WO2022238706A1

WO2022238706A1 - Ret inhibitor for the treatment of ret altered medullary thyroid cancer or ret altered non-small cell lung cancer

Info

Publication number: WO2022238706A1
Application number: PCT/GB2022/051206
Authority: WO
Inventors: Mitchell Keegan
Original assignee: Bp Asset Viii, Inc.
Priority date: 2021-05-14
Filing date: 2022-05-12
Publication date: 2022-11-17

Abstract

Described herein are methods of treating or preventing cancer in a human subject comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof: (I) The methods have particular application in the treatment of cancers exhibiting RET alterations, such as meduallary thyroid cancers (MTC) and non-small cell lung cancers (NSCLC). In particular, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human. Also described are compounds for use in said methods.

Description

RET INHIBITOR FOR THE TREATMENT OF RET ALTERED MEDULLARY THYROID CANCER OR RET

ALTERED NON-SMALL CELL LUNG CANCER

INTRODUCTION

[001] Described herein are methods of treating or preventing cancer in a human subject comprising administering to said subject a compound of formula I (2-[6-(6,7- dimethoxyquinolin-3-yl)pyridin-3-yl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1 ,2-oxazol-5- yljacetamide), or a pharmaceutically acceptable salt thereof:

[002] In particular, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

[003] The method has particular application in the treatment of cancers exhibiting RET gene alterations, such as meduallary thyroid cancers (MTC) and non-small cell lung cancers (NSCLC).

BACKGROUND OF THE INVENTION

[004] The RET proto-oncogene, localized on human chromosome 10q11.2, encodes a receptor-type tyrosine kinase (Ceccherini et al., 1993) with an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. The ligands for RET have been identified as neurotrophic factors of the glial cell-line derived neurotrophic factor (GDNF) family, including GDNF, neurturin, artemin, and persephin. Ligand binding to its corresponding GDNF family receptor-alpha (GFR-a) co-receptor triggers RET dimerization and subsequent trans-phosphorylation of intracellular tyrosines (lchihara et ai, 2004) leading to the activation of different intracellular signaling cascades including the Janus kinases/signal transducer and activator of transcription proteins (JAK/STAT), phosphoinositide 3- kinase/protein kinase B (PI3K/AKT), and RAS/extracellular signal-regulated kinase (ERK) pathways.

[005] Mice deficient in GDNF, GDNF family receptor alpha 1 (GFRal), or the RET protein itself exhibit severe defects in kidney and enteric nervous system development. This implicates RET signal transduction as critical to the development of normal kidneys and the enteric nervous system (Arighi et al., 2005).

[006] The first link between RET and human cancer was established by the discovery of somatic rearrangements of RET gene in papillary thyroid carcinoma (PTC) (Grieco et al., 1990). These rearrangements lead to a constitutive activation of the tyrosine kinase. Up to 30% of sporadic and up to 70% of radiation-induced PTC show a somatic rearrangement of the RET gene. So far, 12 different 5’-fusion partner genes of RET have been described.

[007] In addition to these somatic rearrangements, somatic mutations in the RET gene resulting in constitutive activate oncogenic RET have been identified in 50% of sporadic medullary thyroid cancer (MTC) (Marsh et al., 1996; Romei et al., 1996).

[008] As Next-Generation Sequencing and the molecular profiling of tumors becomes more routine, a growing list of additional tumor types exhibiting both RET gene mutations or rearrangements have been identified. These tumors include chronic myelomonocytic leukemia (CMML; Ballerini etal., 2012), colorectal (Le Rolle et al., 2015), breast (Stransky etal., 2014), and salivary carcinomas (Skalova et al., 2018). Chromosomal rearrangements involving RET gene have also been found in approximately 1%-2% of NSCLC (Takeuchi et al., 2012).

[009] Besides these specific RET gene alterations, an increasing number of tumor types are now being shown to over express the wild-type RET protein which may have implications for tumor progression, locoregional spread and metastases. For example, RET is over expressed in 30%-70% of invasive breast cancers, with expression being relatively more frequent in estrogen receptor-positive tumors (Esseghir et al., 2007). In recurrent breast cancer, RET protein expression levels are significantly increased compared with both normal breast tissues and corresponding primary tumors, and expression correlates with larger tumor size, higher tumor stage, decreased metastasis-free survival, and lower overall survival. Interestingly, increased RET gene expression levels in breast tumors have been correlated with resistance to endocrine therapies, including selective estrogen modulators (such as tamoxifen), agents that block estrogen biosynthesis (such as aromatase inhibitors) and estrogen receptor antagonists (such as fulvestrant) (Morandi et al., 2013; Plaza-Menacho et al., 2010).

[0010] These data suggest that RET could be an important determinant of response to endocrine therapies and that targeting RET signaling could sensitize tumors to these treatments and delay the onset of endocrine resistance.

[0011] Although RET was one of the first kinase fusions cloned from an epithelial tumor (Takahashi et al., 1985), patients with RET-driven cancers have derived only modest benefit from RET-directed strategies to date. It should be noted, however, that RET therapies thus far have largely centered around multi-kinase inhibitors that have been repurposed to treat patients with RET gene alterations. For example, the multi-kinase inhibitors cabozantinib and vandetanib were originally designed to target other kinases, such as VEGFR-2, tyrosine- protein kinase MET, and epidermal growth factor receptor (EGFR), and they inhibit these targets more potently than RET (Carlomagno et a , 2002; Yakes et ai, 2011).

[0012] Cabozantinib and vandetanib are both approved for the treatment of patients with metastatic or locally advanced MTC and have documented activity in patients with RET gene- fusion driven NSCLC, yet each drug has produced limited disease control and lower response rates compared to selective kinase inhibitors targeting other oncogenic drivers in NSCLC (Drilon et al., 2016; Lee et ai, 2017). In addition, the significant adverse event (AE) profiles of each drug can either limit use in certain patient populations or limit the dose that individual patients can tolerate (Cabozantinib Prescribing Information, 2012; Vandetanib Prescribing Information, 2011).

[0013] Furthermore, these agents are biochemically inactive against the RET gene V804L/M mutants. This gatekeeper position is associated with acquired resistance to tyrosine kinase inhibitors in other targeted therapy/kinase pairs and mutations at this residue act as primary driver mutations in a subset of hereditary MTCs.

[0014] In 2017, RET specific kinase inhibitors entered into clinical trials. Notably in a phase 1 study, BLU-667 (pralsetinib; GAVRETO) induced durable responses in patients with RET- altered NSCLC and MTC without notable off target toxicity, establishing initial proof of principle for highly selective RET inhibitors targeting in RET-driven tumors (Subbiah et a , 2018). Subsequently, pralsetinib has been approved by the FDA for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. The recommended dosage is 400 mg orally once daily on an empty stomach (GAVRETO prescribing information).

[0015] Selpercatinib (RETEVMO) is another RET specific kinase inhibitor which has been approved, both in the US and Europe, for the treatment of RET altered NSCLC or thyroid cancer.

[0016] There is a need to develop new effective therapies for treating human patients with RET gene altered tumours.

[0017] WO 2018/060714 describes a series of small molecule RET kinase inhibitors including the compound of formula I below: [0018] In vitro , the compound of formula I was shown to be a highly potent RET inhibitor with a 50% inhibitory concentration (IC₅₀) in the single-digit, nano-molar range. Importantly, the compound of formula I showed similar levels of inhibition to RET gate keeper mutation, V804L, which is known to facilitate resistance to first generation RET inhibitors.

[0019] In both kinase and cell-based assays comparing the compound of formula I to other known drugs with reported RET activity, the compound of formula I was significantly more potent and selective.

[0020] In an in vivo efficacy mouse model, at a dose of 1 to 3 mg/kg, the mesylate of the compound of formula I was found to provide a dose-dependent tumour regression with no significant body weight loss.

[0021] There is a need for a further safe and efficacious treatment for cancer in human subjects in need thereof.

SUMMARY OF THE INVENTION

[0022] In one aspect, the present invention relates to a method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

[0023] In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer in a human subject, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

[0024] In another aspect, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a cancer in a human subject,

[0025] In another aspect, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating or preventing a cancer in a human subject,

[0026] In another aspect, the present invention relates to a method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof: wherein said cancer is RET altered medullary thyroid cancer or RET altered non-small cell lung cancer.

[0027] In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer in a human subject,

wherein said cancer is RET altered medullary thyroid cancer or RET altered non-small cell lung cancer.

[0028] In another aspect, use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a cancer in a human subject,

[0029] In another aspect, use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating or preventing a cancer in a human subject, wherein said cancer is RET altered medullary thyroid cancer or RET altered non-small cell lung cancer.

[0030] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.

BRIEF DESCRIPTION OF THE DRA WINGS

[0031] Figure 1 shows for each patient in the evaluable data set the best percentage change in the size of target tumor lesions from base line and the original dose which the patient received. Note: · at the end of the bars indicates that the patient continued on the study, on treatment; + indicates a patient has a confirmed response; ^L indicates percent change from baseline >100.

[0032] Figure 2 shows for each NSCLC patient in the evaluable data set the best percentage in the size of target tumor lesions from base line and the original dose which the patient received. Note: · at the end of the bars indicates that the patient continued on the study on treatment; + indicates a patient has a confirmed response; ^L indicates percent change from baseline >100.

[0033] Figure 3 shows for each MTC patient in the evaluable data set the best percentage change in size of target tumor lesions from base line and the original dose which the patient received. Note: · at the end of the bars indicates that the patient continued on the study on treatment; + indicates a patient has a confirmed response.

[0034] Figure 4a shows the study duration for each patient and the original dose which the patient received. Note: an arrow at the end of the bars indicates that the patient continued on the study on treatment.

[0035] Figure 4b shows the study duration for each patient and the cancer sub-type of each patient. Note: an arrow at the end of the bars indicates that the patient continued on the study on treatment. [0036] Figure 4c shows the study duration for each NSCLC patient. Note: an arrow at the end of the bars indicates that the patient continued on the study on treatment.

[0037] Figure 4dshows the study duration for each MTC patient. Note: an arrow at the end of the bars indicates that the patient continued on the study on treatment.

[0038] Figure 5a and 5b show CT and MRI images respectively of the lung of a patient with RET-fusion NSCLC at base line and during cycle 2 at 40 mg of the compound of formula I.

[0039] Figure 6 shows PET/CI images of the liver of a patient with RET altered MTC at base line and during cycle 2 at 75 mg of the compound of formula I.

[0040] Figure 7 shows the response of RET-fusion NSCLC liver metastases in a patient following 2 cycles of treatment with 50 mg of the compound of formula I.

[0041] Figure 8 shows the response of a RET-fusion NSCLC brain metastases in a patient following 2 cycles of treatment with 75 mg of formula I.

[0042] Figure 9 shows the mean blood concentrations of the compound of formula I on day 15 post treatment for each dose level in the non-expansion cohort.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0043] As used herein by themselves or in conjunction with another term or terms, “treating” or “treatment” refer to (a) inhibiting a particular disease condition or disorder, or causing an improvement in a particular disease, condition or disorder; or (b) attenuating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder. It should be understood that the terms “treating” and “treatment” encompass any one of the aforementioned effects (a)-(b), either alone or in combination with each other.

[0044] In some embodiments, the terms “treating” and “treatment” refer to curative actions and results as well as actions and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease. For example, treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.

[0045] As used herein “preventing” or “prevention” refers to (a) delaying the onset of one or more symptoms of a particular disease, condition or disorder; or (b) diminishing the likelihood of or likelihood of seriousness of a condition, symptom, or disease state, for a period of time. It should be understood that the term “preventing” or “prevention” as used herein is not intended to be absolute.

[0046] As used herein “RET amplified” in respect of a cancer refers to a cancer which has a RET amplification.

[0047] As used herein, “RET amplification” refers to increased levels of RET gene (e.g. gene duplication) or expression of wildtype RET kinase in a cell.

[0048] As used herein “RET altered” in respect of a cancer refers to a cancer which has a RET alteration.

[0049] As used herein, “RET alteration” refers to an aberration in either RET gene or RET protein. One example of a RET alteration is a chromosomal aberration that results in a RET fusion gene which encodes a RET fusion protein including a RET kinase domain and a fusion partner. Non-limiting examples of RET fusion partners are: KIF5B, CCDC6, NCOA4, TRIM33, ERC1, KIAA1468, EPHA5, ANK3, MY05C, PARD3, SQSTM1, HOOK3, AKAP13, KIAA1217, FRMD4A and MBD1. Another example of a RET alteration is a mutation in a RET gene resulting in expression of a mutated RET protein that includes either (i) one or more point mutations as compared to a wildtype RET protein, (ii) a deletion of at least one amino acid as compared to a wildtype RET protein, (iii) an insertion of an amino acid as compared to a wildtype RET protein. Non-limiting examples of RET protein mutations are V804M, V804L, G810R, G810S and M918T.

[0050] "About" when used herein in conjunction with a measurable value such as, for example, a dose ora period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.

Methods and Medical Uses

[0051] In one aspect, the present invention relates to a method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 10 mg per human to about 150 mg per human.

[0052] In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human; suitably a daily dose of about 40 mg per human to about 150 mg per human; suitably a daily dose of about 50 mg per human to about 150 mg per human; suitably a daily dose of about 75 mg per human to about 150 mg per human; suitably a daily dose of about 100 mg per human to about 150 mg per human.

[0053] In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 10 mg per human to about 100 mg per human; suitably a daily dose of about 20 mg per human to about 100 mg per human; suitably a daily dose of about 40 mg per human to about 100 mg per human; suitably a daily dose of about 50 mg per human to about 100 mg per human; suitably a daily dose of about 75 mg per human to about 100 mg per human; suitably a daily dose of about 100 mg per human.

[0054] In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 10 mg per human to about 75 mg per human; suitably a daily dose of about 20 mg per human to about 75 mg per human; suitably a daily dose of about 40 mg per human to about 75 mg per human; suitably a daily dose of about 50 mg per human to about 75 mg per human; suitably a daily dose of about 75 mg per human.

[0055] In one embodiment, the daily dose of the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose. As used herein, a single daily dose means that the daily dose is administered at once, or substantially at once. However, administration of the single daily dose may be achieved by the administration of one or more dosage forms (e.g. tablets or capsules).

[0056] For example, in one embodiment the compound of formula I, or a pharmaceutically acceptable salt thereof is administered as a single daily dose of about 10 mg per human to about 150 mg per human; suitably a single daily dose of about 20 mg per human to about 150 mg per human; suitably a single daily dose of about 40 mg per human to about 150 mg per human; suitably a single daily dose of about 50 mg per human to about 150 mg per human; suitably a single daily dose of about 75 mg per human to about 150 mg per human; suitably a single daily dose of about 100 mg per human to about 150 mg per human.

[0057] In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a single daily dose of about 10 mg per human to about 100 mg per human; suitably a single daily dose of about 20 mg per human to about 100 mg per human; suitably a single daily dose of about 40 mg per human to about 100 mg per human; suitably a single daily dose of about 50 mg per human to about 100 mg per human; suitably a single daily dose of about 75 mg per human to about 100 mg per human; suitably a single daily dose of about 100 mg per human.

[0058] In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a single daily dose of about 10 mg per human to about 75 mg per human; suitably a single daily dose of about 20 mg per human to about 75 mg per human; suitably a single daily dose of about 40 mg per human to about 75 mg per human; suitably a single daily dose of about 50 mg per human to about 75 mg per human; suitably a single daily dose of about 75 mg per human.

[0059] In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered as a single daily dose of about 75 mg per human or about 100 mg per human. In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof is administered as a single daily dose of 75 mg per human or 100 mg per human.

[0060] In one embodiment, the cancer is a RET altered or RET amplified cancer. In another embodiment, the subject has a cancer exhibiting a RET alteration or RET amplification. The skilled person would be familiar with means of assessing RET alterations or RET amplifications, for example, by means of a kit approved by a regulatory body such as the FDA.

[0061] In one embodiment, the RET alteration is the expression of a RET fusion protein and/or harbouring a RET fusion gene. Suitably, the RET fusion gene or protein comprises a RET fusion partner selected from KIF5B, CCDC6, NCOA4, TRIM33, ERC1, KIAA1468, EPHA5, ANK3, MY05C, PARD3, SQSTM1, HOOK3, AKAP13, KIAA1217, FRMD4A and MBD1. More suitably, the RET fusion partner is KIF5B or CCDC6.

[0062] In another embodiment, the RET alteration is expression of a mutated RET protein. Accordingly, in one embodiment the cancer expresses a mutated RET protein. In one embodiment, the mutated RET protein comprises one or more of the following mutations V804M, V804L, G810R, G810S and M918T. [0063] In another embodiment, the mutated RET protein comprises a M918T mutation.

[0064] In one embodiment, the cancer (e.g. RET altered or RET amplified cancer) is a solid cancer. In another embodiment, the cancer (e.g. RET altered or RET amplified cancer) is an advanced solid cancer.

[0065] In one embodiment, the cancer (e.g. RET altered or RET amplified cancer) is selected from the group consisting of anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primary CNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, respiratory tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromosytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colonic neoplasms, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumors, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, unknown primary carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms’ tumor.

[0066] In another embodiment, the cancer (e.g. RET altered or RET amplified cancer) is selected from a thyroid cancer, a lung cancer, a pancreatic cancer, a prostate cancer, a bladder cancer, a head and neck cancer, a bile duct cancer, an ovarian cancer, a breast cancer and a colorectal cancer.

[0067] In another embodiment, the cancer (e.g. RET altered or RET amplified cancer) is selected from a thyroid cancer, a lung cancer, a pancreatic cancer, an ovarian cancer, a breast cancer and a colorectal cancer.

[0068] In another embodiment, the cancer (e.g. RET altered or RET amplified cancer) is a lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer (e.g., sporadic medullary thyroid cancer or hereditary medullary thyroid cancer), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, or cervical cancer.

[0069] In one embodiment, the cancer (e.g. RET altered or RET amplified cancer) is non small cell lung carcinoma (NSCLC) or medullary thyroid cancer (MTC).

[0070] In one embodiment the cancer is NSCLC expressing a RET fusion protein and/or harbouring a RET fusion gene. In one embodiment, the RET fusion partner is KIF5B or CCDC6.

[0071] In another embodiment, the cancer is MTC expressing a mutated RET protein. In one embodiment, the mutated RET protein comprises a M918T mutation. [0072] In one embodiment, the compound of formula I is administered to said subject orally. The compound of formula I may be processed into a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs etc). Pharmaceutical compositions of the compound of formula I may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more diluent, disintegrant, lubricant, glidant, colouring, sweetening, flavouring and/or preservative agents. Further details of suitable pharmaceutical formulations comprising the compound of formula I are provided in WO 2018/060714, the teaching of which are incorporated herein. In one embodiment the compound of formula I is orally administered to said subject in tablet or capsule form.

[0073] In one embodiment, the compound of formula I is present as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and/or physically compatible with the other ingredients comprising a pharmaceutical formulation, and/or are generally physiologically compatible with the recipient thereof.

[0074] Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

[0075] In general, salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and/or isolated using a single method or a combination of methods. [0076] Suitable examples of the salts are hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, arylsulfonates such as benzenesulfonate and p-toluenesulfonate, organic acid salts such as acetate, malate, fumarate, succinate, adipate (e.g. hemiadipate), citrate, ascorbate, tartrate, oxalate and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate. Preferably, the salt is a hemiadipate.

[0077] Suitably, if a pharmaceutically acceptable salt of the compound of formula I is administered the dose is adjusted so as to deliver a specified dose of the compound of formula I (i.e. the free base).

[0078] For example, in one embodiment of the claimed method for the treatment or prevention of a cancer in a human subject in need thereof, a pharmaceutically acceptable salt of the compound of formula I is administered to said subject such that the daily dose of the compound of formula I (i.e. free base) is about 10 mg per human to about 150 mg per human.

[0079] Suitably, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 150 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 150 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 150 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human to about 150 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 100 mg per human to about 150 mg per human.

[0080] In another embodiment, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 10 mg per human to about 100 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 100 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 100 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 100 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human to about 100 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 100 mg per human. [0081] In another embodiment, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 10 mg per human to about 75 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 75 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 75 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 75 mg per human; suitably a daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human.

[0082] In one embodiment, the daily dose of the pharmaceutically acceptable salt of the compound of formula I is administered to said subject as single daily dose. As used herein, a single daily dose means that the daily dose is administered at once, or substantially at once. However, administration of the single daily dose may be achieved by the administration of one or more dosage forms (e.g. tablets or capsules).

[0083] For example, in one embodiment a pharmaceutically acceptable salt of the compound of formula I is administered to said subject as a single daily dose of the compound of formula I (i.e. the free base) of about 10 mg per human to about 150 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 150 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 150 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 150 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human to about 150 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 100 mg per human to about 150 mg per human.

[0084] In another embodiment, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject as a single daily dose of the compound of formula I (i.e. the free base) of about 10 mg per human to about 100 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 100 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 100 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 100 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human to about 100 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 100 mg per human. [0085] In another embodiment, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject as a single daily dose of the compound of formula I (i.e. the free base) of about 10 mg per human to about 75 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 75 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 75 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 75 mg per human; suitably a single daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human.

[0086] In another embodiment, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject as a single daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human or about 100 mg per human. In another embodiment, the pharmaceutically acceptable salt of the compound of formula I is administered to said subject as a single daily dose of the compound of formula I (i.e. the free base) of 75 mg per human or 100 mg per human.

[0087] In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer in a human subject,

wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject once daily at a dose of about 10 mg per human to about 150 mg per human.

[0088] In another aspect, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a cancer in a human subject, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject once daily at a dose of about 10 mg per human to about 150 mg per human.

[0089] In another aspect, there is provided the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating or preventing a cancer in a human subject,

[0090] Each of the above and below-mentioned embodiments recited with respect to the first mentioned aspect apply equally to the other mentioned aspects of the invention.

[0091] The invention will now be described by the following numbered paragraphs which are not claims:

1. A method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof:

2. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

3. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 40 mg per human to about 150 mg per human.

4. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 50 mg per human to about 150 mg per human.

5. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 150 mg per human.

6. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 100 mg per human.

7. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human.

8. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 100 mg per human.

9. A method according to paragraph 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of 75 mg per human or 100 mg per human.

10. A method according to any one of the preceding paragraphs, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose. 11. A method according to any one of the preceding paragraphs, wherein the said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject orally.

12. A method according to any one of the preceding paragraphs, wherein the cancer has a RET alteration or amplification.

13. A method according to paragraph 12, wherein the RET alteration is expression of a RET fusion protein and/or harbouring a RET fusion gene.

14. A method according to paragraph 13, wherein the RET fusion involves a fusion partner selected from KIF5B, CCDC6, NCOA4, TRIM33, ERC1 , KIAA1468, EPHA5, ANK3, MY05C, PARD3, SQSTM1, HOOK3, AKAP13, KIAA1217, FRMD4A and MBD1.

15. A method according to paragraph 13, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

16. A method according to paragraph 12, wherein the RET alteration is expression of a mutated RET protein.

17. A method according to paragraph 16, wherein the mutated RET protein comprises one or more mutations selected from V804M, V804L, G810R, G810S and M918T.

18. A method according to paragraph 16, wherein the mutated RET protein comprises a M918T mutation.

19. A method according to any one of the preceding paragraphs, wherein the cancer is a solid cancer.

20. A method according to any one of the preceding paragraphs, wherein the cancer is selected from a thyroid cancer, a lung cancer, a pancreatic cancer, an ovarian cancer, a breast cancer and a colorectal cancer.

21. A method according to any one of the preceding paragraphs, wherein the cancer is medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).

22. A method according to paragraph 1 , wherein the cancer is MTC expressing a mutated RET protein. 23. A method according to paragraph 22, wherein the mutated RET protein comprises a M918T mutation.

24. A method according to paragraph 1 , wherein the cancer is NSCLC expressing a RET fusion protein and/or harbouring a RET fusion gene.

25. A method according to paragraph 24, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

26. A method according to any one of the preceding paragraphs, wherein the compound of formula I is administered as a hemiadipate salt.

27. A method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein said cancer is RET altered medullary thyroid cancer (MTC) or RET altered non-small cell lung cancer (NSCLC).

28. A method according to paragraph 27, wherein the RET alteration is expression of a RET fusion protein and/or harbouring a RET fusion gene.

29. A method according to paragraph 28, wherein the RET fusion involves a fusion partner selected from KIF5B, CCDC6, NCOA4, TRIM33, ERC1, KIAA1468, EPHA5, ANK3, MY05C, PARD3, SQSTM1, HOOK3, AKAP13, KIAA1217, FRMD4A and MBD1.

30. A method according to paragraph 28, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

31. A method according to paragraph 27, wherein the RET alteration is expression of a mutated RET protein.

32. A method according to paragraph 31 , wherein the mutated RET protein comprises one or more mutations selected from V804M, V804L, G810R, G810S and M918T. 33. A method according to paragraph 31, wherein the mutated RET protein comprises a M918T mutation.

34. A method according to paragraph 27, wherein the cancer is RET fusion positive NSCLC.

35. A method according to paragraph 34, wherein the RET fusion positive NSCLC comprises RET-KIF5B fusion or RET-CCDC6 fusion.

36. A method according to paragraph 27, wherein the cancer is RET protein mutated MTC.

37. A method according to paragraph 36, wherein the RET protein mutated MTC comprises one or more mutations selected from V804M, V804L, G810R, G810S and M918T.

38. A method according to paragraph 36, wherein the RET protein mutated MTC comprises a M918T mutation.

39. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 10 mg per human to about 150 mg per human.

40. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

41. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 40 mg per human to about 150 mg per human.

42. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 50 mg per human to about 150 mg per human.

43. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 150 mg per human.

44. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 100 mg per human. 45. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human.

46. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 100 mg per human.

47. A method according to any one of paragraphs 27 to 38, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of 75 mg per human or 100 mg per human.

48. A method according to any one of paragraphs 27 to 47, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose.

49. A method according to any one of paragraphs 27 to 48, wherein the said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject orally.

50. A method according to any one of paragraphs 27 to 49, wherein the compound of formula I is administered as a hemiadipate salt.

51. A method according to any one of paragraphs 1 , 10 to 25, 27 to 38, 48 and 49, wherein the compound of formula I is administered as a pharmaceutically acceptable salt.

52. A method according to paragraph 51, wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 10 mg per human to about 150 mg per human.

53. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 20 mg per human to about 150 mg per human.

54. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 40 mg per human to about 150 mg per human. 55. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 50 mg per human to about 150 mg per human.

56. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human to about 150 mg per human.

55. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human to about 100 mg per human.

56. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 75 mg per human.

57. A method according to paragraph 51 , wherein said pharmaceutically acceptable salt of the compound of formula I is administered to said subject at a daily dose of the compound of formula I (i.e. the free base) of about 100 mg per human.

EXAMPLES

[0092] A phase 1, open-label, multi-center, dose-escalation trial was conducted to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics (PD) of the compound of formula I as a monotherapy in human patients with advanced solid tumors with RET gene alterations - including, but not limited to, NSCLC and MTC.

Study Design

[0093] 117 patients with advanced solid tumors with RET gene alterations received the compound of formula I orally once daily in each 28-day cycle at an allotted dose level. Dose escalation decisions were based on safety review from data collected in Cycle 1. Patients without sufficient treatment exposure or safety data from Cycle 1 were replaced for purposes of dose escalation decisions.

[0094] To minimize the number of patients exposed to potentially pharmacologically sub- optimal dose levels, dose escalation was performed using an accelerated titration design. [0095] If any of the following criteria were met within a cohort during their first 28-day cycle (Cycle 1) of the accelerated design, all subsequent dosing cohorts were performed using a 3 + 3 design:

• If a patient in an accelerated cohort experiences a dose-limiting toxicity (DLT)

• If a patient in an accelerated cohort experiences grade ³ 2 or higher drug-related treatment emergent adverse events (TEAEs)

[0096] The compound of formula I was dosed initially at 10 mg in Cohort 1. During escalations in the accelerated design, the dose was doubled for each subsequent accelerated cohort (e.g., 10 mg, 20 mg, etc). When the 3 + 3 design is in use, the dose in subsequent cohorts was increased according to a standard Fibonacci series (67%, 50%, 40%, and 33%).

[0097] In the accelerated design, each cohort consisted of a minimum of 1 patient. In the 3 + 3 design, each cohort consisted of at least 3 patients. In the 3 + 3 design, the second patient enrolled in the cohort was dosed at least 3 days after the first patient had received the first dose.

[0098] Dose escalation proceeded as follows in both the accelerated and 3 + 3 designs:

• If 0 patients in a cohort experienced a DLT, then the next higher dose-level cohort was enrolled.

• If > 1 patients in a cohort experienced a DLT, then the maximum tolerated dose (MTD) had been exceeded, and further enrolment into that cohort ceased.

• If 1 patient in a cohort experienced a DLT, then enrolment into that cohort was expanded to a total of 6 patients.

• If no further patients in an expanded cohort experienced a DLT, then the next higher dose level cohort was enrolled.

• If 1 or more additional patients in a cohort experienced a DLT, then the MTD had been exceeded.

[0099] A DLT was defined as any toxicity attributable to the compound of formula I that occurs before the end of Cycle 1 and which includes:

• Hematologic toxicities:

• Grade 4 neutropenia • Grade 3 febrile neutropenia

• Grade 4 thrombocytopenia (platelets < 25,000/pL)

• Grade 3 thrombocytopenia (platelets < 50,000/pL) with bleeding • Non-hematologic toxicities:

• ³ grade 3 AST (also referred to as serum glutamic oxaloacetic transaminase [SGOT]) or ALT (also referred to as serum glutamic pyruvic transaminase [SGPT]) or increased in grade for patients with liver metastases

• ³ grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain, hyperbilirubinemia, and rash (these become DLTs if the AE persists despite adequate treatment). Alopecia was not be considered a DLT.

• Any drug related-toxicity that results in treatment interruption exceeding 7 consecutive days.

• Any intolerable > grade 2 drug-related non-hematologic toxicity may be considered a DLT following evaluation and agreement by the Investigator, Medical Monitor and Sponsor.

[00100] In the event the MTD were to be exceeded, lower and intermediate dose levels would be explored using a 3 + 3 design until the MTD had been determined. The MTD is defined as the highest dose level studied at which < 2 of 6 experienced a DLT. The recommended Phase II dose can be no higher than the MTD established, but may be selected to be lower than the MTD based on an evaluation of PK, safety, tolerability, and compliance, including dose reductions and delay.

[00101] Following discussion and confirmation with the Medical Monitor, patients with documented stable disease at their last restaging scan, were escalated to the next highest dose level once all patient(s) in that higher cohort have cleared the DLT window period (first 28 days). Patients with an ongoing objective response or progressive disease were not eligible for intra-patient dose escalation. Daily treatment in 28-day cycles will be continued until disease progression or other discontinuation criteria are met.

[00102] Safety and tolerability were assessed on an ongoing basis. A Safety Monitoring

Committee (SMC) comprised of the Medical Monitor, Principal Investigators and Sponsor representatives reviewed safety information to decide upon dose escalation and further patient enrolment. A safety assessment was performed prior to each proposed dose escalation. Safety parameters reviewed included all available SAEs, AEs, DLTs, physical examinations, electrocardiograms (ECGs), vital signs, clinical laboratory evaluations and available PK. [00103] An expansion cohort consisting of 20 patients with RET gene-fusion NSCLC, 7 patients with RET gene-mutant MTC, and 23 patients with other RET gene-altered advanced tumors with prior specific RET gene-targeted therapy were treated orally with the compound of formula I at the recommended dose established by the earlier cohorts (non-expansion cohorts) once daily of each 28-day cycle.

[00104] Treatment was repeated every 28 days until disease progression or other discontinuation criteria were met. In the event that any DLTs occurring in > 33% of patients currently enrolled to the expansion cohort, further recruitment would be halted, and the Investigator, Medical Monitor, and Sponsor would review all available safety, PK and efficacy data to determine if further enrolment is justified or additional dose adjustments are required.

Study Population

[00105] The main eligibility criteria were patients must be at least 18 years of age, with histopathologic diagnosis of an advanced solid tumor with a RET gene alteration, and who have no alternative therapy of proven benefit.

[00106] Any cancer-directed therapy (chemo-, radio-, immuno-, biologic, or hormonal therapy) with the exception of LHRH agonists/antagonists, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, bisphosphonates, and palliative radiotherapy, were prohibited from 28 days before the first dose of the compound of Formula I until the End of Treatment visit.

Study Intervention

[00107] Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study patient according to the study protocol.

[00108] The compound of formula I can be prepared as set out in WO 2018/060714 which is incorporated herein in its entirety. All patients received compound of formula I as either a capsule or a tablet (see Tables 1a-c below) as a monotherapy:

Table 1a - Study Intervention

Table 1b - Capsule formulation

Table 1c - Tablet formulation

[00109] The capsule formulation were prepared by manually mixing the compound of formula I and the lactose followed by sequential blending of the mixture with (i) microcrystalline cellulose and croscarmellose sodium and (ii) magnesium stearate. The resultant excipient blend was filled into #2 HPMC capsules.

[00110] The tablet formulations were prepared by sieving and combining all components except the magnesium stearate and blending together. Magnesium stearate is then blended with the blend. Tablets were prepared from the final blend via direct compression.

Results

[00111] As shown in Table 2, the majority of the patient population studied was male and the median age was 59. Over half of the subjects had an ECOG performance status of 1. Fifty nine percent (59%) of patients had diagnosed advanced non-small cell lung cancer, 26% had medullary thyroid cancer and 15% had other tumor types including pancreatic. The median number of prior systemic therapies was 2. Twenty percent (20%) of patients had brain metastases.

Table 2

‘including, recto-sigmoid, colorectal, cholangiocarcinoma, bladder, pancreatic, prostate, salivary duct, sarcoma, and urothelial. [00112] Of the patients having RET gene fusion positive NSCLC, RET-KIF5B fusions and RET-CCDC6 fusions were harboured by some of the patients. Of the patients having RET mutation position MTC, a M918T mutation was harboured by some of the patients.

[00113] Patients were assigned to the dosing cohort which was active at time of enrolment (unless the current dose level is fully accrued, newly identified patients who meet eligibility criteria may be enrolled into a lower dose level cohort which has already cleared the DLT window, following confirmation by the Sponsor and Medical Monitor). In total, 7 dose levels were assessed. In the expansion cohort all patients started with a dose of 75 mg but could dose reduce if certain tolerability or toxicity concerns were observed.

[00114] The number of patients studied in each cohort is set out in Table 3 below:

Table 3

Efficacy

[00115] Computed tomography (CT), positron emission tomography-computed tomography (PET/CT), or magnetic resonance imaging (MRI) scans were performed at patient screening and then between days 22 to 28 (prior to the beginning of the next cycle). Thereafter scans were taken between days 22 to 28 of all even numbered cycles (i.e. cycle 2, 4, 6, 8, 10, etc.) and at the end of the study.

[00116] Baseline images encompassed all areas of known predilection for metastases in the disease under evaluation and additionally investigated areas that may be involved based on signs and symptoms of individual patients. Baseline assessments were performed no more than 28 days before but as close as possible to the first administration of the compound of formula I. The imaging method used at screening was used at each subsequent visit.

[00117] Tumor measurements were recorded and also evaluation of the treatment response in accordance with by RECIST v.1.1 (Eisenhauer et al., 2009) and recorded as complete response [CR], partial response [PR], stable disease, or progression of disease.

[00118] Table 4 sets out the objective response rate and best overall response for the overall cohort:

Table 4

[00119] The compound of formula I administered orally, once daily at doses ranging from 10-150 mg resulted in clear clinical activity with an overall response rate of 30 percent including one patient with a complete response. Formula I also exhibited significant disease control with a disease control rate of 78% (SD + PR + CR).

[00120] Figure 1 shows for each patient in the evaluable data set the best percentage change in the size of target tumor lesions from base line. The compound of formula I exhibited clear antitumor activity with the majority of NSCLC and MTC patients with RET alterations responding to treatment. In addition one patient with a RET-fusion endocrine pancreatic tumor also showed a significant 100% reduction in the tumor target lesions. [00121] A summary of response for those patients in the evaluable data set with RET altered MTC or NSCLC is provided in Table 5:

Table 5

[00122] The compound of formula I exhibited comparable clinical activity between both NSCLC and MTC patients as assessed by objective response rate and disease control rate (CR + PR + SD).

[00123] Figures 2 and 3 show for each NSCLC and MTC patient respectively in the evaluable data set the best percentage change in size of target tumour lesions from base line and the original dose which the patient received. Among 60 patients with non-small cell lung cancer there was an objective response rate of 30%, including 18 confirmed partial responses. In the 27 MTC patients the objective response rate was 33% with 1 confirmed complete response and 8 confirmed partial responses.

[00124] Figure 4a-d shows the study duration and dosage for each patient (with original dose information (Fig. 4a), or primary tumor type (Fig. 4b)); each NSCLC patient (Fig. 4c) and each MTC patient (Fig. 4d). Patients treated with the compound of formula I remained on study for a median of greater than 230 days highlighting the activity of the compound of formula I in controlling progression of the RET-altered tumors, while being well tolerated. [00125] Figure 5a and 5b show CT and MRI images respectively of the lung of a patient with RET-fusion NSCLC at base line and during cycle 2 at 40 g of the compound of formula I. These figures highlight the anti-tumor activity of Formula I as shown by the clear reduction in tumor lesions (highlighted by RED arrows) following 2 cycles of treatment with Formula I.

[00126] Figure 6 shows PET/CT images of the liver of a patient with RET-altered MTC at base line and during cycle 2 at 75 mg of formula I. Administration of the compound of formula I resulted in a significant and rapid decrease in the large tumor burden in the liver (as shown by blue arrows) of this patient.

[00127] Figure 7 shows the response of RET-fusion NSCLC liver metastases at baseline and during cycle 2 at 50 mg of the compound of formula I. Administration of the compound of formula I resulted in a significant and rapid decrease in the large tumor metastases in the liver (as shown by blue arrows) of this patient.

[00128] Figure 8 shows the response of a RET-fusion NSCLC brain metastases in a patient following 2 cycles of treatment with 75 mg of the compound of formula I. The compound of formula I was able to cross the blood brain barrier and exert a clear anti-tumor effect with a 43% reduction in the patient’s brain lesion (green lines) following 2 cycles of therapy.

Safety

[00129] With a median duration of exposure to the compound of formula I of 231 days, the most common treatment emergent adverse events (TEAEs) seen in 117 patients are listed in Table 6. Most TEAEs were grade £2 and deemed not related to the compound of formula I.

[00130] The most common grade 3 or higher TEAE deemed related by study investigators to the compound of formula I was asymptomatic creatinine phosphokinase increase. The MTD was not reached.

Table 6

[00131] The compound of formula I was found to be generally well tolerated across all doses tested in the phase 1 study (10-150 mg).

PK

[00132] In the non-expansion cohorts, blood samples were collected over 24 hours on both Cycle 1 , Day 1 and Day 15 to establish the PK profile of the compound of formula I. An additional PK sample was also collected pre-dose on Day 1 of Cycle 2, Cycle 3, and Cycle 4.

[00133] Figure 9 shows the mean blood concentrations of the compound of formula I on day 15 post treatment for each dose level. Day 15 is the approximate or expected steady state and was therefore used for this analysis.

[00134] The compound of formula I demonstrates liner PK with concentrations achieved maintaining 24 hour coverage over the RET enzymatic IC90 at the 20mg dose level and above.

Conclusion

[00135] The compound of formula I exhibited clear anti-tumor activity and clinical responses at tested doses of 10 mg per human and up to and including 150 mg per human, consistent with a clear and robust inhibition of the RET-alterations found in this phase 1 patient population. Daily doses of 75 mg or 100 mg per human maximized clinical activity whilst minimizing potential toxicities.

[00136] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

[00137] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[00138] The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.

[00139] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

[00140] This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law.

REFERENCES

Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005;16:441-67.

Ballerini P, Struski S, Cresson C, et al.. RET fusion genes are associated with chronicmyelomonocytic leukemia and enhance monocytic differentiation. Leukemia. 2012;26:2384-89.

Cabozantinib Prescribing Information. Accessed from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf.

Carlomagno F, Vitagliano D, Guida T, etai. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62:7284-90.

Ceccherini I, Bocciardi R, Luo Y, etai. Exon structure and flanking intronic sequences ofthe human RET proto-oncogene. Biochem Biophys Res Commun. 1993;196:1288-95.

Drilon A, Rekhtman N, Arcila M, etai. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17:1653-60.

Eisenhauer EA, Therasse P, Bogaerts J, etai. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). EurJ Cancer. 2009;45:228- 47.

Esseghir S, Todd SK, Hunt T, et al.. A role for glial cell derived neurotrophic factor induced expression by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer Res. 2007;67:11732-41.

GAVRETO prescribing information. Accessed from: https://www.accessdataida.gov/drugsatfda docs/label/2020/213721 sOOOIbl.pdf

Grieco M, Santoro M, Berlingieri MT, etai.. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990;60:557-63.

Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett. 2004;204:197-211.

Le Rolle AF, Klempner SJ, Garrett CR, et al.. Identification and characterization of RET fusions in advanced colorectal cancer. Oncotarget. 2015;6:28929-37.

Lee SH, Lee JK, Ahn MJ, et al.. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.

Ann Oncol. 2017;28:292-97. Marsh DJ, Learoyd DL, Andrew SD, et al.. Somatic mutations in the RET proto oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf). 1996;44:249-57.

Morandi A, Martin LA, Gao Q, et al.. GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors. Cancer Res. 2013;73:3783-95.

Plaza-Menacho I, Morandi A, Robertson D, etal.. Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene. 2010;29:4648-57.

Romei C, Elisei R, Pinchera A, etal.. Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab. 1996;81 : 1619-22.

Skalova A, Stenman G, Simpson RHW, etal.. The Role of Molecular Testing in the Differential Diagnosis of Salivary Gland Carcinomas. Am J Surg Pathol. 2018;42:e11-e27.

Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.

Subbiah V, Gainor JF, Rahal R, et al.. Precision Targeted Therapy With BLU-667 for RET-Driven Cancers. Cancer Discov. 2018; CD-18-0338.

Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42:581-88.

Takeuchi K, Soda M, Togashi Y, etal.. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378-81.

Vandetanib Prescribing Information. Accessed from: https://www.accessdataida.qov/druqsatfda docs/labei/2011 /Q22405sQQ0lbLpdf.

Yakes FM, Chen J, Tan J, etal.. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 ; 10:2298- 308.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer in a human subject,

wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

2. A compound for use according to claim 1, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 40 mg per human to about 150 mg per human.

3. A compound for use according to claim 1 or claim 2, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 50 mg per human to about 150 mg per human.

4. A compound for use according to any one of the preceding claims, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 150 mg per human.

5. A compound for use according to any one of the preceding claims, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 100 mg per human.

6. A compound for use according to any one of the preceding claims, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human.

7. A compound for use according to any one of claims 1 to 5, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 100 mg per human.

8. A compound for use according to any one of the preceding claims, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose.

9. A compound for use according to any one of the preceding claims, wherein the cancer has a RET alteration or amplification.

10. A compound for use according to claim 9, wherein the RET alteration is expression of a RET fusion protein and/or harbouring a RET fusion gene.

11. A compound for use according to claim 10, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

12. A compound for use according to claim 9, wherein the RET alteration is expression of a mutated RET protein.

13. A compound for use according to claim 12 wherein the mutated RET protein comprises a M918T mutation.

14. A compound for use according to any one of the preceding claims, wherein the cancer is a solid cancer.

15. A compound for use according to any one of the preceding claims, wherein the cancer is selected from a thyroid cancer, a lung cancer, a pancreatic cancer, an ovarian cancer, a breast cancer and a colorectal cancer.

16. A compound for use according to any one of the preceding claims, wherein the cancer is medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).

17. A compound for use according to any one of the preceding claims, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject orally.

18. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer in a human subject, wherein said cancer is RET altered medullary thyroid cancer (MTC) or RET altered non-small cell lung cancer (NSCLC).

19. A compound for use according to claim 18, wherein the RET alteration is expression of a RET fusion protein and/or harbouring a RET fusion gene.

20. A compound for use according to claim 19, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

21. A compound for use according to claim 18, wherein the RET alteration is expression of a mutated RET protein.

22. A compound for use according to claim 21, wherein the mutated RET protein comprises a M918T mutation.

23. A compound for use according to any one of claims 18 to 22, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

24. A compound for use according to any one of claims 18 to 23, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose.

25. A compound for use according to any one of claims 18 to 24, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject orally.

26. A method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof: wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

27. A method according to claim 26, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 40 mg per human to about 150 mg per human.

28. A method according to claim 26, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 50 mg per human to about 150 mg per human.

29. A method according to claim 26, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 150 mg per human.

30. A method according to claim 26, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human to about 100 mg per human.

31. A method according to claim 26, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 75 mg per human.

32. A method according to claim 26, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 100 mg per human.

33. A method according to any one of claims 26 to 32, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose.

34. A method according to any one of claims 26 to 33, wherein the cancer has a RET alteration or amplification.

35. A method according to claim 34, wherein the RET alteration is expression of a RET fusion protein and/or harbouring a RET fusion gene.

36. A method according to claim 35, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

37. A method according to claim 34, wherein the RET alteration is expression of a mutated RET protein.

38. A method according to claim 37 wherein the mutated RET protein comprises a M918T mutation.

39. A method according to any one of claims 26 to 38, wherein the cancer is a solid cancer.

40. A method according to any one of claims 26 to 39, wherein the cancer is selected from a thyroid cancer, a lung cancer, a pancreatic cancer, an ovarian cancer, a breast cancer and a colorectal cancer.

41. A method according to any one of claims 26 to 40, wherein the cancer is medullary thyroid cancer (MTC) or non-small cell lung cancer (NSCLC).

42. A method according to any one of claims 26 to 41 , wherein the compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject orally.

43. A method for the treatment or prevention of a cancer in a human subject in need thereof, comprising administering to said subject a compound of formula I, or a pharmaceutically acceptable salt thereof:

44. A method according to claim 43, wherein the RET alteration is expression of a RET fusion protein and/or harbouring a RET fusion gene.

45. A method according to claim 44, wherein the RET fusion involves a fusion partner selected from KIF5B and CCDC6.

46. A method according to claim 43, wherein the RET alteration is expression of a mutated RET protein.

47. A method according to claim 46, wherein the mutated RET protein comprises a M918T mutation.

48. A method according to any one of claims 43 to 47, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject at a daily dose of about 20 mg per human to about 150 mg per human.

49. A method according to any one of claims 43 to 48, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject as a single daily dose.

50. A method according to any one of claims 43 to 49, wherein the said compound of formula I, or a pharmaceutically acceptable salt thereof is administered to said subject orally.