylcarbonyl)-1-[4-(morpholin-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide. Alternatively, the above structure can be written as [6-fluoro-1-(4-morpholin-4-yl-methylphenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiochromeno[4,3-C]pyrazol-3-yl]-morpholin-4-yl-methanone.

[0040] Compound 1 can be prepared and characterized as described in published patent application WO2011058149A1 (see compound 339 on page 69, preparation on pages 303-307, and characterization on pages 481 and 414-418), the information of which is specifically incorporated herein by reference.

[0041] Based on the process disclosed in WO2011 / 058149A1, the authors Haselmayer et al. describe a five-step preparation procedure for the compound (Haselmayer, 2014). The procedure begins with the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is then cyclized with 4-(4-hydrazinylbenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, followed by coupling with morpholine to obtain the compound of formula I.

[0042] Alternatively, the intermediate from the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. The benzoic acid is reduced using borane-THF complex, and the thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. The ethyl ester is saponified to the corresponding acid, and both the acid and alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine to give compound 1.

[0043] Compound 1 can be provided as a pharmaceutically acceptable salt.Suitable pharmaceutically acceptable salts are known in the art.Some pharmaceutically acceptable salts of compound 1 are described in WO2014121901, which is incorporated by reference in its entirety.

[0044] As used herein, compound 1 is provided as anhydrous hemifumarate (shown in formula). Its synthesis and characterization are described in WO2014121901 (page 4). It is referred to as solid form A1. A hemifumarate hydrate (H1) has also been identified. The anhydrous hemifumarate used is crystalline and has a powder X-ray peak list described in WO2014121901. It will be understood that the discovery of the present invention is not limited to the use of this solid form, although it is preferred. [ka]

[0045] Haselmayer et al. also describe the characterization of the compound as a highly selective PI3Kδ inhibitor. The favorable in vitro and in vivo properties of compound 1 are further described by Johnson et al. (Johnson, Z. et al., AACR 2020, poster 666).

[0046] formulation Compound 1 is suitably provided as the above-mentioned hemifumarate salt. Suitably, compound 1 is provided in a pharmaceutical composition that is formulated for oral administration. The pharmaceutical composition may be provided in a capsule or in a tablet. In some cases, it is provided as a tablet, for example, a coated tablet or plain tablet that is produced by compression of a powder or granular composition. In other cases, it is provided as a powder or granular composition in a capsule, for example, a hard or soft shell capsule, for example, a hydroxymethylcellulose (HPMC) capsule. In other words, oral dosage form is preferred.

[0047] The formulation suitably comprises one or more pharma- ceutically acceptable excipients, disintegrants, glidants, and / or lubricants.

[0048] In some cases, the oral dosage form can contain 5mg of compound 1 provided as hemifumarate. In some cases, the oral dosage form can contain 20mg of compound 1 provided as hemifumarate. Both oral dosage forms are manufactured as described in Table 1. It can be seen that the dosage burden (number of capsules or tablets) imposed on the patient is relatively low with respect to the dose of the method, especially when the 20mg solid dosage form is used. This is advantageous for patient compliance.

[0049] However, it will be appreciated that for some patients, a smaller dosage form may be preferred, for example if the patient has difficulty swallowing, and patient burden (number of capsules or tablets) is not uncommon in the treatment of the claimed conditions, even with the use of the smaller 5 mg antibody dosage forms. [Table 1]

[0050] The oral dosage form may contain 40mg of compound 1 provided as hemifumarate. The oral dosage form may contain 80mg of compound 1 provided as hemifumarate. Both oral dosage forms may be manufactured similarly to the dosage forms described in Table 1. It will be understood that, with respect to the dosage of the method, when a single solid dosage form is used, the dosage burden (number of capsules or tablets) imposed on the patient is the lowest. This is the most favorable for patient compliance.

[0051] Thus, the present invention further relates to pharmaceutical compositions comprising Compound 1, preferably provided as the hemifumarate salt, formulated for oral administration.

[0052] An exemplary formulation comprises Compound 1 hemifumarate, microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate. The formulation can be provided as a solid dosage form, for example, a tablet or a powder or granular composition enclosed in a shell capsule. It is understood that a single tablet can accommodate a higher dose of Compound 1 hemifumarate than a single capsule. Therefore, tablets are preferred for higher dosage units. Tablets can be coated to improve taste or swallowing.

[0053] The amount of the hemifumarate salt of Compound 1 can be from 5 mg to 20 mg, for example, 5 mg or 20 mg. In another embodiment, the amount of Compound 1 can be from 5 mg to 80 mg, for example, 5 mg, 20 mg, 40 mg, or 80 mg.

[0054] Thus, in some embodiments, the present invention provides a solid dosage unit comprising a pharmaceutical composition comprising 5 mg of the hemifumarate salt of Compound 1. Thus, in some embodiments, the present invention provides a solid dosage unit comprising a pharmaceutical composition comprising 20 mg of the hemifumarate salt of Compound 1. Thus, in some embodiments, the present invention provides a solid dosage unit comprising a pharmaceutical composition comprising 40 mg of the hemifumarate salt of Compound 1. Thus, in some embodiments, the present invention provides a solid dosage unit comprising a pharmaceutical composition comprising 80 mg of the hemifumarate salt of Compound 1.

[0055] Thus, in some embodiments, the present invention provides a tablet comprising a pharmaceutical composition comprising 40 mg of the hemifumarate salt of Compound 1. Thus, in some embodiments, the present invention provides a tablet comprising a pharmaceutical composition comprising 80 mg of the hemifumarate salt of Compound 1. It will be appreciated that the pharmaceutical composition of the tablet may be similar to that of the capsule or may be optimized for tableting.

[0056] Methods of the Invention As described in more detail below, the present inventors have surprisingly found that compound 1 has a favorable safety profile in humans, particularly with respect to hepatotoxicity, diarrhea / colitis, respiratory infection, and hematological toxicity.Furthermore, treatment of patients with compound 1 does not result in elevated liver enzymes, diarrhea, and neutropenia.Thus, a PI3K inhibitor with specificity for isoform δ and favorable safety profile for patients can be provided.

[0057] Further advantageous properties of treatment methods using Compound 1 may include one or more of greater efficacy, longer duration of administration, less dose reduction, or interruption or cessation.

[0058] In other words, the inventors have surprisingly found that patients (in this case patients with melanoma, uveal melanoma and mesothelioma, and thus this is expected to apply to all human subjects) can be treated with Compound 1 with fewer side effects than would be expected with a treatment regimen using a PI3K inhibitor, which may make the treatment suitable for long-term prescription without the need to reduce or interrupt dosing.

[0059] In the clinical trials and examples described herein, Compound 1 is administered as a hemifumarate salt. Thus, in some cases, Compound 1 is administered as a hemifumarate salt. However, it will be understood that the invention is not so limited and that other solid forms (e.g., other pharma- ceutically acceptable salts) are also contemplated.

[0060] The weight equivalent of Compound 1 as the free base contained in a 40 mg dose is calculated to be approximately 36 mg (i.e., approximately 90% of the weight of the hemifumarate salt of Compound 1 corresponds to the free base, with the remaining approximately 10% of the weight corresponding to the salt-forming acid).

[0061] The weight equivalent of Compound 1 as the free base contained in an 80 mg dose is calculated to be approximately 72 mg (i.e., approximately 90% of the weight of the hemifumarate salt of Compound 1 corresponds to the free base, with the remaining approximately 10% of the weight corresponding to the salt-forming acid).

[0062] The present invention thus relates to a method for treating a disease or condition in which signaling through the PI3Kδ pathway is pathologically implicated in a patient, the method comprising administering compound 1 in an amount of 18 mg to 108 mg per day. Optionally, the amount is 18 mg to 72 mg per day. Optionally, the amount is 27 mg to 54 mg per day. Optionally, the amount is 27 mg to 45 mg per day, for example, about 36 mg per day. Optionally, the amount is 27 mg to 108 mg per day. Optionally, the amount is 27 mg to 72 mg per day. Optionally, the amount is 36 mg to 90 mg per day, for example, about 72 mg per day. Optionally, the amount is 36 mg to 72 mg per day.

[0063] When compound 1 is administered as the hemifumarate salt (formula Ia), the present invention relates to a method of treating a disease or condition in which signaling through the PI3Kδ pathway is pathologically implicated in a patient, the method comprising administering compound 1 as the hemifumarate salt in an amount of 20 mg to 120 mg per day. Optionally, the amount is 20 mg to 80 mg per day. Optionally, the amount is 30 to 60 mg per day. Optionally, the amount is 30 to 50 mg per day, for example, about 40 mg per day. Optionally, the amount is 30 to 120 mg per day. Optionally, the amount is 30 to 80 mg per day. Optionally, the amount is 40 to 100 mg per day, for example, about 80 mg per day. Optionally, the amount is 40 to 80 mg per day.

[0064] Lower doses are also contemplated and contemplated. Thus, it will be understood that in any method described herein, the method may include administering compound 1 in an amount of 9 mg to 108 mg per day. In some cases, the amount of compound 1 is 9 mg to 72 mg per day. When compound 1 is administered as a hemifumarate salt, in any method described herein, the method may include administering compound 1 as the hemifumarate salt in an amount of 10 mg to 120 mg per day. In some cases, the amount of compound 1 as the hemifumarate salt is 10 mg to 80 mg per day.

[0065] Inhibition of the PI3Kδ pathway in patients can be demonstrated by measuring the pharmacodynamic activity (PD) of compound 1 in blood samples. A PD marker specific for PI3Kδ inhibition in blood is CD63 expression on basophils. Treatment of patients with compound 1 as the hemifumarate salt reduces the percentage of CD63-positive basophils in the patient's blood samples in a dose-dependent manner comparable to that reported for other PI3Kδ inhibitors (e.g., idelalisib). Especially at the 40 mg dose, the percentage of CD63-positive basophils is low in all samples measured, confirming effective inhibition of the PI3Kδ pathway over the course of treatment. Especially at the 80 mg dose, the percentage of CD63-positive basophils is similarly low in all samples measured, confirming effective inhibition of the PI3Kδ pathway over the course of treatment.

[0066] Thus, certain preferred embodiments relate to a 40 mg dose of a salt of formula Ia, or a 36 mg dose of a compound of formula I.

[0067] However, it is understood that higher doses are included and envisioned.For example, the dose can be 60mg of the salt of formula Ia or 54mg of the compound of formula I.For example, the dose can be 80mg of the salt of formula Ia or 72mg of the compound of formula I, and in some embodiments, this may be preferred.

[0068] In some cases, lower doses are envisaged. For example, the dose may be 10 mg of the salt of formula Ia or 9 mg of the compound of formula I.

[0069] The inventors have found that once-daily administration is effective and well tolerated. Once-daily administration has advantages when compared with some known and used PI3K inhibitors (e.g., idelalisib is prescribed as a dose of 150 mg twice a day unless dose reduction due to side effects is required). Once-daily administration can improve patient experience and improve patient compliance. Cancer patients, especially those with advanced cancer, often experience a significant tablet burden and may have difficulty swallowing. Therefore, in the method of the present invention, the dose can be taken once a day. In other words, the dose is not divided and distributed throughout the day. It can be taken as a single dosage unit (e.g., a single tablet or capsule) or as multiple dosage forms (e.g., two or more tablets or capsules).

[0070] Thus, in some cases, the method includes administering one or more solid dosage units. For example, in some cases, the daily dose is 40 mg and the method includes administering two 20 mg solid dosage units (i.e., a solid dosage unit containing 20 mg of Compound 1 as the hemifumarate salt), or more preferably, one 40 mg solid dosage unit.

[0071] In another example, the daily dose may be 60 mg and the administration may include three solid dosage units, each containing 20 mg of the salt of formula Ia. In another example, the daily dose may be 80 mg and the administration may include four solid dosage units, each containing 20 mg of the salt of formula Ia. In another embodiment, the administration may include two dosage units containing 40 mg of the salt of formula Ia, or more preferably, one dosage unit containing 80 mg of the salt of formula Ia.

[0072] As described herein, the inventors have confirmed that compound 1 has a surprisingly good safety profile in humans and have observed that treatment can result in lower treatment-related grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations than would be expected for this class of inhibitors.

[0073] Thus, in some cases, treatment of patients with Compound 1 does not result in treatment-related grade 3 elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in more than 5% of patients. More preferably, treatment of patients with Compound 1 does not result in treatment-related grade 3 elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in more than 1% of patients. Most preferably, treatment of patients with Compound 1 does not result in clinically significant treatment-related elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in patients.

[0074] The inventors further confirmed from initial testing that treatment with compound 1 has fewer side effects than would be expected with this class of inhibitors. In particular, it is expected that there will be less severe diarrhea and / or colitis. This is most surprising, especially at the 80 mg dose, at which dose level an almost complete inhibition of PI3Kδ activity can be expected.

[0075] Thus, in some cases, treatment of patients with Compound 1 does not result in treatment-related grade 3 diarrhea or colitis in more than 5% of patients. More preferably, treatment of patients with Compound 1 does not result in treatment-related grade 3 diarrhea or colitis in more than 1% of patients. Most preferably, treatment of patients with Compound 1 does not result in clinically significant treatment-related diarrhea or colitis in patients.

[0076] As described in the Examples, the inventors have found that treatment with Compound 1 does not appear to result in clinically significant, treatment-related decreases in neutrophil counts below the normal range.

[0077] Thus, in some cases, treatment of patients with Compound 1 does not result in treatment-related grade 3 neutropenia in more than 5% of patients. More preferably, treatment of patients with Compound 1 does not result in treatment-related grade 3 neutropenia in more than 1% of patients. Most preferably, treatment of patients with Compound 1 does not result in clinically significant treatment-related neutropenia in patients.

[0078] It will be appreciated that side effects, depending on their severity, may interrupt or even preclude ongoing treatment. If severe side effects are observed, treatment may be suspended, the dose may be adjusted downward (which may adversely affect efficacy), or even lead to a decision to terminate treatment. In the treatment of cancer, any of these interruptions may have a significant adverse effect on the patient's health, prognosis, and / or morale.

[0079] The inventors have confirmed from initial testing that treatment with compound 1 provides a longer duration of treatment than would be expected with this class of inhibitor. In particular, the longer duration of treatment in the absence of severe side effects is expected to be beneficial for patients. In solid tumors, a partial antitumor response has already occurred in one patient at a dose of 20 mg, and several other patients at dose levels of 40 mg and 80 mg have achieved long-term disease stabilization.

[0080] Its excellent safety profile means that Compound 1 provides a treatment regimen that can be suitable for long-term use without interruption.It is therefore envisioned that patients can be prescribed a treatment regimen that spans several months.In some cases, the treatment is prescribed for at least one month.In some cases, the treatment is prescribed for at least two months.In some cases, the treatment is prescribed for at least three months.In some cases, the treatment is prescribed for at least four months.In some cases, the treatment is prescribed for at least five months.In some cases, the treatment is prescribed for at least six months.In some cases, the treatment is prescribed for at least one year.

[0081] In some cases, the treatment period is at least 1 month without interruption. In some cases, the treatment period is at least 2 months without interruption. In some cases, the treatment period is at least 3 months without interruption. In some cases, the treatment period is at least 4 months without interruption. In some cases, the treatment period is at least 5 months without interruption. In some cases, the treatment period is at least 6 months without interruption. In some cases, the treatment period is at least 1 year without interruption.

[0082] In some cases, the treatment is administered in 28 day cycles. The treatment period can be multiple 28 day cycles without interruption. In some cases, the treatment period is at least one year of 28 day cycles without interruption.

[0083] It will be appreciated that the methods of the present invention may be particularly useful in treating certain patient populations, for example elderly and / or frail patients who are currently ineligible to receive PI3Kδ inhibitors due to poor tolerability.

[0084] Thus, in some cases, the patient is 50 years or older, such as 55 years or older, such as 60 years or older, such as 65 years or older, such as 70 years or older, such as 75 years or older, such as 80 years or older.

[0085] In some cases, the patient is not suitable, or is deemed by the physician to be not suitable, for treatment with idelalisib and / or other PI3Kδ inhibitors.

[0086] In some cases, the patient has previously been diagnosed with a gastrointestinal disorder, such as colitis or chronic diarrhea.

[0087] Treatment of diseases or conditions in which signaling through the PI3Kδ pathway is pathologically implicated with compound 1 Compound 1 is a PI3Kδ inhibitor.It is recognized in the art that PI3K pathway is frequently activated in various diseases.Therefore, the method of the present invention is intended for treating diseases that are involved in and preferably causally related to the activation of PI3K pathway (compared to the state of healthy individuals), such as inflammatory disease, autoimmune disease or cancer.

[0088] Thus, the methods of the invention may relate to the treatment of a disease or disorder characterized by upregulation of the PI3K pathway. Thus, the methods of the invention may relate to the treatment of a disease or disorder by modulation of the PI3K pathway in a patient.

[0089] In some embodiments, the inflammatory disease or autoimmune disease can be activated PI3K delta syndrome (APDS), allergic disease, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS), primary Sjogren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic lupus erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and idiopathic thrombocytopenic purpura (ITP).

[0090] PI3K pathway is frequently activated in solid tumors and hematological malignancies. In some embodiments, the method of the present invention is directed to the treatment of cancer. The cancer can be a solid tumor or a hematological malignancy. In some embodiments, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including Waldenstrom's disease), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer and colorectal cancer.

[0091] In some embodiments, the cancer is melanoma, lymphoma, myelofibrosis, non-small cell lung cancer, or mesothelioma.

[0092] In some embodiments, the melanoma is selected from progressive or metastatic melanoma or ocular / uveal melanoma.Progressive or metastatic melanoma can be histologically confirmed unresectable stage III or stage IV melanoma.In some embodiments, the melanoma is uveal melanoma.

[0093] In some embodiments, the lymphoma is selected from a B cell lymphoma or a T cell lymphoma. ***

[0094] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, and presented in a particular form or in terms of means for performing a disclosed function, or a method or process for achieving a disclosed result, may be used separately or in any combination of such features, as appropriate, to realize the invention in its diverse forms.

[0095] Although the present invention has been described in conjunction with the above exemplary embodiments, many equivalent modifications and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the above exemplary embodiments of the present invention are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the present invention.

[0096] For the avoidance of doubt, the theoretical explanations provided herein are provided for the purpose of enhancing the understanding of the reader, and the inventors do not wish to be bound by any of these theoretical explanations.

[0097] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0098] Throughout this specification, including the claims which follow, unless the context specifically requires, the words "comprise" and "include", as well as variations such as "comprises", "comprising" and "including", are understood to imply the inclusion of stated elements or steps, or groups of elements or steps, but not the exclusion of other elements or steps, or groups of elements or steps.

[0099] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. The term "about" in connection with numerical values ​​is arbitrary and may mean, for example, + / - 10%. EXAMPLES

[0100] Example 1 First-in-Human Dosing Study of IOA-244 in Patients with Advanced or Metastatic Cancer A clinical study was conducted in patients with advanced or metastatic cancer to determine the safety and tolerability profile of Compound 1 in patients. This clinical study is listed on clinicaltrials.gov under number NCT04328844, and Compound 1 is provided as the hemifumarate salt. The estimated baseline completion date is September 2022, and the estimated study completion date is April 2023.

[0101] Example 2 Measurement of ALT levels in blood samples from patients administered Compound 1 Hepatotoxicity of Compound 1 in patients was identified by measuring ALT levels in blood samples from patients receiving the hemifumarate salt of Compound 1. Initial dose groups received 10, 20, and 40 mg once daily in an oral formulation as described herein. Data for these dose groups are shown in FIG. 1a. Additional dose groups received 80 mg once daily in an oral formulation as described herein. Data for all dose groups, including 80 mg once daily, are shown in FIG. 1b. This also shows additional dosing cycles for the 10, 20, and 40 mg once daily dose groups. The x-axis indicates the time of sample collection, with "Cx" meaning x cycles of 28 days and "Dy" meaning y days within the 28 day cycle. Thus, for each successive dosing period, C1D1 corresponds to dosing day 1, C1D8 corresponds to dosing day 8, etc., C2D1 corresponds to dosing day 29, C3D1 corresponds to dosing day 57, etc.

[0102] Surprisingly, it was observed that administration of compound 1 to patients did not result in clinically significant treatment-related elevations of ALT above the normal range. Even more surprisingly, administration of compound 1 reduced ALT levels in one patient who had elevated ALT levels prior to administration of compound 1. Figure 1b shows that compound 1 reduced ALT levels in three patients who had elevated ALT levels on day 1 of cycle 1 prior to administration of compound 1. In one other patient, ALT levels increased during administration of compound 1, and this increase was associated with the growth of tumor lesions in the liver.

[0103] This is surprising given that administration of idelalisib to patients has been reported to result in increased ALT levels in 42.9% of patients, which is considered to be a PI3Kδ target- and class-specific toxicity (see Table 57 in the CHMP evaluation report for Zydelig).

[0104] Example 3 Measurement of AST levels in blood samples from patients administered compound 1 The hepatotoxicity of Compound 1 in patients was identified by measuring AST levels in blood samples of patients receiving Compound 1. The initial dose groups were 10, 20, and 40 mg taken once daily in an oral formulation as described herein. The data for these dose groups is shown in FIG. 2a. An additional dose group was 80 mg taken once daily in an oral formulation as described herein. The data for all dose groups, including 80 mg once daily, is shown in FIG. 2b. This also shows additional dosing periods for the 10, 20, and 40 mg once daily dose groups.

[0105] Surprisingly, it was observed that administration of compound 1 to patients did not result in clinically significant treatment-related elevation of AST above normal range. Even more surprisingly, administration of compound 1 reduced ALT levels in one patient who had elevated AST levels before administration of compound 1. Even more surprisingly, administration of compound 1 reduced AST levels in three patients who had elevated AST levels on day 1 of cycle 1 before administration of compound 1. In one other patient, AST levels increased during administration of compound 1, and this increase was associated with the growth of tumor lesions in the liver.

[0106] The finding that administration of compound 1 did not increase AST levels is surprising given that administration of idelalisib to patients has been reported to result in increased AST levels in 41.8% of patients, which is considered to be a PI3Kδ target- and class-specific toxicity (see Table 57 in the CHMP evaluation report for Zydelig).

[0107] Example 4 Treatment-related adverse events (AEs) reported in patients receiving Compound 1 Treatment-related AEs reported by the treating investigators for patients administered Compound 1 were mild, grade 1, except for one case of grade 2 uveitis. Surprisingly, it was observed that administration of Compound 1 to patients did not result in typical toxicities observed for other PI3Kδ inhibitors, such as diarrhea / colitis and (respiratory) infections. There was only one suspected case of diarrhea, which was mild (grade 1) and short-lived (2 days) and could have been related to the food poisoning outbreak. There were no cases of colitis or (respiratory) infections. This is very surprising, since administration of idelalisib to patients has been reported to result in diarrhea / colitis in 38.2% of patients and infections in 59.3% of patients (see Table 49 in the CHMP assessment report for Zydelig). Table 2 documents the adverse events assessed by the investigators in relation to administration of Compound 1. No side effects were recorded in patients administered 80 mg QD. [Table 2]

[0108] Example 5 Measurement of neutrophils in blood samples from patients administered compound 1 The hematological toxicity of Compound 1 in patients was determined by measuring the neutrophil count in blood samples of patients receiving Compound 1. The initial dose groups received 10, 20, and 40 mg once a day in the oral formulation described herein. The data for these dose groups is shown in Figure 3a. The additional dose groups received 80 mg once a day in the oral formulation described herein. The data for all dose groups, including 80 mg once a day, is shown in Figure 3b. This also shows additional dosing cycles for the dose groups of 10, 20, and 40 mg once a day.

[0109] Surprisingly, it was observed that administration of Compound 1 to patients did not result in clinically significant, treatment-related neutrophil reduction below the normal range.

[0110] This is surprising given that administration of idelalisib to patients has been reported to result in a decrease in neutrophil counts in 45.5% of patients, which is considered to be a PI3Kδ target- and class-specific toxicity (Table 55 of Zydelig's CHMP evaluation report).

[0111] Example 6 CD63 marker information The pharmacodynamic (PD) activity of Compound 1 in patients was determined by measuring the percentage of CD63-positive basophils using the Basophil Activation Test (BAT) in blood samples of patients administered Compound 1 after ex vivo stimulation with anti-IgE. See Figures 4a and 4b.

[0112] Basophil degranulation following cross-linking of the FcεR1 receptor has been shown to be PI3Kδ-dependent (Ali 2008), and the activity of PI3Kδ inhibitors on basophil degranulation can be measured by inhibition of IgE-mediated CD63 expression ex vivo (Lannutti 2011). Compound 1 shows a dose-dependent reduction in CD63-positive basophils in patient blood samples comparable to that reported for idelalisib (Horak 2016).

[0113] References A number of publications are cited above in order to more fully describe and disclose the present invention and the state of the art to which it pertains. Full citations for these references are provided below. Each of these references is incorporated herein in its entirety. WO2011058149 WO201412190 CHMP assessment report on Zydelig(2014) Ali, K. et al. (2008). Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110δ but Not p110γ Promotes Optimal Allergic Responses In Vivo. J Immunol 180, 2538-2544. Brock, C. et al. (2003). Roles of Gβγ in membrane recruitment and activation of p110γ / p101 phosphoinositide 3-kinase γ. J Cell Biology 160, 89-99. Buchanan, C. M. Et al. (2019). For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors. Biomol 9, 402. Curigliano and Shah(2019). Safety and Tolerability of Phosphatidylinositol-3-Kinase(PI3K) Inhibitors in Oncology. Drug Saf. 42(2), 247-262. Esposito, A. Et al. (2019). Safety, Tolerability, and Management of Toxic Effects of Phosphatidylinositol 3-Kinase Inhibitor Treatment in Patients With Cancer. Jama Oncol 5, 1347-1354. Haselmayer, P. et al., Frontiers in Immunology(2014), Vol.5, Art.233, p.1-15; p.2, col.2, section “Chemical Synthesis”, par.1 refer to Horak,F.et al.(2016).Randomized phase 1 study of the phosphatidylinositol 3-kinase δ inhibitor idelalisib in patients with allergic rhinitis.J Allergy Clin Immun 137,1733-1741. Jimenez,C.et al.(2002).The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras.J Biol Chem 277,41556-62. Johnson,Z.et al.,AACR 2020,poster 666 Lannutti,B.J.et al.(2011).CAL-101,a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies,inhibits PI3K signaling and cellular viability.Blood 117,591-594 Phillips,T.J.et al.(2020).Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma? Clin Lymphoma Myeloma Leukemia 21,8-20.e3. Vanhaesebroeck,B.et al.(2005).Signalling by PI3K isoforms:insights from gene-targeted mice.Trends Biochem Sci 30,194-204.

[0114] For standard molecular biology techniques, see Sambrook, J., Russell, DW Molecular Cloning, A Laboratory Manual. 3rd ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

Claims

1. Compounds of formula I for use in a method for the treatment of cancer or an inflammatory or autoimmune disease 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The compound of formula I or a pharma- ceutically acceptable salt thereof, wherein said method comprises administering said compound at a dose of from 36 mg to 72 mg of said compound per day.

2. 2. The compound or salt for use in the method of claim 1, wherein said dosage is about 36 mg per day.

3. 2. The compound or salt for use in the method of claim 1, wherein said dosage is about 72 mg per day.

4. Salts of formula Ia for use in a method for the treatment of cancer or an inflammatory or autoimmune disease 【Chemistry 2】 wherein the method comprises administering the salt of formula Ia at a dosage of from 40 mg to 80 mg of the salt per day.

5. 5. The method of claim 4, wherein the dosage is about 40 mg per day.

6. 5. The method of claim 4, wherein said dosage is about 80 mg per day.

7. The compound or salt for use in the method of any one of claims 1 to 6, wherein said administration is once daily.

8. 8. The compound or salt for use in the method of any of claims 1 to 7, wherein said administration comprises one solid dosage unit containing 40 mg or 80 mg of said salt of formula Ia.

9. 9. The compound or salt for use in the method of any of claims 1 to 8, wherein the dose comprises two solid dosage units, each dosage unit containing 20 mg or 40 mg of the salt of formula Ia.

10. 8. The compound or salt for use in the method of any of claims 1, 3, 4, 6, or 7, wherein the dosage comprises four solid dosage units, each dosage unit containing 20 mg of the salt of formula Ia.

11. A compound or salt for use in the method of any one of claims 1 to 10, wherein the disease is cancer.

12. 12. The compound or salt for use in the method of claim 11, wherein the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including Waldenstrom's disease), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer and colorectal cancer, optionally wherein the cancer is selected from melanoma, lymphoma, myelofibrosis, non-small cell lung cancer and mesothelioma.

13. A compound or salt for use in the method of any one of claims 1 to 10, wherein the disease or condition is an inflammatory disease or an autoimmune disease.

14. 14. The compound or salt for use in the method of claim 13, wherein the disease or condition is selected from allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS), primary Sjogren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic lupus erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and idiopathic thrombocytopenic purpura (ITP).

15. A solid dosage unit comprising 20 mg, 40 mg or 80 mg of a salt of formula Ia, 【Chemistry 3】 Optionally, the salt of formula Ia is formulated in a pharmaceutical composition comprising microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate; Optionally, the solid dosage unit wherein the pharmaceutical composition is provided in a shell capsule or tablet.

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