PI3K-delta inhibitors for the treatment of pancreatic cancer

Abstract

A PI3K-delta inhibitor or a pharma- ceutical acceptable salt thereof for use in a method for treating pancreatic cancer in a patient, optionally the method further comprising administration of an autotaxin (ATX) inhibitor or a pharma-ceutical acceptable salt thereof.

Description

[Technical field]

[0001] This application claims priority to GB2104416.9, filed March 29, 2021, GB2108242.5, filed June 9, 2021, and GB2117511.2, filed December 3, 2021, the contents and elements of which are incorporated herein by reference for all purposes.

[0002] The present invention relates to compounds, or pharma- ceutically acceptable salts thereof, for use in a method for the treatment of pancreatic cancer, and combination methods comprising said compounds. [Background technology]

[0003] Pancreatic cancer is a malignant tumor of the pancreas. Early stage pancreatic cancer usually does not cause symptoms, so it is called a "silent" disease. Therefore, it is difficult to detect it in the early stages.

[0004] Pancreatic cancer is one of the most lethal types of cancer, with a very low 5-year survival rate of only 7%. Only 25% of pancreatic cancer patients are candidates for surgery at the time of diagnosis, and only about 20% of patients who undergo surgical resection survive beyond 5 years. Chemotherapy with gemcitabine is the standard of care, with a response rate of 5-10% and a median mean overall survival of 6 months (Burris et al. 1997).

[0005] Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic cancer, is an increasingly serious health problem with increasing mortality rates worldwide, placing a significant economic burden on healthcare systems, and severely impacting patients' quality of life. In some regions, PDAC is predicted to become the second leading cause of cancer death. The incidence of pancreatic cancer is increasing in Western countries, necessitating a greater understanding of the risk factors and symptoms associated with this disease to inform both healthcare professionals and the general population about potential preventive measures and / or early detection criteria. Currently, there is a lack of therapeutic approaches for early detection that would increase patient survival.

[0006] Pancreatic cancer progression is usually characterized by a dramatic desmoplastic response, including fibroblasts, immune cells, and a dense extracellular matrix. Due to this highly fibrotic tumor microenvironment (TME), conventional chemotherapy and radiation therapy have only moderate antitumor activity against pancreatic tumors. Similarly, immunotherapies, such as anti-PD-1 therapy, have been shown to be highly effective against other cancer types but ineffective against pancreatic cancer. Therefore, new treatments for pancreatic cancer, especially those that can enhance the efficacy of immunotherapy, are desperately needed.

[0007] The PI3K pathway is frequently activated in a variety of solid tumors and hematological malignancies, making PI3K an attractive therapeutic target in oncology. The pathway is also essential for many cancer-related activities, including endothelial cell sprouting for angiogenesis, transcriptional reprogramming of macrophages, T-cell differentiation and homeostasis, and chemoresistance by fibroblasts (Conway et al., 2019). Taken together, this suggests that the application of PI3K pathway inhibitors as a pancreatic cancer treatment may provide an opportunity for dual targeting of cancer cells and deregulated cancer-associated stromal components.

[0008] Pancreatic cancer is usually associated with PI3K pathway activation, and patients with high PI3K pathway activity have been shown to have significantly poorer survival than those with low activation. Given the various roles of different PI3K isoforms in both tumors and associated stromal cells, isoform-specific inhibitors could individually target oncogenic signaling, theoretically allowing redundancy to mitigate off-target side effects in healthy tissues. However, despite the promising efficacy of isoform-specific inhibitors in preclinical models of monotherapy or combination therapy, clinical development of these inhibitors has been largely hampered by tolerability issues, as exemplified by a recent study of the PI3Kδ inhibitor idelalisib in patients with pancreatic cancer (Borazanci et al., 2020). Therefore, isoform-specific PI3K inhibitors for the treatment of pancreatic cancer, especially those that are well tolerated, are desperately needed.

[0009] In view of the above, there is a need in the art for PI3K modulators that inhibit specific PI3K isoforms, particularly PI3Kδ, for the treatment of pancreatic cancer. Additionally, there is a need in the art for improved methods of treating pancreatic cancer with (combinations of) compounds that have high selectivity and a favorable safety profile.

[0010] The present inventors recognized this need and embarked on the devising of the present invention.

[0011] 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

[0012] The present invention is directed to a compound for use in the treatment of pancreatic cancer.The compound is a PI3K-delta inhibitor.The inventors have recognized that PI3K δ inhibitors can be useful in targeted therapy for the treatment of pancreatic cancer.

[0013] In a first aspect, the present invention provides a compound of formula I for use in a method of treating pancreatic cancer in a patient: [ka] or a pharma- ceutically acceptable salt thereof. The compound of formula I is sometimes referred to herein as "Compound 1."

[0014] The term pancreatic cancer includes all exocrine or neuroendocrine pancreatic cancer types.In some cases, pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).PDAC is the most common neoplastic disease of the pancreas, and accounts for more than 90% of all pancreatic malignancies.

[0015] Compound 1 may be used as a monotherapy.The present invention further relates to combination treatment methods.

[0016] In some cases, the treatment is a combination therapy and includes a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof. The compound of formula II may be referred to herein as "Compound 2."

[0017] The combination of Compound 1 and Compound 2 may be synergistic and / or may otherwise result in improved therapeutic outcome or patient prognosis.

[0018] Suitably, compound 1 is administered in a pharmaceutical composition comprising compound 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent, carrier or excipient.Preferably, but not necessarily, the pharmaceutical composition is suitable for oral administration.Suitably, compound 2 is administered in a pharmaceutical composition comprising compound 2 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent, carrier or excipient.Preferably, but not necessarily, the pharmaceutical composition is suitable for oral administration.

[0019] The treatment may include administration of a checkpoint inhibitor. Suitably, the checkpoint inhibitor targets PD-1, PD-L1 or LAG3. For example, the checkpoint inhibitor may be an anti-PD-1 and / or anti-PDL1 monoclonal antibody. Exemplary checkpoint inhibitors are described herein.

[0020] Thus, in some cases, the method can include administration of Compound 1 or a salt thereof and a checkpoint inhibitor. In some cases, the method can include administration of Compound 1 or a salt thereof, Compound 2 or a salt thereof, and a checkpoint inhibitor (a triple combination).

[0021] In some cases, the treatment is a combination therapy and includes one or more additional chemotherapeutic agents.

[0022] For example, the methods described herein may include administering a therapeutically effective amount of an additional chemotherapeutic agent, optionally two additional chemotherapeutic agents. Suitable chemotherapeutic agents include gemcitabine and nab-paclitaxel. Thus, the methods of the present invention may include administering gemcitabine and / or nab-paclitaxel. Combination therapy may result in improved activity (tumor growth inhibition) and / or reduced side effects when compared with a single chemotherapeutic agent.

[0023] Thus, in some cases, the method may include administration of compound 1 or a salt thereof, and one or more additional chemotherapeutic agents, such as gemcitabine and / or nab-paclitaxel. In some cases, the method may include administration of compound 1 or a salt thereof, a checkpoint inhibitor (e.g., an anti-PD-1 and / or an anti-PDL1 monoclonal antibody), and one or more additional chemotherapeutic agents (e.g., gemcitabine and / or nab-paclitaxel).

[0024] Thus, in some cases, the method may include administration of compound 1 or a salt thereof, compound 2 or a salt thereof, and one or more additional chemotherapeutic agents, such as gemcitabine and / or nab-paclitaxel. In some cases, the method may include administration of compound 1 or a salt thereof, compound 2 or a salt thereof, a checkpoint inhibitor (e.g., an anti-PD-1 and / or an anti-PDL1 monoclonal antibody), and one or more additional chemotherapeutic agents (e.g., gemcitabine and / or nab-paclitaxel).

[0025] 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]

[0026] [Figure 1] Figures 1a and 1b show the activity of Compound 1 and the activity of Compound 1 in combination with an ATX inhibitor in the KPC mouse model of pancreatic cancer. [Diagram 2]Figures 1a and 1b show the activity of compound 1 in combination with checkpoint inhibitors in the Pan02 mouse model of pancreatic cancer. [Diagram 3] 1 shows the effect of the combination of compound 1 and a checkpoint inhibitor on body weight in the Pan02 mouse model of pancreatic cancer. [Figure 4a] 1 shows the activity of Compound 1 and in combination with an ATX inhibitor in the orthotopic KPC mouse model of pancreatic cancer. [Figure 4b] 1 shows the activity of Compound 1 and in combination with an ATX inhibitor in the orthotopic KPC mouse model of pancreatic cancer. [Figure 4c] 1 shows the activity of Compound 1 and in combination with an ATX inhibitor in the orthotopic KPC mouse model of pancreatic cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] 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.

[0028] compound 1 Compound 1 is Example 339 of WO2011 / 058149, which is incorporated herein by reference in its entirety. Its structure is according to Formula I: [ka]

[0029] 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.

[0030] Compound 1 may be prepared and characterized as described in published patent application WO2011 / 058149A1 (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.

[0031] 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.

[0032] 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 20-thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine to give compound 1.

[0033] 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.

[0034] 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.

[0035] Thus, in some cases, Compound 1 is administered as the hemifumarate salt (Formula Ia). 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. [ka]

[0036] 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).

[0037] compound 2 WO2016124939 describes various ATX inhibitor compounds, including compound 2, and their use in the treatment of proliferative diseases in which ATX activity is implicated.

[0038] Compound 2 is Example 40 of WO2016124939, which is incorporated herein by reference in its entirety. WO2016124939 describes over 200 examples. The structure of Compound 2 is according to Formula II: [ka]

[0039] Its IUPAC name is N-[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide. Its synthesis and characterization are described in WO2016124939, pages 77 and 82, respectively, the information of which is specifically incorporated herein by reference.

[0040] Compound 2 may be provided and administered as a free base or as a pharma- ceutically acceptable salt. In some cases, Compound 2 is provided and administered as a free base.

[0041] Checkpoint inhibitors Some methods of the present invention are directed to combination therapy that includes checkpoint inhibitors.The potential of checkpoint inhibitors in the treatment of cancer has been recognized in the art.Checkpoint inhibitors may target either PD-1 or PD-L1 protein to block the binding of PD-1 and PD-L1, or may target LAG3 to enhance immune response against cancer cells.

[0042] In some methods of the invention, Compound 1 is administered in combination with a PD-1 inhibitor (also called anti-PD-1). Examples of anti-PD-1 monoclonal antibodies include pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), spartalizumab, camrelizumab, sintilimab, dostallimab, tislelizumab, toripalimab, and retifanlimab.

[0043] In some methods of the invention, Compound 1 is administered in combination with a PD-L1 inhibitor (also called anti-PD-L1). Examples of anti-PD-L1 monoclonal antibodies include atezolizumab (Tecentriq®), durvalumab (Imfinzi®), avelumab (Bavencio®), M7824, and KN035.

[0044] In some methods of the invention, compound 1 is administered in combination with a LAG3 inhibitor (also called anti-LAG3). Examples of anti-LAG3 monoclonal antibodies include leratolimab, tebotelimab, faveselimab, leramilimab, IMP-321, TSR-033, SYM-022, INCAGN02385, RG6139, and BI754111.

[0045] Checkpoint inhibitors are typically administered by IV infusion, and the appropriate dose and dosing regimen is known for each approved checkpoint inhibitor.

[0046] Methods of the Invention As described in more detail below, the inventors have surprisingly found that compound 1 exhibits potent antitumor activity and is well tolerated in preclinical models of pancreatic cancer. Thus, a PI3K inhibitor with specificity for the δ isoform, antitumor activity, and a favorable safety profile for pancreatic cancer may be provided.

[0047] Furthermore, the present inventors have surprisingly found that compound 1 increases the antitumor activity of immunotherapy such as autotaxin (ATX) and checkpoint inhibition.Therefore, a specific PI3Kδ inhibitor can be provided that can enhance the efficacy of immunotherapy in pancreatic cancer.

[0048] In other words, the inventors have surprisingly found that pancreatic cancer can be treated with Compound 1, with or without immunotherapy, and that this treatment is well tolerated.

[0049] Thus, the present invention is directed to a method of treating pancreatic cancer using Compound 1. Compound 1 may be suitable as a monotherapy or may be provided in combination with another agent.

[0050] More specifically, the inventors have found that compound 1 has a favorable safety profile in humans, particularly with respect to hepatotoxicity, diarrhea / colitis, respiratory infections, 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 a favorable safety profile for patients may be provided. These results are described in GB2104416.9 (filed March 29, 2021).

[0051] Further advantageous properties of treatment methods using Compound 1 may include one or more of greater efficacy, longer duration of administration, and less dose reduction or interruption or cessation.

[0052] In other words, the inventors have surprisingly found that patients can be treated with Compound 1 with fewer side effects than would be expected from a treatment regimen using a PI3K inhibitor, making the treatment suitable for long-term prescription without the need to reduce or interrupt dosing.

[0053] Administration of Compound 1 can be once a day (QD) or twice a day (BID), preferably once a day, and preferably, but not necessarily, can be administered orally. Other administration methods may be used. A suitable daily dose may be 5 mg to 2 g, for example, 10 mg to 1 g. In some cases, when Compound 1 is administered in combination therapy, administration of Compound 1 continues during the cessation of administration of the other agent (e.g., between days 21 and 28 of a 28-day chemotherapy cycle).

[0054] In some cases, Compound 1 is administered as a hemifumarate salt, however, it will be understood that the invention is not so limited and other solid forms (e.g., other pharma- ceutically acceptable salts) are also contemplated.

[0055] 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).

[0056] An exemplary method may include administering Compound 1 in an amount of 18 mg to 108 mg per day, for example, 18 mg to 72 mg per day. In some cases, the amount is 27 mg to 90 mg per day, for example, 27 mg to 54 mg per day. In some cases, the amount is 27 mg to 45 mg per day, for example, about 36 mg per day. In some cases, the amount is 54 mg to 90 mg per day, for example, about 72 mg per day.

[0057] When compound 1 is administered as a hemifumarate salt (Formula Ia), an exemplary method includes administering compound 1 as the hemifumarate salt in an amount of 20 mg to 120 mg per day, for example, 20 mg to 80 mg per day. In some cases, the amount is 30 mg to 100 mg per day, for example, 30 mg to 60 mg per day. In some cases, the amount is 30 mg to 50 mg per day, for example, about 40 mg per day. In some cases, the amount is 60 mg to 100 mg per day, for example, about 80 mg per day.

[0058] Lower doses are also contemplated and contemplated.Thus, it is understood that in any method described herein, the method can include administering compound 1 in an amount of 9mg to 108mg per day, for example, 9mg to 72mg per day.When compound 1 is administered as a hemifumarate, in any method described herein, the method can include administering compound 1 as the hemifumarate in an amount of 10mg to 120mg per day, for example, 10mg to 80mg per day.

[0059] Inhibition of the PI3Kδ pathway in patients can be demonstrated by measuring the pharmacodynamic activity (PD) of compound 1 in blood samples. A specific PD marker for PI3Kδ inhibition in blood is CD63 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 similar to that reported for other PI3Kδ inhibitors (e.g., idelalisib). Especially at the 40 mg dose, the percentage of CD63-positive basophils was low in all samples measured, confirming effective inhibition of the PI3Kδ pathway over the course of treatment.

[0060] 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.

[0061] However, it is understood that higher doses are included and contemplated.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.

[0062] 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.

[0063] The inventors have found that once-daily dosing is effective and well tolerated. Once-daily dosing 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 side effects require dose reduction). Once-daily dosing can improve patient experience and improve patient compliance. Cancer patients, especially those with advanced cancer, often experience a significant pill burden and may have difficulty swallowing.

[0064] 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).

[0065] 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., solid dosage units containing 20 mg of Compound 1 as the hemifumarate salt).

[0066] 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.

[0067] 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. These results are described in GB2104416.9 (filed March 29, 2021).

[0068] 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.

[0069] The inventors further confirmed from initial testing that treatment with Compound 1 results in fewer side effects than would be expected with this class of inhibitors. In particular, less severe diarrhea and / or colitis is expected to occur. These results are described in GB2104416.9 (filed March 29, 2021).

[0070] 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.

[0071] The inventors have observed that treatment with Compound 1 does not appear to result in clinically significant, treatment-related reductions in neutrophil counts below the normal range. These results are described in GB2104416.9 (filed March 29, 2021).

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] In some cases, the patient has previously been diagnosed with a gastrointestinal disorder, such as colitis or chronic diarrhea.

[0080] Combination with Compound 2 The present inventors have observed that the combination of Compound 1 and Compound 2 shows obvious synergistic activity against high grade and acinar ductal metaplasia (ADM) tumor burden and high grade and ADM lesion count. The combination of Compound 1 and Compound 2 also shows obvious synergistic activity against pancreatic cancer-related activities, including tumor fibrosis, tumor regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs).

[0081] In some embodiments, the present invention provides compound 1, or a pharma- ceutical acceptable salt thereof, for use in a method for treating pancreatic cancer, the method comprising administering compound 1, or a pharma- ceutical acceptable salt thereof, and compound 2, or a pharma-ceutical acceptable salt thereof.

[0082] In some embodiments, the present invention provides a combination of compound 1, or a pharma- ceutically acceptable salt thereof, and compound 2, or a pharma- ceutically acceptable salt thereof, for use in a method for the treatment of pancreatic cancer.

[0083] The administration of compound 2 may be administered once a day (QD), preferably twice a day (BID), preferably, but not necessarily, orally. Other methods of administration may also be used. A suitable daily dose may be 5 mg to 2 g, for example, 10 mg to 1 g.

[0084] Compound 1 and compound 2 may be administered at the same time or at different times. For example, compound 1 may be administered once a day and compound 2 may be administered twice a day. Suitably, but not necessarily, compound 1 and compound 2 are provided in separate formulations (e.g., separate dosage units such as tablets or capsules).

[0085] Combination with checkpoint inhibitors The inventors have observed that the combination of Compound 1 with checkpoint inhibitors may be advantageous, and that the combination of Compound 1 with anti-PD-1 antibody shows much stronger anti-tumor growth activity than anti-PD-1 antibody alone. Body weight data suggests that the combination may be well tolerated.

[0086] Thus, in some embodiments, the present invention provides compound 1, or a pharma- ceutically acceptable salt thereof, for use in a method for treating pancreatic cancer, the method comprising administering compound 1, or a pharma- ceutically acceptable salt thereof, and a checkpoint inhibitor. Suitably, the checkpoint inhibitor is a PD-1 or PD-L1 inhibitor. Optionally, it is a PD-1 inhibitor. Optionally, it is a PD-L1 inhibitor.

[0087] Combination with additional chemotherapy agents In some embodiments, the methods described herein may include administering a therapeutically effective amount of an additional chemotherapeutic agent, optionally two additional chemotherapeutic agents. Suitable chemotherapeutic agents include gemcitabine and nab-paclitaxel. Thus, the methods of the present invention may include administering gemcitabine and / or nab-paclitaxel.

[0088] Thus, in some cases, the methods of the present invention are directed to combination therapy, which includes treatment of a patient with Compound 1 or a pharma- ceutically acceptable salt thereof and an additional chemotherapeutic agent, such as gemcitabine (Gemzar®) or nab-paclitaxel (Abraxane®). Optionally, a checkpoint inhibitor may also be administered.

[0089] It is understood that compound 1 and the additional chemotherapeutic agent(s) can be suitably administered at different times and / or different schedules, and can be formulated for administration by different routes, although not necessarily.For example, compound 1 or its pharmaceutically acceptable salt can be administered as an oral dose, for example, a daily oral dose, and the additional chemotherapeutic agent can be administered as an infusion.For example, both gemcitabine and nab-paclitaxel can be administered on days 1, 8, and 15 in a 28-day cycle.

[0090] In some cases, the combination therapy includes treating the patient with Compound 1, or a pharma- ceutically acceptable salt thereof, and gemcitabine and nab-paclitaxel.

[0091] 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.

[0092] The formulation suitably comprises one or more pharma- ceutically acceptable excipients, disintegrants, glidants, and / or lubricants.

[0093] In some cases, the oral dosage form may contain 5 mg of Compound 1 provided as a hemifumarate salt. In some cases, the oral dosage form may contain 20 mg of Compound 1 provided as a hemifumarate salt. Both oral dosage forms are manufactured as described in Table 1.

[0094] 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]

[0095] 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.

[0096] Thus, the present invention further relates to pharmaceutical compositions comprising Compound 1, preferably provided as the hemifumarate salt, formulated for oral administration.

[0097] 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.

[0098] 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.

[0099] Thus, in some embodiments, Compound 1 is provided as a solid dosage unit comprising a pharmaceutical composition comprising 5 mg of the hemifumarate salt of Compound 1. Thus, in some embodiments, Compound 1 is provided as 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.

[0100] 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.

[0101] Suitably, compound 2 is provided in a pharmaceutical composition that is formulated for oral administration.The pharmaceutical composition may be provided in capsule or tablet.In some cases, it is provided in tablet.In other cases, it is provided as a powder or granular composition or liquid composition in capsule, for example, hard or soft shell capsule, for example, gelatin or hydroxymethylcellulose (HPMC) capsule.In other words, oral dosage form is preferred.

[0102] The formulation suitably comprises one or more pharma- ceutically acceptable excipients, disintegrants, glidants, and / or lubricants.

[0103] The checkpoint inhibitor and / or additional chemotherapeutic agent may be provided in any suitable formulation and in any suitable dosage, by any suitable means of administration. Suitably, but not necessarily, the checkpoint inhibitor and / or additional chemotherapeutic agent may be an approved drug prescribed and administered in accordance with its label.

[0104] Treatment of pancreatic cancer using compound 1 Compound 1 is a PI3Kδ inhibitor.It is recognized in the art that PI3K pathway is frequently activated in pancreatic cancer.Therefore, the method of the present invention is intended for the treatment of pancreatic cancer, including but not limited to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET or PNET).

[0105] Thus, the methods of the invention may be relevant to the treatment of pancreatic cancer characterized by upregulation of the PI3K pathway.Thus, the methods of the invention may be relevant to the treatment of pancreatic cancer by modulation of the PI3K pathway in a patient.

[0106] The pancreatic cancer may include any exocrine or neuroendocrine pancreatic cancer type.Thus, the method of the present invention is directed to the treatment of pancreatic cancer, including but not limited to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET or PNET).In some cases, the pancreatic cancer is pancreatic ductal adenocarcinoma.In some cases, the pancreatic cancer is pancreatic neuroendocrine tumor.

[0107] The treatment may be a monotherapy or a combination therapy as described herein. ***

[0108] 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.

[0109] 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.

[0110] 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.

[0111] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0112] 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.

[0113] 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

[0114] Example 1 Activity of Compound 1 with and without ATX inhibitors in the KPC mouse model of pancreatic cancer The KPC mouse is an established, clinically relevant model of pancreatic ductal adenocarcinoma (PDAC) that expresses many key features observed in human PDAC, such as pancreatic intraepithelial neoplasia along with a robust inflammatory response including elimination of effector T cells. Metastases are observed in approximately 80% of these mice, primarily located in the liver and lungs. Mutations in both the KRAS and TP53 genes are found in approximately 80% and 70% of all human PDAC, respectively. The genetic background of the KPC mouse includes a deletion in the transformation-associated protein 53 gene (p53 floxflox ), and a conditionally activating point mutation in the KRAS gene (KRAS G12D). A lox-stop-lox termination sequence is encoded upstream of the KRAS mutant gene to prevent expression in the absence of Cre recombinase. Exposure to Cre recombinase removes the loxP-introduced p53 sequence, creating a null allele (+ / -). The pancreas-specific Pdx-1 promoter allows expression of Cre recombinase in acinar, islet and ductal cells of the pancreas. Cre-mediated recombination excises the lox-stop-lox termination sequence, allowing expression of KRAS G12D in pancreatic tissue. This genetic background results in the development of malignant cells early after conception, leading to tumor growth and, if left untreated, death of the mouse.

[0115] Five-week-old KPC mice were treated with either Compound 1 in drinking water, Compound 2 (ATX inhibitor) in mixed feed, or a combination of both drugs. Control animals received regular drinking water and standard feed. Six weeks after the start of treatment, i.e., at 11 weeks of age, treatment was stopped and mice were euthanized. Pancreases were harvested and analyzed by histological analysis of the number of lesions and tumor burden according to arbitrary scoring units of differentiation grade (from acinar-ductal metaplasia [ADM] to increasingly severe pancreatic intraepithelial neoplasia [PanIN-1 / 2 / 3] and PDAC).

[0116] As shown in Figure 1, compound 1 alone reduces high grade (PanIN-3 and PDAC) tumor burden without significantly affecting the number of lesions in this model. Compound 2 alone reduces low grade (PanIN-1 and PanIN-2) lesion number in this model without significantly affecting tumor burden. Surprisingly, the combination of compound 1 and compound 2 shows obvious synergistic activity against high grade and ADM tumor burden and high grade and ADM lesion number.

[0117] Example 2 Activity of Compound 1 in Combination with Checkpoint Inhibitors in the Syngeneic Pan02 Mouse Model of Pancreatic Cancer (Anti-Mouse PD-1 mAb Clone RMP1-14) Pan02 is a well-established pancreatic ductal adenocarcinoma (PDAC) mouse model derived from chemically induced (3-methylcholanthrene, 3-MCA) tumor cells in male C57BL / 6 mice. The non-immunogenic ("cold") tumor profile and relatively slow tumor growth of this model make it an ideal model for evaluation of anti-cancer immunotherapy responses and immune system pharmacodynamics.

[0118] Ten 6- to 8-week-old female C57BL / 6 mice per group were injected with 3x10 6 The cells were injected subcutaneously in 100 μl of serum-free RPMI medium. The average tumor volume was 60 mm 3 At the time of reaching 10 days, the animals were randomly assigned to different test groups, i.e., vehicle, anti-PD-1 alone, and anti-PD-1 plus compound 1. Vehicle (1% methylcellulose solution) and compound 1 (30 mg / kg) were administered by oral gavage twice per day (BID). Anti-PD-1 (10 mg / kg) in PBS was administered by intraperitoneal (IP) injection twice weekly (BIW).

[0119] As shown in Figure 2, the tumor volume and area under the curve (AUC) indicate that anti-PD-1 antibody has only a moderate effect on tumor growth in this model. Surprisingly, the combination of anti-PD-1 antibody and compound 1 shows much stronger anti-tumor growth activity compared to anti-PD-1 antibody alone. Furthermore, as also seen in Figure 3, compound 1 and the combination of anti-PD-1 antibody and compound 1 are well tolerated as they do not result in weight loss. This is surprising given the poor tolerability observed with idelalisib in pancreatic cancer patients and the warning letter issued by the US Food and Drug Administration (FDA) regarding the increased incidence of adverse events, including deaths, in clinical trials of idelalisib in combination with other cancer medicines (Borazanci et al., 2020).

[0120] Example 3 Activity of Compound 1 with and without ATX inhibitors in the KPC / WCB3 orthotopic mouse model of pancreatic cancer We evaluated the therapeutic efficacy of compound 1 with and without an ATX inhibitor in the orthotopic KPC / WCB3 mouse model of pancreatic cancer. This model consists of transplanting KPC / WBC3 cells derived from a donor tumor that developed spontaneously in KPC mice into the pancreas of male wild-type C57BL / 6J recipient mice. The pathology and tumor microenvironment of this model closely resemble human pancreatic cancer.

[0121] 2x10 5 KPC / WCB3 cells were orthotopically injected into the pancreas of 8-week-old mice (Charles River Laboratories). Treatment with drinking water containing compound 1, mixed feed containing compound 2, or a combination of both drugs was initiated 7 days after injection of KPC / WCB3 cells. Control animals received regular drinking water and standard feed. One month after initiation, treatment was discontinued and mice were euthanized. Pancreases were harvested and analyzed by histological analysis for the level of fibrosis, the number of Tregs, and the number of proliferative CAFs.

[0122] As shown in Figure 4, compound 1 alone has limited effect on tumor fibrosis score and proliferative CAF, but significantly reduces Treg. Compound 2 alone has limited effect on tumor fibrosis score, but significantly reduces Treg and proliferative CAF. Surprisingly, the combination of compound 1 and compound 2 shows obvious synergistic activity on fibrosis score and proliferative CAF while maintaining a strong reduction in Treg.

[0123] 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 Borazanci, E., Pishvaian, MJ, Weekes, C., Huang, J. & Rajakumaraswamy, NA Phase Ib Study of Single Agent Idelalisib Followed by Idelalisib in Combination with Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma. Oncol(2020)doi:10.1634 / theoncologist.2020-0321. Burris, HA et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15, 2403-2413 (1997). Conway, JR, Herrmann, D., Evans, TJ, Morton, JP & Timpson, P. Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalized medicine.Gut 68,742(2019). See Haselmayer, P. et al., Frontiers in Immunology (2014), Vol. 5, Art. 233, p. 1-15; p. 2, col. 2, section “Chemical Synthesis”, par. 1

[0124] 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. A compound of formula I for use in a method of treating pancreatic cancer in a patient: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. The method further comprises: 【Chemistry 2】 2. The compound or salt for use according to claim 1, comprising administration of:

3. 3. The compound or salt for use according to claim 1 or claim 2, wherein the compound of formula I is administered in a pharmaceutical composition comprising the compound or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable diluent, carrier or excipient, the pharmaceutical composition being suitable for oral administration.

4. The compound or salt of formula II for use according to claim 2 or claim 3, wherein the compound is administered in a pharmaceutical composition comprising the compound or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent, carrier or excipient, the pharmaceutical composition being suitable for oral administration.

5. The compound or salt for use according to any one of claims 1 to 4, wherein the method further comprises administration of a checkpoint inhibitor.

6. The compound or salt for use according to claim 5, wherein the checkpoint inhibitor is an anti-PD-1 and / or anti-PDL1 monoclonal antibody.

7. The compound or salt for use according to any one of claims 1 to 6, wherein the method comprises the administration of a therapeutically effective amount of an additional chemotherapeutic agent.

8. 8. The compound or salt for use according to claim 7, wherein the additional chemotherapeutic agent is gemcitabine.

9. 8. The compound or salt for use according to claim 7, wherein the additional chemotherapeutic agent is nab-paclitaxel.

10. 8. The compound or salt for use according to claim 7, wherein two additional chemotherapeutic agents are used.

11. 11. The compound or salt for use according to claim 10, wherein the two additional chemotherapeutic agents are gemcitabine and nab-paclitaxel.

12. The compound or salt for use according to any one of claims 1 to 11, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

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