Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152

Definitions

• the present invention relates to a compound or pharmaceutically acceptable salt thereof for use in a method of treatment of pancreatic cancer, and to combination methods including said compound.
• Pancreatic cancer is a malignant tumour of the pancreas. Pancreatic cancer has been called a ‘silent’ disease because early pancreatic cancer usually does not cause symptoms. It is therefore difficult to detect in its early stages.
• Pancreatic cancer is one of the deadliest types of cancer with a very poor 5-year survival rate of only 7%. A mere 25% of pancreatic cancer patients are surgical candidates at the time of diagnosis, and of those who receive surgical resection, only about 20% live longer than 5 years. Chemotherapy with gemcitabine is a standard treatment with a 5-10% response rate and average median overall survival of 6 months (Burris et al. 1997).
• Pancreatic ductal adenocarcinoma the most prevalent form of pancreatic cancer, is a growing health problem with increasing mortality worldwide, exerting a huge economic burden on our healthcare system and significantly impacting the quality of life of patients. It is predicted that PDAC will become the second leading cause of cancer death in some regions.
• the incidence of pancreatic cancer is increasing in the Western world and a better understanding of the risk factors and symptoms associated with this disease is needed to inform both health professionals and the general population of potential preventive and/or early detection measures. There is currently a lack of therapeutic approaches for early-stage detection which would increase patient survival.
• Pancreatic cancer progression typically features a dramatic desmoplastic reaction, including fibroblasts, immune cells, and a dense extracellular matrix. Because of this highly fibrotic tumour microenvironment (TME), conventional chemotherapy and radiotherapy have only moderate anti-tumour activity in pancreatic tumours. Similarly, immune therapies, which are highly effective in other cancer types, such as anti-PD-1 therapy, have shown to be ineffective in pancreatic cancer. Therefore new treatments for pancreatic cancer, especially those that can enhance the efficacy of immune therapies, are urgent searched for.
• the PI3K pathway is frequently activated in a variety of solid tumours and haematological malignancies, making PI3K an attractive therapeutic target in oncology.
• the pathway is also essential for many cancer- associated activities, including endothelial cell sprouting for angiogenesis, macrophage transcriptional reprogramming, T cell differentiation and homeostasis and fibroblast-supported chemoresistance (Conway et al 2019).
• Pancreatic cancer is regularly associated with PI3K pathway activation and patients with high PI3K pathway activity show a significantly poorer survival than those with low activation.
• isoform-specific inhibitors provide isolated targeting of oncogenic signalling and in theory allow redundancy to alleviate off-target side effects in healthy tissues.
• clinical development of these inhibitors has been severely hampered by tolerability issues such as exemplified by a recent study of RI3Kd inhibitor idelalisib in pancreatic cancer patients (Borazanci et al 2020).
• isoform specific PI3K inhibitors for the treatment pancreatic cancer especially those that are well tolerated, are urgent searched for.
• WO2011058149 describes Tricyclic Pyrazol Amine Derivatives which are PI3K inhibitors and their use for treating autoimmune diseases, inflammatory disorders, multiple sclerosis and other diseases like cancers.
• the present invention is directed to a compound for use in the treatment of pancreatic cancer.
• the compound is an PI3K-delta inhibitor.
• the inventors recognised that RI3Kd inhibitors may be useful in targeted therapy for the treatment of pancreatic cancer.
• the invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof for use in a method of treatment of pancreatic cancer in a patient.
• the compound of Formula I may be referred to herein as “Compound 1”.
• the term pancreatic cancer includes any exocrine or neuroendocrine pancreatic cancer type.
• the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).
• PDAC pancreatic ductal adenocarcinoma
• Compound 1 may be used as a monotherapy.
• the invention further relates to combination therapy methods.
• the treatment is a combination therapy and comprises administration of a compound of Formula II: or a pharmaceutically acceptable salt thereof.
• the compound of Formula II may be referred to herein as “Compound 2”.
• the combination of Compound 1 and Compound 2 may be synergistic, and/or may otherwise result in improved treatment outcomes or patient prognosis.
• Compound 1 is administered in a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, carrier or excipient.
• the pharmaceutical composition is suitable for oral administration.
• Compound 2 is administered in a pharmaceutical composition comprising Compound 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, carrier or excipient.
• the pharmaceutical composition is suitable for oral administration.
• the treatment may comprise administration of a checkpoint inhibitor.
• the checkpoint inhibitor targets PD-1 , PD-L1 or LAG3.
• the checkpoint inhibitor may be an anti-PD-1 and/or anti- PDL1 monoclonal antibody. Exemplary checkpoint inhibitors are described herein.
• the method may comprise administration of Compound 1 or a salt thereof and a checkpoint inhibitor.
• the method may comprise administration of Compound 1 or a salt thereof, Compound 2 or a salt thereof, and a checkpoint inhibitor (a triple therapy).
• the treatment is a combination therapy and comprises one or more additional chemotherapeutic agents.
• a method described herein may comprise administration of a therapeutically effective amount of an additional chemotherapeutic agent, optionally two additional chemotherapeutic agents.
• Suitable chemotherapeutics agents include gemcitabine and nab-paclitaxel.
• methods of the present invention may comprise administration of gemcitabine and/or nab-paclitaxel.
• Combination therapies may result in improved activity (tumour growth inhibition) and/or reduced adverse effects when compared to the chemotherapeutic agent alone.
• the method may comprise administration of Compound 1 or a salt thereof and one or more additional chemotherapeutic agents, for example gemcitabine and/or nab-paclitaxel.
• the method may comprise administration of Compound 1 or a salt thereof, a checkpoint inhibitor (for example an anti-PD-1 and/or anti-PDL1 monoclonal antibody) and one or more additional chemotherapeutic agents (for example gemcitabine and/or nab-paclitaxel).
• the method may comprise administration of Compound 1 or a salt thereof, Compound 2 or a salt thereof, and one or more additional chemotherapeutic agents, for example gemcitabine and/or nab-paclitaxel.
• the method may comprise administration of Compound 1 or a salt thereof, Compound 2 or a salt thereof, a checkpoint inhibitor (for example an anti- PD-1 and/or anti-PDL1 monoclonal antibody) and one or more additional chemotherapeutic agents (for example gemcitabine and/or nab-paclitaxel).
• Figures 1a and b 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.
• Figures 2a and b show the activity of Compound 1 in combination with a checkpoint inhibitor in the Pan02 mouse model of pancreatic cancer.
• Figure 3 shows the effect of the combination of Compound 1 with a checkpoint inhibitor on body weight in the Pan02 mouse model of pancreatic cancer.
• Figures 4a, b and c show the activity of Compound 1 and the activity of Compound 1 in combination with an ATX inhibitor in the orthotopic KPC mouse model of pancreatic cancer.
• the above Compound 1 may 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.
• the structural formula shown above may be described as [6-fluoro-1-(4-morpholin-4-yl- methylphenyl)-5,5-dioxo-4,5-dihydro-1 H-5A6-thiochromeno[4,3-C]pyrazol-3-yl]-morpholin-4-yl-methanone.
• Compound 1 can be prepared and characterized as described in published patent application WO 2011/058149 A1 (see compound 339 on p. 69; the preparation on p. 303-307; and the characterization on p. 481 with p. 414-418), which information is specifically incorporated herein by reference.
• Haselmayer et al. describe a five- step preparation procedure for the compound (Haselmayer, 2014). This procedure starts with reaction of 8-fluoro-2,3-dihydro-4Hthiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is 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 into the corresponding acid and subsequent coupling with morpholine to yield the compound of formula I.
• the intermediate of 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. Saponification of the ethyl ester into the corresponding acid and chlorination of both the acid and alcohol with excess 20 thionyl chloride in the presence of dimethylformamide and subsequent coupling with morpholine then yields Compound 1 .
• Compound 1 may 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 W02014121901 , which is incorporated by reference in its entirety.
• Compound 1 is provided as an anhydrous hemifumarate salt (formula illustrated). Its synthesis and characterisation are described in W02014121901 (page 4). It is referred to as solid form A1. A hemifumarate hydrate (H1 ) has also been identified. The anhydrous hemifumarate salt used is crystalline and has a powder X-ray peak list as described in W02014121901 . It will be appreciated that the findings of the invention are not limited to use of this solid form, although it is preferred.
• Compound 1 is administered as the hemifumarate salt (Formula la).
• Haselmayer et al. also describe the characterisation of the compound as highly selective RI3Kd inhibitor.
• the favourable in vitro and in vivo properties of Compound 1 are further described by Johnson et al. (Johnson, Z. et al., AACR 2020, poster 666).
• WO2016124939 describes various ATX inhibitor compounds and their use in the treatment of proliferative disorders in which ATX activity is implicated, including Compound 2.
• Compound 2 is example 40 in WO2016124939, which document is incorporated herein by reference in its entirety.
• WO2016124939 describes over 200 examples.
• Compound 2’s structure is according to Formula II.
• lUPAC name is A/-[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-( 4-trifluoromethoxy-benzyl)-3/-/-imidazo[4,5- b]pyridin-2-yl]-propionamide. Its synthesis and characterisation are described in WO2016124939 at pages 77 and 82, respectively, which information is specifically incorporated herein by reference.
• Compound 2 may be provided and administered as the free base or as a pharmaceutically acceptable salt. In some cases, Compound 2 is provided and administered as the free base.
• Some methods of the invention are directed to combination therapy that includes checkpoint inhibitors.
• the potential for checkpoint inhibitors in the treatment of cancer is recognised in the art.
• Checkpoint inhibitor drugs may target either the PD-1 or PD-L1 protein to block PD-1 to PD-L1 binding, or target LAG3, and boost immune response against cancer cells.
• Compound 1 is administered in combination with a PD-1 inhibitor (also referred to as anti-PD-1).
• a PD-1 inhibitor also referred to as anti-PD-1.
• anti-PD-1 monoclonal antibodies include pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), spartalizumab, camrelizumab, sintilimab, dostarlimab, tislelizumab, toripalimab and retifanlimab.
• Compound 1 is administered in combination with a PD-L1 inhibitor (also referred to as anti-PD-L1).
• a PD-L1 inhibitor also referred to as anti-PD-L1.
• anti-PD-L1 monoclonal antibodies include atezolizumab (Tecentriq®), durvalumab (Imfinzi®), avelumab (Bavencio®), M7824, and KN035.
• Compound 1 is administered in combination with a LAG3 inhibitor (also referred to as anti-LAG3).
• LAG3 inhibitor also referred to as anti-LAG3
• anti-LAG3 monoclonal antibodies include relatlimab, tebotelimab, bootsselimab, leramilimab, IMP-321. TSR-033, SYM-022, INCAGN02385, RG6139, and BI754111.
• Checkpoint inhibitors are typically administered by I.V. infusion. Suitable doses and dosage regimens are known for each approved checkpoint inhibitor drug. Methods of the invention
• Compound 1 shows robust anti-tumour activity in preclinical models of pancreatic cancer and is well tolerated.
• a PI3K inhibitor with specificity for the d isoform, anti-tumour activity and favourable safety characteristics in pancreatic cancer can be provided.
• the present inventors surprisingly found that the Compound 1 increases the anti-tumour activity of immune therapies such as autotaxin (ATX) and checkpoint inhibition.
• immune therapies such as autotaxin (ATX) and checkpoint inhibition.
• RI3Kd inhibitor that can increase the efficacy of immune therapy in pancreatic cancer can be provided.
• pancreatic cancer can be treated with Compound 1 with or without immune therapies and this treatment is well tolerated.
• the present invention is directed to methods of treatment of pancreatic cancer using Compound 1.
• Compound 1 may be suitable as a monotherapy or may be provided in combination with another agent.
• Compound 1 has a favourable safety profile in humans, in particular with regard hepatotoxicity, diarrhoea/colitis, respiratory infections, and hematologic toxicities. Moreover, treatment of patients with Compound 1 does not lead to elevated liver enzymes, diarrhoea and neutropenia. Thus, a PI3K inhibitor with specificity for the isoform d and favourable safety characteristics in patients can be provided. These results are described in GB2104416.9 (filed 29 March 2021).
• Further advantageous properties of methods of treatment using Compound 1 may include one or more of higher efficacy, long treatment duration, and few dose reductions or interruptions or discontinuations.
• the dose of Compound 1 may be provided once daily (QD) or twice daily (BID), preferably once daily, and preferably but not necessarily administered orally. Other methods of administration may be used.
• a suitable daily dose may be between 5 mg and 2 g, for example between 10 mg and 1g.
• administration of Compound 1 continues during pauses in administration of other agents (for example, during days 21-28 of 28 day chemotherapeutic cycles).
• Compound 1 is administered as the hemifumarate salt.
• the invention is not so limited, and other solid forms (for example, other pharmaceutically acceptable salts) are envisaged.
• the weight equivalent of Compound 1 as a free base in a 40 mg dose is calculated at about 36 mg (that is, about 90% of the weight of Compound 1 hemifumarate corresponds to the free base, with the remaining about 10% of the weight corresponding to the salt former acid.
• An exemplary method may comprise administration of Compound 1 in an amount of between 18 mg and 108 mg per day, for example between 18 mg and 72 mg per day. In some cases, the amount is between 27 mg and 90 mg per day, for example between 27 mg and 54 mg per day. In some cases, the amount is between 27 mg and 45 mg per day, for example about 36 mg per day. In some cases, the amount is between 54 mg and 90 mg per day, for example about 72 mg per day.
• an exemplary method comprising administration of Compound 1 as the hemifumarate in an amount of between 20 mg and 120 mg per day, for example between 20 mg and 80 mg per day.
• the amount is between 30 mg and 100 mg per day, for example between 30 mg and 60 mg per day.
• the amount is between 30 mg and 50 mg per day, for example about 40 mg per day.
• the amount is between 60 mg and 100 mg per day, for example about 80 mg per day.
• the method may comprise administration of Compound 1 in an amount of between 9 mg and 108 mg per day, for example between 9 mg and 72 mg per day.
• the method may comprise administration of Compound 1 as the hemifumarate salt in an amount of between 10 mg and 120 mg per day, for example between 10 mg and 80 mg per day.
• Inhibition of the RI3Kd pathway in patients can be demonstrated by measuring the pharmacodynamic activity (PD) of Compound 1 in blood samples.
• a specific PD marker for RI3Kd inhibition in blood is CD63 on basophils.
• Treatment of patients with Compound 1 as the hemifumarate salt results in a dose dependent reduction of the percentage CD63 positive basophils in blood samples of patients comparable to that reported for other RI3Kd inhibitors (for example idelalisib).
• the percentage of CD63 positive basophils is low in all samples measured confirming effective inhibition of the RI3Kd pathway during the course of treatment.
• certain preferred embodiments relate to a dose of 40 mg of a salt of Formula la, or a dose of 36 mg of a compound of Formula I.
• the dose may be 60 mg of a salt of Formula la, or a dose of 54 mg of a compound of Formula I.
• the dose may be 80 mg of a salt of Formula la, or a dose of 72 mg of a compound of Formula I.
• the dose may be 10 mg of a salt of Formula la, or a dose of 9 mg of a compound of Formula I.
• the inventors have found a once daily dose effective and well-tolerated. Once daily dosing offers advantages when compared to some known and used PI3K inhibitors (for example, idelasib is prescribed as a twice daily 150 mg dose unless dosage reduction due to adverse effects is required).
• a once daily dose improves patient experience and may improve patient compliance. Patients with, especially advanced, cancers often experience a considerable pill burden and may have difficulty swallowing. Accordingly, in the methods of the invention the dose may be taken once daily. In other words, the dose is not divided and spaced throughout the day. It may be taken as in a single dosage unit (for example, a single tablet or capsule), or in multiple dosage forms (for example, as two or more tablets or capsules).
• the method comprises administering one or more solid dosage units.
• the daily dose is 40 mg and the method comprises administering two 20 mg solid dosage units (that is, a solid dosage unit comprising 20 mg of Compound 1 as the hemifumarate).
• the daily dose may be 60 mg and administration may comprise three solid dosage units, each dosage unit comprising 20 mg of a salt of Formula la. In another example, the daily dose may be 80 mg and the administration may comprise four solid dosage units, each dosage unit comprising 20 mg of a salt of Formula la.
• Compound 1 has a surprisingly good safety profile in humans, observing that treatment may result in less treatment-related grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation than would be expected for an inhibitor of this class.
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• treatment of patients with Compound 1 does not result in treatment-related grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation in more than 5% of patients. More preferably treatment of patients with Compound 1 does not result in treatment-related grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation in more than 1% of patients. Most preferably, treatment of patients with Compound 1 does not result in any clinically significant treatment-related alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation in patients.
• treatment of patients with Compound 1 does not result in treatment-related grade 3 diarrhoea or colitis in more than 5% of patients. More preferably treatment of patients with Compound 1 does not result in treatment-related grade 3 diarrhoea or colitis in more than 1% of patients. Most preferably, treatment of patients with Compound 1 does not result in any clinically significant treatment-related diarrhoea or colitis in patients.
• 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 any clinically significant treatment-related neutropenia in patients.
• Compound 1 offers treatment regimens that may be suitable for long term use without interruption. Accordingly, it is envisaged that patients may be prescribed a treatment regimen for a duration of months. In some cases, the treatment is prescribed for at least 1 month. In some cases, the treatment is prescribed for at least 2 months. In some cases, the treatment is prescribed for at least 3 months. In some cases, the treatment is prescribed for at least 4 months. In some cases, the treatment is prescribed for at least 5 months. In some cases, the treatment is prescribed for at least 6 months. In some cases, the treatment is prescribed for at least 1 year.
• the treatment duration is at least 1 month without interruption. In some cases, the treatment duration is at least 2 months without interruption. In some cases, the treatment duration is at least 3 months without interruption. In some cases, the treatment duration is at least 4 months without interruption. In some cases, the treatment duration is at least 5 months without interruption. In some cases, the treatment duration is at least 6 months without interruption. In some cases, the treatment duration is at least 1 year without interruption.
• the methods of the invention may be particularly useful in the treatment of certain patient groups, for example elderly and/or frail patients who are not presently eligible to receive RI3Kd inhibitors because of their poor tolerability.
• the patient is 50 years old or older, for example 55 years old or older, for example 60 years old or older, for example 65 years old or older, for example 70 years old or older, for example 75 years old or older, for example 80 years old or older.
• the patient is or would be considered by a physician unsuitable for treatment with idelalisib and/or other RI3Kd inhibitors.
• the patient is a patient who has been previously diagnosed as suffering from a gastrointestinal disorder, for example colitis or chronic diarrhoea.
• the inventors have observed that a combination of Compound 1 and Compound 2 shows apparent synergistic activity on high-grade and acinar-to-ductal metaplasia (ADM) tumour burden as well as high- grade and ADM number of lesions.
• the combination of Compound 1 and Compound 2 also shows apparent synergistic activity on pancreatic cancer associated activities including tumour fibrosis, tumour T regulatory cells (Tregs) and cancer associated fibroblasts (CAFs).
• the invention provides Compound 1 , or a pharmaceutically acceptable salt thereof, for use in a method of treatment of pancreatic cancer, wherein the method comprises administration of Compound 1 , or a pharmaceutically acceptable thereof, and Compound 2, or a pharmaceutically acceptable salt thereof.
• the invention provides a combination of Compound 1 , or a pharmaceutically acceptable thereof, and Compound 2, or a pharmaceutically acceptable salt thereof, for use in a method of treating pancreatic cancer.
• the dose of Compound 2 may be provided once daily (QD), preferably twice daily (BID), preferably but not necessarily administered orally. Other methods of administration may be used.
• a suitable daily dose may be between 5 mg and 2 g, for example between 10 mg and 1g.
• Compound 1 and Compound 2 may be administered simultaneously or at different times.
• Compound 1 may be administered once daily, and Compound 2 may be administered twice daily.
• Compound 1 and Compound 2 are provided in separate formulations (for example, separate dosage units such as tablets or capsules).
• the inventors have observed that a combination of Compound 1 and a checkpoint inhibitor may be advantageous, a combination of Compound 1 and an anti-PD-1 antibody showing much stronger anti tumour growth activity compared to the anti-PD-1 antibody alone. Body weight data suggest the combination may be we 11 -tolerated.
• the invention provides Compound 1 , or a pharmaceutically acceptable salt thereof, for use in a method of treatment of pancreatic cancer, wherein the method comprises administration of Compound 1 , or a pharmaceutically acceptable thereof, and a checkpoint inhibitor.
• the checkpoint inhibitor is a PD-1 or PD-L1 inhibitor. In some cases, it is a PD-1 inhibitor. In some cases, it is a PD-L1 inhibitor.
• a method described herein may comprise administration of a therapeutically effective amount of an additional chemotherapeutic agent, optionally two additional chemotherapeutic agents.
• Suitable chemotherapeutics agents include gemcitabine and nab-paclitaxel.
• methods of the present invention may comprise administration of gemcitabine and/or nab-paclitaxel.
• the methods of the invention are directed to combination therapy, the combination therapy comprising treatment of a patient with Compound 1 or a pharmaceutically acceptable salt thereof and an additional chemotherapeutic agent, for example gemcitabine (Gemzar®) or nab-paclitaxel (Abraxane®).
• an additional chemotherapeutic agent for example gemcitabine (Gemzar®) or nab-paclitaxel (Abraxane®).
• a checkpoint inhibitor may also be administered.
• Compound 1 and the additional chemotherapeutic agent(s) will suitably, although not necessarily, be given at different times and/or on different schedules and may be formulated for administration by different routes.
• Compound 1 or a pharmaceutically acceptable salt thereof may be given as an oral dose, for example, a daily oral dose, while the additional chemotherapeutic agent may be given as infusion.
• both gemcitabine and nab-paclitaxel may be given in a 28 day cycle on days 1 , 8, and 15.
• the combination therapy comprises treating the patient with Compound 1 or a pharmaceutically acceptable salt thereof and gemcitabine and nab-paclitaxel.
• Compound 1 is suitably provided as a hemifumarate as described above.
• Compound 1 is provided in a pharmaceutical composition formulated for oral administration.
• the pharmaceutical composition may be provided in a capsule or may be provided in a tablet. In some cases, it is provided in a tablet for example, as a coated or non-coated tablet produced by compression of a powdered or granulated composition. In other cases, it is provided in a capsule, for example, as a powdered or granulated composition within a hard- or soft-shell capsule, for example, a hydroxymethyl cellulose (HPMC) capsule. In other words, an oral dosage form is preferred.
• HPMC hydroxymethyl cellulose
• the formulation suitably comprises one or more pharmaceutically acceptable fillers, disintegrants, glidants, and/or lubricants.
• the oral dosage form may comprise 5 mg of Compound 1 , provided as the hemifumarate. In some cases, the oral dosage form may comprise 20 mg of Compound 1 , provided as the hemifumarate. Both oral dosage forms have been made as described in Table 1.
• the oral dosage form may also comprise 40 mg of Compound 1 , provided as the hemifumarate.
• the oral dosage form may also comprise 80 mg of Compound 1 , provided as the hemifumarate.
• Both oral dosage forms can be made similarly to the dosage forms described Table 1. It will be appreciated that, for the doses of the method, the lowest dosage burden (number of capsules or tablets) is placed on patients, when a single solid dosage form is used. This is most advantageous for patient compliance.
• the invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising Compound 1 , preferably provided as the hemifumarate salt, formulated for oral administration.
• An exemplary formulation includes Compound 1 hemifumarate, microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate.
• the formulation may be provided in a solid dosage form, for example as tablet or powder or granulated composition encapsulated in a shell capsule. It will be appreciated that a single tablet can accommodate a higher dose of Compound 1 hemifumarate than a single capsule. Therefore, tablets are preferred for higher dose units. Tablets may be coated to improve taste or swallowing.
• the amount of Compound 1 hemifumarate may be 5 mg to 20 mg, for example 5 mg or 20 mg. In another embodiment the amount of compound 1 may be 5 mg to 80 mg, for example 5 mg, 20 mg, 40 mg or 80 mg.
• Compound 1 is provided as a solid dosage unit comprising a pharmaceutical composition comprising 5 mg of Compound 1 hemifumarate. Accordingly, in some embodiments Compound 1 is provided as a solid dosage unit comprising a pharmaceutical composition comprising 20 mg of Compound 1 hemifumarate. Accordingly, in some embodiments the invention provides a solid dosage unit comprising a pharmaceutical composition comprising 40 mg of Compound 1 hemifumarate. Accordingly, in some embodiments the invention provides a solid dosage unit comprising a pharmaceutical composition comprising 80 mg of Compound 1 hemifumarate.
• the invention provides a tablet comprising a pharmaceutical composition comprising 40 mg of Compound 1 hemifumarate. Accordingly, in some embodiments the invention provides a tablet comprising a pharmaceutical composition comprising 80 mg of Compound 1 hemifumarate. It will be appreciated that the pharmaceutical composition of the tablet can be similar to that of the capsule or can be optimised for tableting. Suitability, Compound 2 is provided in a pharmaceutical composition formulated for oral administration.
• the pharmaceutical composition may be provided in a capsule or may be provided in a tablet. In some cases, it is provided in a tablet.
• a capsule for example, as a powdered or granulated composition or a liquid composition within a hard- or soft-shell capsule, for example, a gelatin or hydroxymethyl cellulose (HPMC) capsule.
• a powdered or granulated composition or a liquid composition within a hard- or soft-shell capsule for example, a gelatin or hydroxymethyl cellulose (HPMC) capsule.
• HPMC hydroxymethyl cellulose
• the formulations suitably comprise one or more pharmaceutically acceptable fillers, disintegrants, glidants, and/or lubricants.
• Checkpoint inhibitors and/or additional chemotherapeutic agents may be provided in any suitable formulation and any suitable dosage, by any suitable means of administration.
• checkpoint inhibitors and/or additional chemotherapeutic agents may be approved drugs prescribed and administered according to the label.
• Compound 1 is a RI3Kd inhibitor. It is recognised in the art that the PI3K pathway is frequently activated in pancreatic cancer. Accordingly, the methods of the present invention are directed to the treatment of pancreatic cancer, such as but not limited to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (PanNETs or PNETs).
• pancreatic cancer such as but not limited to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (PanNETs or PNETs).
• the methods of the present invention may therefore relate to treatment of pancreatic cancer characterised by upregulation of the PI3K pathway.
• the methods of the present invention may therefore relate to treatment of pancreatic cancer by modulation of PI3K pathway in a patient.
• the pancreatic cancer may be any exocrine or neuroendocrine pancreatic cancer type. Accordingly, the methods of the present invention are directed to the treatment of pancreatic cancer, such as but not limited to pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (PanNETs or PNETs). In some cases, the pancreatic cancer is pancreatic ductal adenocarcinoma. In some cases, the pancreatic cancer is pancreatic neuroendocrine tumours.
• PDAC pancreatic ductal adenocarcinoma
• PanNETs or PNETs pancreatic neuroendocrine tumours
• the treatment may be a monotherapy or a combination therapy as described herein.
• the KPC mouse is an established and clinically relevant model of pancreatic ductal adenocarcinoma (PDAC) which develops many key features observed in human PDAC including pancreatic intraepithelial neoplasia alongside a robust inflammatory reaction including exclusion of effector T cells. Metastases are observed in around 80% of the mice and are located primarily in the liver and lungs. Mutations in both KRAS and TP53 genes are found in around 80% and 70% of all human PDACs respectively.
• the genetic background of KPC mouse contains loxP sites flanking exons 2-10 of the transformation related protein 53 gene (p53 floxflox ), and a conditional activation point mutation in the KRAS gene (KRAS G12D).
• a lox- stop-lox termination sequence is encoded upstream of KRAS mutated genes to prevent expression in the absence of Cre recombinase. Exposure to Cre recombinase removes the floxed p53 sequence - creating a null allele (+/-).
• the pancreas-specific Pdx-1 promoter enables expression of Cre recombinase in acini, islet and duct cells of the pancreas. Cre-mediated recombination excises the lox-stop-lox termination sequences and enables expression of KRAS G12D in pancreatic tissue. This genetic background leads to the development of malignant cells early after conception and results in tumour growth to which mice succumb when left untreated.
• KPC mice were treated with either Compound 1 in drinking water, Compound 2 (an ATX inhibitor) in mixed chow, or a combination of the two drugs. Control animals received normal drinking water and standard chow.
• ADM acinar-to- ductal metaplasia
• PDAC pancreatic intraepithelial neoplasia
• Compound 1 alone reduces high-grade (PanlN-3 and PDAC) tumour burden without having significant effects on the number of lesions in this model.
• Compound 2 alone in the model reduces the number of low-grade (PanlN-1 and PanlN-2) lesions without having significant effects tumour burden.
• the combination of Compound 1 and Compound 2 shows an apparent synergistic activity on high-grade and ADM tumour burden as well as high-grade and ADM number of lesions.
• Pan02 is a well-established pancreatic ductal adenocarcinoma (PDAC) mouse model and originates from tumour cells that were chemically induced (3-methylcholanthrene, 3-MCA) in male C57BL/6 mice.
• PDAC pancreatic ductal adenocarcinoma
• 3-MCA 3-methylcholanthrene
• mice Female 6-8 week old C57BL/6 mice, 10 per group, were subcutaneously injected with 3 x 10 6 cells in 100m I serum free RPMI medium into the flank. When the average tumour volume reached 60 mm 3 , animals were randomly allocated to the different study groups: vehicle, anti-PD-1 alone and anti-PD-1 with Compound 1 . Vehicle (1% methylcellulose solution), Compound 1 (30 mg/kg) was dosed twice daily (BID) via oral gavage. Anti-PD1 (10 mg/kg) in PBS was dosed twice weekly (BIW) via intraperitoneal (IP) injection.
• Vehicle 1% methylcellulose solution
• Compound 1 (30 mg/kg) was dosed twice daily (BID) via oral gavage.
• Anti-PD1 (10 mg/kg) in PBS was dosed twice weekly (BIW) via intraperitoneal (IP) injection.
• the anti-PD-1 antibody has only a modest effect on tumour outgrowth in this model.
• the combination of the anti-PD-1 antibody with Compound 1 shows much stronger anti-tumour growth activity compared to the anti-PD-1 antibody alone.
• Compound 1 and the combination of the anti-PD-1 antibody with Compound 1 do not result in any body weight loss and are thus well tolerated.
• the therapeutic efficacy of Compound 1 with or without ATX inhibitor was evaluated in the orthotopic KPC/WCB3 mouse model of pancreatic cancer.
• This model is constituted by the implantation of KPC/WBC3 cells originating from a spontaneous developed donor tumour in KPC mice into the pancreas of male wildtype C57BL/6J recipient mice.
• the pathology and tumour microenvironment in this model closely resemble human pancreatic cancer.
• KPC/WCB3 cells were orthotopically injected into the pancreas of 8-week-old mice (Charles River Laboratories). Treatments with Compound 1 in drinking water, Compound 2 in mixed chow, or a combination of the two drugs were started 7 days after the injection of KPC/WCB3 cells. Control animals received normal drinking water and standard chow. One month after initiation treatment was stopped and mice were euthanized. Pancreata were harvested and analysed by histological analysis for level of fibrosis, number of Tregs and number of proliferating CAFs.
• Compound 1 alone has a limited effect on tumour fibrosis score and proliferating CAFs but significantly reduces Tregs.
• Compound 2 alone has a limited effect on tumour fibrosis score but significantly reduces Tregs as well as proliferating CAFs.
• the combination of Compound 1 and Compound 2 shows an apparent synergistic activity on fibrosis score as well as proliferating CAFs whilst maintaining a strong reduction of Tregs.
• Borazanci E., Pishvaian, M. J., Weekes, C., Huang, J. & Rajakumaraswamy, N.
• a Phase lb 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.

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