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WO2025056741A1 - Azd1390, ou sel pharmaceutiquement acceptable de celui-ci, en combinaison avec un rayonnement destiné à être utilisé dans une méthode de traitement d'une tumeur du snc - Google Patents

Azd1390, ou sel pharmaceutiquement acceptable de celui-ci, en combinaison avec un rayonnement destiné à être utilisé dans une méthode de traitement d'une tumeur du snc Download PDF

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Publication number
WO2025056741A1
WO2025056741A1 PCT/EP2024/075613 EP2024075613W WO2025056741A1 WO 2025056741 A1 WO2025056741 A1 WO 2025056741A1 EP 2024075613 W EP2024075613 W EP 2024075613W WO 2025056741 A1 WO2025056741 A1 WO 2025056741A1
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Prior art keywords
azd1390
pharmaceutically acceptable
acceptable salt
treatment
administered
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Inventor
Djuro KARANOVIC
Colin Paul Jonathan GLOVER
Urszula Maria POLANSKA
Chara STAVRAKA
William John Trigg
Chunling FAN
Gillian Elizabeth Mundin
Petra HAMERLINK
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AstraZeneca AB
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AstraZeneca AB
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to methods of treatment of CNS tumours.
  • Glioblastoma (also known as GBM) is the most common primary brain malignancy in adults (48.6% of all malignant CNS tumors) with an average incidence rate of 3.23 per 100000 population in the United States (Ostrom 2020). It is the most lethal primary brain tumor and less than 10% of patients survive 5 years post diagnosis (Ajaz 2014, Cloughesy 2014, Delgado-Lopez and Corrales-Garcia 2016, Ostrom 2020). Glioblastoma is a very aggressive and infiltrative tumor. Its ability to rapidly invade surrounding brain parenchyma with an intact BBB, and its intrinsic resistance to radio-and chemotherapies significantly limit the curative intent of surgery and other therapeutic interventions (Cuddapah 2014).
  • GBM The standard of care for GBM has not changed in over a decade and consists of maximal- safe surgical resection, followed by radiotherapy (RT) with or without temozolamide (TMZ), which is given concomitantly with and after RT (NCCN 2022, Stupp 2005).
  • Standard irradiation regimens in GBM vary based on the age of patients but are typically delivered by intensity-modulated radiation therapy (IMRT) with daily fractions of 2 Gy over 4 to 6 weeks.
  • IMRT intensity-modulated radiation therapy
  • O 6 methylguanine-DNA methyl-transferase promoter methylation has been found to be a favourable prognostic and predictive factor of response to TMZ in GBM patients (Alnahhas 2020, Hegi 2005).
  • MGMT MGMT
  • alkylating agents such as TMZ
  • mean overall survival (mOS) was 14.11 months for those with MGMT unmethylated tumors versus 24.59 months for patients harbouring MGMT promoter methylation (Alnahhas 2020).
  • AAAIR age-adjusted incidence rate
  • AZD1390 is an ATP-competitive kinase inhibitor with a cellular IC50 of 0.78 nM and is highly selective against other phosphatidylinositol 3-kinase-related kinases (PIKKs) including ATR (ataxia- and Rad3-related), DNA-PK (DNA-dependent protein kinase, and mTOR (mammalian target of rapamycin).
  • PIKKs phosphatidylinositol 3-kinase-related kinases
  • AZD1390 has been disclosed as having blood brain barrier penetrance in pre-clinical models (Durant 2018) and in human microdosing studies (Jucaite 2021) and has been shown to significantly prolong the survival of patient-derived xenograft and syngeneic models of adult malignant gliomas and brain metastases in pre- clinical studies (Durant 2018).
  • AZD1390 has also been shown to enhance the efficacy of radiation in vivo in both TP53 wild-type and TP53 mutant paediatric xenograft models of paediatric high-grade gliomas (pHGG) (Xie 2023).
  • AZD1390 for use in a method of treatment of a CNS tumour, wherein said treatment comprises the separate, sequential or simultaneous administration of i) a total daily dose of about 300 mg of AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof and ii) radiation therapy, to said subject.
  • the CNS tumour is recurrent glioblastoma.
  • the glioblastoma has unmethylated MGMT.
  • the glioblastoma has methylated MGMT.
  • Fig. 4 shows time from 1 st AZD1390 treatment to discontinuation, death or second data cutoff for 6 patients with recurrent GBM treated with a combination of 150 mg QD AZD1390 and radiation therapy.
  • Fig. 5 shows time from 1 st AZD1390 treatment to discontinuation, death or second data cutoff for 6 patients with newly diagnosed GBM treated with a combination of 400 mg QD AZD1390 and radiation therapy.
  • Fig. 6 shows time from 1 st AZD1390 treatment to discontinuation, death or second data cutoff for 6 patients with newly diagnosed GBM treated with a combination of 300 mg QD AZD1390 and radiation therapy.
  • Fig. 7 shows time from 1 st AZD1390 treatment to discontinuation, death or second data cutoff for 6 patients with newly diagnosed GBM treated with a combination of 120 mg QD AZD1390 and radiation therapy.
  • Fig. 8 shows an X-Ray Powder Diffraction Pattern of Form B of AZD1390.
  • Fig. 9 shows a DSC Thermogram of Form B of AZD1390.
  • a free base AZD1390 is administered to a subject.
  • a pharmaceutically acceptable salt of AZD1390 is administered to a subject.
  • crystalline free base AZD1390 or a crystalline pharmaceutically acceptable salt of AZD1390 is administered to a subject.
  • Form B of AZ1390 is administered to a subject.
  • Form B of AZ1390 is described in WQ2017/046216 in Table 2 and Figures 3 and 4. It has the following characteristic peaks in X-ray powder diffraction: (20): 3.4, 11.7, 13.1, 13.5, 17.5, 18.1 , 19.0, 22.7, 23.4, and 24.0.
  • Form B is characterised in providing an X-ray powder diffraction pattern substantially as shown in Figure 8. Ten X-Ray powder diffraction peaks are shown in Table 1. Table 1 : Characteristic X-Ray powder diffraction peaks for Form B, 7-Fluoro-1-isopropyl-3- methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one
  • X-ray powder diffraction spectra were determined (using a Bruker D4 Analytical Instrument) by mounting a sample of the crystalline material on a Bruker single silicon crystal (SSC) wafer mount and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 40kV and 40mA with a wavelength of 1.5418 angstroms. The collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 5.89mm antiscatter slit and a 9.55mm detector slit.
  • SSC Bruker single silicon crystal
  • the sample was exposed for 0.03 seconds per 0.00570° 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode.
  • the running time was 3 minutes and 36 seconds.
  • the instrument was equipped with a Position sensitive detector (Lynxeye). Control and data capture was by means of a Dell Optiplex 686 NT 4.0 Workstation operating with Diffrac+ software.
  • Form B displays a melting endotherm with an onset of 144.7°C and a peak at 145.8°C when analysed by differential scanning calorimetry (DSC) at a scanning rate of 10°C/mins ( Figure 3).
  • Differential Scanning Calorimetry was performed on a TA Instruments Q1000 DSC. Typically, less than 5 mg of material contained in a standard aluminium pan fitted with a lid was heated over the temperature range 25°C to 300°C at a constant heating rate of 10°C per minute. A purge gas using nitrogen was used at a flow rate 50ml per minute.
  • compositions may be in 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), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing), or as a suppository for rectal dosing.
  • the compositions may be obtained by conventional procedures well known in the art.
  • Compositions intended for oral use may contain additional components, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.
  • AZD1390 or a pharmaceutically acceptable salt thereof are administered in a treatment cycle. In some embodiments, AZD1390 or a pharmaceutically acceptable salt thereof is continuously administered in the treatment cycle.
  • continuous refers to administration of a therapeutic agent, e.g. AZD1390, at regular intervals without stopping or interruption, i.e., no void day.
  • void day it is meant a day when a therapeutic agent is not administered.
  • Administration once daily or twice daily is a form of continuous administration.
  • a “cycle”, “treatment cycle” or “dosing schedule”, as used herein, refers to a period of treatment that is repeated on a regular schedule.
  • the treatment can be given for one week, two weeks, or three weeks wherein AZD1390 is administered.
  • a treatment cycle is about 1 week to about 3 months.
  • a treatment cycle is about 5 days to about 1 month.
  • a treatment cycle is about 1 week to about 3 weeks.
  • a treatment cycle is about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.
  • AZD1390 or a pharmaceutically acceptable salt thereof is administered to the human subject in one or more treatment cycles, e.g., a treatment course.
  • a “treatment course” comprises one or more treatment cycles, which can be repeated on a regular schedule, or adjusted as a tapered schedule as the patient’s disease progression is monitored.
  • a patient's treatment cycles can have longer periods of treatment and/or shorter periods of rest at the beginning of a treatment course (e.g., when the patient is first diagnosed), and as the cancer enters remission, the rest period lengthens, thereby increasing the length of one treatment cycle.
  • the period of time for treatment and rest in a treatment cycle, the number of treatment cycles, and the length of time for the treatment course can be determined and adjusted throughout the treatment course by the skilled artisan based on the patient’s disease progression, treatment tolerance, and prognosis.
  • the method comprises 1 to 10 treatment cycles. In some embodiments, the method comprises 1 to 5 treatment cycles.
  • AZD1390 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle.
  • AZD1390 or a pharmaceutically acceptable salt thereof is administered before the start of radiotherapy.
  • a single dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered before the start of radiotherapy. This single dose may be administered 1 to 7 days, or 2 to 4 or 6 hours before the first dose of radiotherapy.
  • AZD1390 or a pharmaceutically acceptable salt thereof is administered continuously (i.e. every day) whilst radiotherapy is being administered.
  • the (or the first) dose may be administered at least two hours before the fraction.
  • the (or the first) dose may be administered no more than six hours before the fraction, or no more than four hours before the fraction.
  • a second dose of AZD1390 or a pharmaceutically acceptable salt is administered on the same day, this may be administered at least eight hours after the first dose. This second dose may be administered no more that fourteen hours after the first dose.
  • the AZD1390 or a pharmaceutically acceptable salt thereof is administered only on the days that radiotherapy is administered.
  • AZD1390 or a pharmaceutically acceptable salt thereof is administered after the last dose of radiotherapy in a cycle.
  • This adjuvant phase may last for at least 1 day, at least 3 days, at least 5 days, or at least 1 week.
  • This adjuvant phase may last up to 4 weeks, up to 3 weeks, or up to 2 weeks.
  • AZD1390 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, AZD1390 or a pharmaceutically acceptable salt thereof is in tablet dosage form.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of about 300 mg to treat primary GBM.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of about 300 mg.
  • the total daily dose may be up to 340 mg, 330 mg, 320 mg, 310 mg, or 300 mg.
  • the total daily dose may be at least 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of 300 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, once a day (QD). In some embodiments, AZD1390 is administered in a once daily dose (QD) of about 300 mg.
  • the once daily dose may be up to 340 mg, 330 mg, 320 mg, 310 mg, or 300 mg.
  • the once daily dose may be at least 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, twice a day (BID). In some embodiments, AZD1390 is administered in a twice daily dose (BID) of about 150 mg.
  • the twice daily dose may be up to 170 mg, 165 mg, 160 mg, 155 mg, or 150 mg.
  • the twice daily dose may be at least 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a twice daily dose (BID) of 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, or 170 mg.
  • BID twice daily dose
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a twice daily dose (BID) of 150 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of about 400 mg to treat recurrant GBM.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of about 400 mg.
  • the total daily dose may be up to 450 mg, 440 mg, 430 mg, 420 mg, 410 mg, or 400 mg.
  • the total daily dose may be at least 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg or 450 mg. In some embodiments, AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose (QD) of 400 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, once a day (OD). In some embodiments, AZD1390 is administered in a once daily dose (OD) of about 400 mg.
  • the once daily dose may be up to 450 mg, 440 mg, 430 mg, 420 mg, 410 mg, or 400 mg.
  • the once daily dose may be at least 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a once daily dose (OD) of 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg or 450 mg.
  • OD once daily dose
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a once daily dose (OD) of 400 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, twice a day (BID). In some embodiments, AZD1390 is administered in a twice daily dose (BID) of about 200 mg.
  • the twice daily dose may be up to 225 mg, 220 mg, 215 mg, 210 mg, 205 mg, or 200 mg.
  • the twice daily dose may be at least 175 mg, 180 mg, 185 mg, 190 mg, 195 mg or 200 mg.
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a twice daily dose (BID) of 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg or 225 mg.
  • BID twice daily dose
  • AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a twice daily dose (BID) of 200 mg.
  • Radiation therapy is a therapy using ionizing radiation.
  • the radiation therapy may involve the use of x-rays, gamma rays, or charged particles.
  • the radiation therapy may be external beam radiation therapy or internal radiation therapy (also called brachytherapy).
  • Systemic radiation therapy using radioactive substances, such as radioactive iodine, may also be employed.
  • External-beam radiation therapy includes 3D conformational radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, tomotherapy, stereotactic radiosurgery, proton therapy, or other charged particle beams.
  • the radiotherapy is intensity-modulated radiation therapy (IMRT).
  • IMRT intensity-modulated radiation therapy
  • the radiotherapy is whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT).
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • the radiation therapy is fractionated radiation therapy, wherein the total dose of radiation is split into a number of smaller doses, i.e. fractions.
  • the number of fractions may be at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7.
  • the number ef fractions may be less than 40, less than 35, less than 30, less than 25, less than 20 or less than 15.
  • the radiation therapy fractions are administered in sequential days. In other embodiments, the radiation therapy fractions are administered for some days sequentially, with some rest days. In some of these embodiments, the radiation therapy fractions are administered for five days sequentially, followed by two rest days, which administration pattern is repeated until all fractions have been administered.
  • the total dose of radiotherapy is at least 20 Gy, at least 30 Gy, at least 40 Gy, or at least 50 Gy. In some embodiments, the total dose of radiotherapy is less than 70 Gy, less than 60 Gy, less than 50 Gy, or less than 40 Gy.
  • the total dose of radiotherapy is 60 Gy.
  • the radiotherapy is delivered by IMRT with daily fractions of 3.5 Gy over 2 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 35 Gy. This may be used to treat recurrent GBM.
  • the radiotherapy is delivered by PBRT/WBRT with daily fractions of 3.0 Gy over 2 week (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 30 Gy.
  • This may be used to treat CNS metastases of solid tumors who are not candidates for stereotactic radiosurgery (SRS).
  • SRS stereotactic radiosurgery
  • the radiotherapy is delivered by IMRT with daily fractions of 2.0 Gy over 4 to 6 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 40 Gy to 60 Gy, and AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose of about 300 mg on the same days as radiotherapy, followed by a 2 week adjuvant phase of dosing AZD1390 at 300 mg QD.
  • This may be used to treat primary GBM, such as primary GBM with unmethylated MGMT.
  • the radiotherapy is delivered by IMRT with daily fractions of 3.5 Gy over 2 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 35 Gy and AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose of about 300 mg on the same days as radiotherapy, followed by a 2 week adjuvant phase of dosing AZD1390 at 300 mg QD.
  • This may be used to treat recurrent GBM.
  • the radiotherapy is delivered by PBRT/WBRT with daily fractions of 3.0 Gy over 2 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 30 Gy and AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose of about 300 mg on the same days as radiotherapy.
  • This may be used to treat CNS metastases of solid tumors who are not candidates for stereotactic radiosurgery (SRS).
  • SRS stereotactic radiosurgery
  • the radiotherapy is delivered by IMRT with daily fractions of 2.0 Gy over 4 to 6 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 40 Gy to 60 Gy, and AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose of about 400 mg on the same days as radiotherapy, followed by a 2 week adjuvant phase of dosing AZD1390 at 400 mg QD.
  • This may be used to treat primary GBM, such as primary GBM with unmethylated MGMT.
  • the radiotherapy is delivered by IMRT with daily fractions of 3.5 Gy over 2 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 35 Gy and AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose of about 400 mg on the same days as radiotherapy, followed by a 2 week adjuvant phase of dosing AZD1390 at 400 mg QD.
  • This may be used to treat recurrent GBM.
  • the radiotherapy is delivered by PBRT/WBRT with daily fractions of 3.0 Gy over 2 weeks (on 5 days out of 7, such as weekdays only), i.e. with a total dose of 30 Gy and AZD1390 is administered, optionally as a pharmaceutically acceptable salt, in a total daily dose of about 400 mg on the same days as radiotherapy.
  • This may be used to treat CNS metastases of solid tumors who are not candidates for stereotactic radiosurgery (SRS).
  • SRS stereotactic radiosurgery
  • the language “treat,” “treating” and “treatment” includes the reduction of size or mass of the CNS tumour, the slowing or delaying of progression of the CNS tumour, and/or prolonging the survival of the patient.
  • the language “treat,” “treating” and “treatment” also includes the reduction or inhibition of the growth of the CNS tumor.
  • inhibitor includes a decrease in the baseline activity of a biological activity or process.
  • subject includes warm-blooded mammals, for example, primates, dogs, cats, rabbits, rats, and mice.
  • the subject is a primate.
  • the subject is a human.
  • Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
  • the term “about” in relation to a numerical value is optional and means for example +/- 10%, or +/- 5%.
  • Nonclinical in vitro pharmacology studies have shown that AZD1390 at concentrations ⁇ 10 nM led to >50% inhibition of ATM kinase enzyme and radiosensitized a panel of GBM cell lines.
  • radiosensitization mediated by AZD1390 was confirmed in a series of preclinical mouse models of GBM and lung carcinoma (orthotopic and subcutaneous PDX grown in immunocompromised mice, as well as murine immunocompetent syngeneic GBM models), showing dose-dependent tumor growth inhibition (Durant 2018).
  • the unbound brain to plasma partition coefficient p , uu (C u ,brain/C u , plasma) was calculated using the following equation:
  • AZD1390 was radiolabeled with carbon-11 and a microdose (mean injected mass 1.21 g) was injected in 8 male subjects (21-65 years old).
  • the radioactivity concentration of [ 11 C]AZD1390 in brain was measured using a high resolution PET system. Radioactivity in arterial blood was measured to obtain a metabolite corrected arterial input function for quantitative image analysis.
  • the brain radioactivity concentration of [ 11 C]AZD1390 was 0.64 SUV (standard uptake value) and reached maximum 1.00% of injected dose at T ma x[brain] of 21 minutes (time of maximum brain radioactivity concentration) after i.v. injection.
  • the whole brain total distribution volume was 5.20 mL*cm" 3 . This led to the Kp, uu (C u ,brain/C u , plasma) in humans to be calculated as 0.24. No adverse events related to [ 11 C] AZD1390 were reported.
  • the original predicted clinically efficacious daily dose for AZD1390 was 11mg based on (1) early PK-PD-efficacy data in a very sensitive model, (2) Kpuu delivered in primates and (3) predictions of human PK.
  • Brain tumor samples were collected intraoperatively between 2 to 6 hours (corresponding to Cmax) and ⁇ 24h (corresponding to Cmin) following the last dose of AZD1390 for PK and PD analysis along with blood and CSF.
  • Resected GBM tumor tissue is immediately transferred to the laboratory, sliced into sections, and incubated in neuronal stem cell media before, during and after ex vivo radiation.
  • No radiation (OGy/sham radiation therapy, control) or a single dose of radiation (5Gy) is delivered to individual parts of the tumor, which are then incubated for 30 minutes before the samples are formalin-fixed, paraffin-embedded and ATM pathway activity assessed by evaluating the level of phosphorylated RAD50 biomarker by immunohistochemistry.
  • PD calculated from 7 AZD1390 dosed patient samples following ex vivo irradiation vs 5 control samples from the pilot study was: 93.7%, 90.0%, 96.3%, 95.6%, 97.5%, 99.0%, and 88.3%* pRAD50 inhibition (mean 95.3% 2 to 6 hours; 94.3% including ⁇ 24 hour [27 hours] sample).
  • the clinical pRAD50 biomarker data in recurrent GBM tumors analyzed in the surgical PhO WoO study demonstrates up to 99% (90% to 99%) of pRAD50 inhibition at the early timepoint (2 to 6 hours post-dose near Cmax) in 6 out of 6 evaluable samples from patients treated with AZD1390 at 400 mg QD and radiotherapy compared to those treated with radiotherapy alone.
  • Study D6940C00002 is a Phase I, multicenter study to assess the safety, tolerability, and PK of ascending doses of AZD1390 in combination with RT in patients with GBM and brain metastases from solid tumors.
  • the study comprises 3 arms, each of which provides standard of care IMRT for the disease setting indicated, with AZD1390 being administered in escalating dose cohorts.
  • Arm A enrolled patients with recurrent GBM
  • Arm B enrolled patients with brain metastases from solid tumors, but was closed due to poor recruitment
  • Arm C is enrolling patients with newly diagnosed GBM harbouring unmethylated MGMT promoter.
  • FFPE formalin-fixed paraffin embedded
  • KPS Karnofsky Performance Score
  • aPTT Activated partial thromboplastin time
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Females of childbearing potential must have a negative pregnancy test during screening and must not be breastfeeding or intending to become pregnant during the study.
  • Patient is not eligible for SRS treatment of brain tumor. 16.
  • Patient has not received any previous brain RT to the area that is to be irradiated.
  • Prior PBRT may be allowed after discussion with the Medical Monitor who may consult with a radiation oncologist to ensure that there is not significant overlap between the prior and new radiation fields, specifics of which are provided in the radiation manual.
  • Non-CNS malignant disease must be sufficiently controlled so that patients can be without additional systemic therapy for the required washout period before starting therapy until 5 days after the end of RT.
  • Patient has no history of seizures related to the brain metastases or LMD.
  • PBRT (rather than WBRT) during Cycle 1 as standard of care for brain metastases are eligible for this arm.
  • I DH 1 isocitrate dehydrogenase 1
  • Sensitive substrates of BCRP, OATP1B1, MATE1 , MATE2K and P-gp such as prazosin, cimetidine, simvastatin, dofetilide, metformin, dabigatran, digoxin and fexofenadine; Other anticancer agents and investigational agents; Live virus and bacterial vaccines.
  • interstitial lung disease ILD
  • drug-induced ILD ILD
  • radiation pneumonitis which required steroid treatment
  • any evidence of clinically active interstitial lung disease ILD
  • pneumotoxic drugs e.g., busulfan, bleomycin
  • nitrosoureas e.g., BCNU, CCNU
  • CK History or presence of myopathy or raised CK >5 x ULN on 2 occasions at screening. CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase, which may confound interpretation of the results. If CK levels are significantly elevated at baseline (>5 x ULN) a confirmatory test should be carried out within 5 -7 days. If the repeat test confirms a baseline CK >5 x ULN, treatment should not be started.
  • Cardiac dysfunction defined as: Myocardial infarction within six months of study entry, NYHA Class ll/lll/IV heart failure, unstable angina or unstable cardiac arrhythmias.
  • any evidence of severe or uncontrolled systemic diseases including uncontrolled hypertension, atrial fibrillation, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
  • uncontrolled hypertension including atrial fibrillation, active bleeding diatheses, or active infection
  • active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • QTcF Mean resting corrected QT interval
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, type 2 second degree atrioventricular block, third degree heart block.
  • AZD1390 is administered as a single dose (in the amount of the tested daily dose) to allow for PK measurements in the week prior to starting radiation treatment (Cycle 0).
  • Concomitant therapy with photon beam RT is given at the tested daily dose for the duration of radiation treatment (2 weeks: 3.5 Gy IMRT each day for 5 days followed by 2 rest days (Cycle 1 Week 1) which is repeated (Cycle 1 Week 2)).
  • AZD1390 is given daily at the tested dose for 14 days (Cycle 2).
  • PBRT Partial Brain Radiation Treatment
  • AZD1390 is administered as a single dose (in the amount of the tested daily dose) to allow for PK measurements in the week prior to starting radiation treatment (Cycle 0). This may be omitted.
  • Concomitant therapy with photon beam RT is given at the tested daily dose for the duration of radiation treatment (6 weeks: 2 Gy IMRT each day for 5 days followed by 2 rest days (Cycle 1 Week 1) which is repeated 5 times (Cycle 1 Weeks 2 to 6)).
  • AZD1390 is given daily at the tested dose for 14 days (Cycle 2).
  • the trial involves dose escalation such that a number of different daily dosages of AZD1390 are tested.
  • the trial seeks to establish the maximum tolerated dose (MTD) in each setting, followed by further assessment of the safety, tolerability and efficacy at this dose, or a dose lower than the MTD.
  • Selected doses in each arm tested are:
  • Arm A 150 mg, 200 mg, 400 mg, 600 mg, 900 mg
  • Arm C 120 mg, 300 mg, 400 mg
  • a DLT is defined as any toxicity not attributable to the disease, an extraneous cause or disease-related processes under investigation, which occurs after initiation of therapy during Cycle 0, 1 , and 2 for Arms A and C or Cycle 1 only for Arm B during treatment and before the end of the DLT assessment period.
  • the DLT assessment period ends at the end of Cycle 2 (1 week after the end of AZD1390 treatment) for Arms A and C and 5 days after the end of treatment in Arm B. Toxicity is graded according to the NCI CTCAE v4.03.
  • DLTs include:
  • Thrombocytopenia >CTCAE Grade 4, or >CTCAE Grade 3 associated with bleeding.
  • Non-hematological toxicity >CTCAE Grade 3 including but not limited to:
  • Grade 4 seizure e.g., prolonged repetitive seizures
  • Grade 3 seizure with increased severity or frequency above baseline.
  • AEs pulmonary adverse events
  • toxicity e.g., congestive heart failure, pulmonary embolism, pneumonia, pulmonary hypertension.
  • a dose of AZD1390 that prevents patients from receiving at least 75% of their scheduled course of RT is considered a DLT.
  • a dose of AZD1390 that prevents patients from receiving at least 85% of their scheduled course of RT is considered a DLT.
  • a DLT excludes:
  • the MTD is defined as the highest dose at which the predicted probability of a DLT is less than 25% in that specific RT setting. Due to the differences in patient populations and RT cumulative dose, each arm may be determined to have a distinct MTD.
  • Radiation therapy AEs are classified as follows:
  • Expected acute radiation-induced toxicities include hair loss, fatigue, and erythema or soreness of the scalp.
  • Potential acute toxicities include nausea and vomiting as well as temporary aggravation of brain tumor symptoms such as headaches, seizures, and weakness.
  • Possible early delayed radiation effects include lethargy and transient worsening of existing neurological deficits occurring 1 to 3 months after radiotherapy treatment.
  • Late Delayed Possible late delayed effects of radiotherapy include risk of radiation necrosis, and endocrine dysfunction.
  • neurocognitive deficits which could lead to mental slowing and behavioural change, are possible. Permanent hearing impairment and visual damage are rare. Cataracts can be encountered.
  • An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
  • An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).
  • an AE can include an undesirable medical condition occurring at any time, including run-in or washout periods, even if no study treatment has been administered.
  • AE is used generally to include any AE whether serious or non-serious.
  • SAE serious AE
  • any study phase i.e. , run-in, treatment, washout, follow-up
  • the timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterization of the plasma concentration-time profiles.
  • a PDc sample will be collected immediately before administration of AZD1390 or RT, and 1 hour after AZD1390 or RT, In addition there will be PK samples collected at the same time as PDc samples post AZD1390. This will allow deriving exposure/PDc relationships.
  • PBMCs Peripheral blood mononuclear cells
  • PBMCs will be isolated from whole blood and analysed for protein levels and post-translational modifications of pharmacodynamic biomarkers, PBMCs may also be stimulated ex vivo to induce DNA damage prior to protein analysis.
  • archival tumor tissue may include, but is not limited to:
  • Brain tumors will be assessed by brain MRI. Patients in Arm A and C will undergo MRI at screening and every 8 weeks until progression, starting 4 weeks after the end of RT. For patients in Arm A and C, standard of care brain MRI scans will be assessed for radiation necrosis until death, withdrawal of consent or the end of the study, whichever is sooner.
  • Brain MRI scans performed outside the study can be used as the baseline evaluation for all arms, provided that they are performed within 3 weeks of the patient starting treatment (Cycle 0 or Cycle 1 [RT] if Cycle 0 is omitted).
  • the response criteria to evaluate treatment for CNS disease are based on The Response Assessment in Neuro-Oncology (RANO) Working Group for GBM (Arms A and C) and RANO-Brain Metastases (Arm B).
  • the 400 mg QD dose in Arm C is open for enrolment.
  • Fig. 1 shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off (18 May 2023) for the initial 6 patients dosed at 400 mg QD in Arm A.
  • the circles for patient 5 indicate that at 1 .5 months the investigator considered the disease to be stable disease and at 3.3 months, progressive disease.
  • the circle for patient 6 indicates that at 1 .4 months the investigator considered the disease to be stable disease.
  • Fig. 2A shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the initial 6 patients dosed at 400 mg QD in Arm A
  • Fig. 2B shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the additional patients dosed at 400 mg QD in Arm A.
  • Fig. 3 shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the 6 patients dosed at 200 mg QD in Arm A.
  • Fig. 4 shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the 6 patients dosed at 150 mg QD in Arm A.
  • Fig. 5 shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the initial 6 patients dosed at 400 mg QD in Arm C.
  • Fig. 6 shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the 11 patients dosed at 300 mg QD in Arm C.
  • Fig. 7 shows time from 1 st AZD1390 treatment to discontinuation, death or data cut-off for the 2 patients dosed at 120 mg QD in Arm C.
  • a method of treating a CNS tumour in a subject in need thereof comprising administering to the subject a total daily dose of about 300 mg of AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof, and an amount of radiation therapy.
  • the CNS tumour is selected from glioblastoma, IDH mutant glioma (WHO Grade 2-4), ependymoma, high grade meningioma, paediatric high-grade glioma, Diffuse Intrinsic Pontine Glioma (DIPG), choroid plexus carcinoma, astrocytoma (such as Grade 4 astrocytoma), adult and/or paediatric medulloblastoma and metastatic CNS tumour (such as leptomeningeal disease).
  • DIPG Intrinsic Pontine Glioma
  • choroid plexus carcinoma astrocytoma (such as Grade 4 astrocytoma)
  • adult and/or paediatric medulloblastoma and metastatic CNS tumour (such as leptomeningeal disease).
  • radiotherapy is whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT).
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • AZD1390 for use in a method of treatment of a CNS tumour, wherein said treatment comprises the separate, sequential or simultaneous administration of i) a total daily dose of about 300 mg of said AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof, and ii) radiation therapy, to said subject.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to statement 44, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is administered before the start of radiotherapy.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to statement 45, wherein a single dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered before the start of radiotherapy.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 45, wherein the single dose is administered 1 to 7 days, or 2 to 6 hours before the first dose of radiotherapy.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 47, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered continuously whilst radiotherapy is being administered.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 47, wherein, whilst radiotherapy is being delivered, AZD1390 or a pharmaceutically acceptable salt thereof is administered only on the days that radiotherapy is administered.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 49, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered at least two hours before the fraction.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 50, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered no more than six hours before the fraction.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to statement 51, wherein the, or the first, dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered no more than four hours before the fraction.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 52, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered after the last dose of radiotherapy in a cycle as an adjuvant phase.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 53, wherein the adjuvant phase lasts for at least 1 day, at least 3 days, at least 5 days, or at least 1 week.
  • the adjuvant phase lasts up to 4 weeks, up to 3 weeks, or up to 2 weeks.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 55, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is administered orally.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 56, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is in tablet form.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the total daily dose of AZD1390 is up to 340 mg, 330 mg, 320 mg, 310 mg, or 300 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 58, wherein the total daily dose of AZD1390 is at least 250, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the total daily dose of AZD1390 is 300 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 61, wherein the once daily dose of AZD1390 is up to 340 mg, 330 mg, 320 mg, 310 mg, or 300 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to either statement 61 or statement 62, wherein the once daily dose of AZD1390 is at least 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the once daily dose of AZD1390 is 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein AZD1390 is administered twice a day.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 65, wherein the twice daily dose of AZD1390 is up to 170 mg, 165 mg, 160 mg, 155 mg, or 150 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the twice daily dose of AZD1390 is 150 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 68, wherein the CNS tumour is selected from glioblastoma, IDH mutant glioma (WHO Grade 2-4), ependymoma, high grade meningioma, paediatric high-grade glioma, Diffuse Intrinsic Pontine Glioma (DIPG), choroid plexus carcinoma, astrocytoma (such as Grade 4 astrocytoma), adult and/or paediatric medulloblastoma and metastatic CNS tumour (such as leptomeningeal disease).
  • glioblastoma IDH mutant glioma (WHO Grade 2-4)
  • ependymoma high grade meningioma
  • paediatric high-grade glioma paediatric high-grade glioma
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 69, wherein the CNS tumour is glioblastoma.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 70, wherein the CNS tumour is primary glioblastoma.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 71, wherein the glioblastoma has unmethylated MGMT (O 6 -methylguanine-DNA methyltransferase).
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 71, wherein the glioblastoma has methylated MGMT.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is intensity-modulated radiation therapy (IMRT).
  • IMRT intensity-modulated radiation therapy
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT).
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 75, wherein the radiation therapy is fractionated radiation therapy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 76, wherein the radiation therapy fractions are administered for some days sequentially, with some rest days.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 78, wherein the radiation therapy fractions are administered for five days sequentially, followed by two rest days.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 76 to 79, wherein the total dose of radiotherapy is at least 20 Gy, at least 30 Gy, at least 40 Gy, or at least 50 Gy.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 76 to 80, wherein the total dose of radiotherapy is less than 70 Gy, less than 60 Gy, less than 50 Gy, or less than 40 Gy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 76 to 81 , wherein the total dose of radiotherapy is 60 Gy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 76 to 81 , wherein the total dose of radiotherapy is 35 Gy.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is delivered by IMRT with daily fractions of 2.0 Gy over 4 to 6 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is delivered by IMRT with daily fractions of 3.5 Gy over 2 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is delivered by PBRT/WBRT with daily fractions of 3.0 Gy over 2 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treatment a CNS tumour, wherein said treatment comprises the separate, sequential or simultaneous administration of i) a total daily dose of about 300 mg of said AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof, and ii) radiation therapy, to said subject.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to statement 89, wherein the single dose is administered 1 to 7 days, or 2 to 6 hours before the first dose of radiotherapy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 90, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered continuously whilst radiotherapy is being administered.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 90, wherein, whilst radiotherapy is being delivered, AZD1390 or a pharmaceutically acceptable salt thereof is administered only on the days that radiotherapy is administered.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 92, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered at least two hours before the fraction.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 93, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered no more than six hours before the fraction.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to statement 94, wherein the, or the first, dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered no more than 4 hours before the fraction.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 95, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered after the last dose of radiotherapy in a cycle as an adjuvant phase.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 98, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is administered orally.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to statement 99, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is in tablet form.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the total daily dose of AZD1390 is up to 340 mg, 330 mg, 320 mg, 310 mg, or 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 101, wherein the total daily dose of AZD1390 is at least 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the total daily dose of AZD1390 is 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein AZD1390 is administered once a day.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to statement 104, wherein the once daily dose of AZD1390 is up to 340 mg, 330 mg, 320 mg, 310 mg, or 300 mg.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to either statement 104 or statement 105, wherein the once daily dose of AZD1390 is at least 250, 260 mg, 270 mg, 280 mg, 290 mg, or 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the once daily dose of AZD1390 is 300 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein AZD1390 is administered twice a day.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to statement 108, wherein the twice daily dose of AZD1390 is up to 170 mg, 165 mg, 160 mg, 155 mg, or 150 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to either statement 108 or statement 109, wherein the twice daily dose of AZD1390 is at least 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, or 150 mg.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the twice daily dose of AZD1390 is 150 mg. 112.
  • the CNS tumour is selected from glioblastoma, IDH mutant glioma (WHO Grade 2-4
  • glioblastoma has unmethylated MGMT (O 6 -methylguanine-DNA methyltransferase).
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is intensity-modulated radiation therapy (IMRT).
  • IMRT intensity-modulated radiation therapy
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 122, wherein the total dose of radiotherapy is at least 20 Gy, at least 30 Gy, at least 40 Gy, or at least 50 Gy.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 123, wherein the total dose of radiotherapy is less than 70 Gy, less than 60 Gy, less than 50 Gy, or less than 40 Gy. 125. Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 122, wherein the total dose of radiotherapy is 60 Gy.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 122, wherein the total dose of radiotherapy is 35 Gy. 127. Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is delivered by IMRT with daily fractions of 2.0 Gy over 4 to 6 weeks on 5 days out of 7, such as weekdays only.
  • a method of treating a CNS tumour in a subject in need thereof comprising administering to the subject a total daily dose of about 400 mg of AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof, and an amount of radiation therapy.
  • the CNS tumour is selected from glioblastoma, IDH mutant glioma (WHO Grade 2-4), ependymoma, high grade meningioma, paediatric high-grade glioma, Diffuse Intrinsic Pontine Glioma (DIPG), choroid plexus carcinoma, astrocytoma (such as Grade 4 astrocytoma), adult and/or paediatric medulloblastoma and metastatic CNS tumour (such as leptomeningeal disease).
  • DIPG Intrinsic Pontine Glioma
  • choroid plexus carcinoma astrocytoma (such as Grade 4 astrocytoma)
  • adult and/or paediatric medulloblastoma and metastatic CNS tumour (such as leptomeningeal disease).
  • radiotherapy is whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT).
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • AZD1390 for use in a method of treatment of a CNS tumour, wherein said treatment comprises the separate, sequential or simultaneous administration of i) a total daily dose of about 400 mg of said AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof, and ii) radiation therapy, to said subject.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to statement 44, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is administered before the start of radiotherapy.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to statement 45, wherein a single dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered before the start of radiotherapy.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 45, wherein the single dose is administered 1 to 7 days, or 2 to 6 hours before the first dose of radiotherapy.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 47, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered continuously whilst radiotherapy is being administered.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 47, wherein, whilst radiotherapy is being delivered, AZD1390 or a pharmaceutically acceptable salt thereof is administered only on the days that radiotherapy is administered.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 49, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered at least two hours before the fraction.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 50, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered no more than six hours before the fraction.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to statement 51, wherein the, or the first, dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered no more than four hours before the fraction.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 52, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered after the last dose of radiotherapy in a cycle as an adjuvant phase.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 53, wherein the adjuvant phase lasts for at least 1 day, at least 3 days, at least 5 days, or at least 1 week.
  • the adjuvant phase lasts up to 4 weeks, up to 3 weeks, or up to 2 weeks.
  • AZD1390, or a pharmaceutically acceptable salt thereof for use in a method of treatment of a CNS tumour according to any one of statements 44 to 55, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is administered orally.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 56, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is in tablet form.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the total daily dose of AZD1390 is up to 450 mg, 440 mg, 430 mg, 420 mg, 410 mg, or 400 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 58, wherein the total daily dose of AZD1390 is at least 350, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the total daily dose of AZD1390 is 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein AZD1390 is administered once a day.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 61, wherein the once daily dose of AZD1390 is up to 450 mg, 440 mg, 430 mg, 420 mg, 410 mg, or 400 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to either statement 61 or statement 62, wherein the once daily dose of AZD1390 is at least 350, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the once daily dose of AZD1390 is 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein AZD1390 is administered twice a day.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 65, wherein the twice daily dose of AZD1390 is up to 225 mg, 220 mg, 215 mg, 210 mg, 205 mg, or 200 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 44 to 57, wherein the twice daily dose of AZD1390 is 200 mg.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 68, wherein the CNS tumour is selected from glioblastoma, IDH mutant glioma (WHO Grade 2-4), ependymoma, high grade meningioma, paediatric high-grade glioma, Diffuse Intrinsic Pontine Glioma (DIPG), choroid plexus carcinoma, astrocytoma (such as Grade 4 astrocytoma), adult and/or paediatric medulloblastoma and metastatic CNS tumour (such as leptomeningeal disease).
  • glioblastoma IDH mutant glioma (WHO Grade 2-4)
  • ependymoma high grade meningioma
  • paediatric high-grade glioma paediatric high-grade glioma
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 69, wherein the CNS tumour is glioblastoma.
  • AZD1390 for use in a method of treatment of a CNS tumour according to statement 71, wherein the glioblastoma has unmethylated MGMT (O 6 -methylguanine-DNA methyltransferase).
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 71, wherein the glioblastoma has methylated MGMT.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT).
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 75, wherein the radiation therapy is fractionated radiation therapy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to statement 78, wherein the radiation therapy fractions are administered for five days sequentially, followed by two rest days.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 76 to 79, wherein the total dose of radiotherapy is at least 20 Gy, at least 30 Gy, at least 40 Gy, or at least 50 Gy.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 76 to 80, wherein the total dose of radiotherapy is less than 70 Gy, less than 60 Gy, less than 50 Gy, or less than 40 Gy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 76 to 81 , wherein the total dose of radiotherapy is 60 Gy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a CNS tumour according to any one of statements 76 to 81 , wherein the total dose of radiotherapy is 35 Gy.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is delivered by IMRT with daily fractions of 2.0 Gy over 4 to 6 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is delivered by IMRT with daily fractions of 3.5 Gy over 2 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 for use in a method of treatment of a CNS tumour according to any one of statements 44 to 73, wherein the radiotherapy is delivered by PBRT/WBRT with daily fractions of 3.0 Gy over 2 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of treatment a CNS tumour, wherein said treatment comprises the separate, sequential or simultaneous administration of i) a total daily dose of about 400 mg of said AZD1390, optionally in the form of a pharmaceutically acceptable salt thereof, and ii) radiation therapy, to said subject.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to statement 89, wherein the single dose is administered 1 to 7 days, or 2 to 6 hours before the first dose of radiotherapy.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 90, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered continuously whilst radiotherapy is being administered.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 90, wherein, whilst radiotherapy is being delivered, AZD1390 or a pharmaceutically acceptable salt thereof is administered only on the days that radiotherapy is administered.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 92, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered at least two hours before the fraction.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 93, wherein when AZD1390 or a pharmaceutically acceptable salt thereof is administered on the same day as a fraction of radiotherapy, the, or the first, dose is administered no more than six hours before the fraction.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to statement 94, wherein the, or the first, dose of AZD1390 or a pharmaceutically acceptable salt thereof is administered no more than 4 hours before the fraction.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 95, wherein AZD1390 or a pharmaceutically acceptable salt thereof is administered after the last dose of radiotherapy in a cycle as an adjuvant phase.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 98, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is administered orally.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to statement 99, wherein the AZD1390 or a pharmaceutically acceptable salt thereof is in tablet form.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the total daily dose of AZD1390 is up to 450 mg, 440 mg, 430 mg, 420 mg, 410 mg, or 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 101, wherein the total daily dose of AZD1390 is at least 350, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the total daily dose of AZD1390 is 400 mg.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to statement 104, wherein the once daily dose of AZD1390 is up to 450 mg, 440 mg, 430 mg, 420 mg, 410 mg, or 400 mg.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to either statement 104 or statement 105, wherein the once daily dose of AZD1390 is at least 350, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the once daily dose of AZD1390 is 400 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein AZD1390 is administered twice a day.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to statement 108, wherein the twice daily dose of AZD1390 is up to 225 mg, 220 mg, 215 mg, 210 mg, 205 mg, or 200 mg.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to either statement 108 or statement 109, wherein the twice daily dose of AZD1390 is at least 175 mg, 180 mg, 185 mg, 190 mg, 195 mg or 200 mg.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 100, wherein the twice daily dose of AZD1390 is 200 mg. 112.
  • the CNS tumour is selected from glioblastoma, IDH mutant glioma (WHO Grade 2-4
  • glioblastoma has unmethylated MGMT (O 6 -methylguanine-DNA methyltransferase).
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is intensity-modulated radiation therapy (IMRT).
  • IMRT intensity-modulated radiation therapy
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT).
  • WBRT whole brain radiation therapy
  • PBRT partial brain radiation therapy
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 122, wherein the total dose of radiotherapy is at least 20 Gy, at least 30 Gy, at least 40 Gy, or at least 50 Gy.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 123, wherein the total dose of radiotherapy is less than 70 Gy, less than 60 Gy, less than 50 Gy, or less than 40 Gy. 125. Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 122, wherein the total dose of radiotherapy is 60 Gy.
  • AZD1390 Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 119 to 122, wherein the total dose of radiotherapy is 35 Gy. 127. Use of AZD1390, or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is delivered by IMRT with daily fractions of 2.0 Gy over 4 to 6 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is delivered by IMRT with daily fractions of 3.5 Gy over 2 weeks on 5 days out of 7, such as weekdays only.
  • AZD1390 or a pharmaceutically acceptable salt thereof, according to any one of statements 87 to 116, wherein the radiotherapy is delivered by PBRT/WBRT with daily fractions of 3.0 Gy over 2 weeks on 5 days out of 7, such as weekdays only.

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Abstract

L'invention concerne l'AZD1390, ou un sel pharmaceutiquement acceptable de celui-ci, destiné à être utilisé dans une méthode de traitement d'une tumeur du SNC, ledit traitement comprenant l'administration séparée, séquentielle ou simultanée d'i) une dose quotidienne totale d'environ 300 mg dudit AZD1390, éventuellement sous la forme d'un sel pharmaceutiquement acceptable de celui-ci, et ii) une radiothérapie, audit sujet.
PCT/EP2024/075613 2023-09-13 2024-09-13 Azd1390, ou sel pharmaceutiquement acceptable de celui-ci, en combinaison avec un rayonnement destiné à être utilisé dans une méthode de traitement d'une tumeur du snc Pending WO2025056741A1 (fr)

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US63/582,283 2023-09-13
US202463564659P 2024-03-13 2024-03-13
US63/564,659 2024-03-13

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Citations (1)

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WO2017046216A1 (fr) 2015-09-17 2017-03-23 Astrazeneca Ab Dérivés 8-[6-[3-(amino)propoxy]-3-pyridyl]-1-isopropyl-imidazo[4,5-c]quinoléin-2-one utilisés en tant que modulateurs sélectifs de l'ataxie télangiectasie mutée (atm) kinase pour le traitement du cancer

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WO2017046216A1 (fr) 2015-09-17 2017-03-23 Astrazeneca Ab Dérivés 8-[6-[3-(amino)propoxy]-3-pyridyl]-1-isopropyl-imidazo[4,5-c]quinoléin-2-one utilisés en tant que modulateurs sélectifs de l'ataxie télangiectasie mutée (atm) kinase pour le traitement du cancer

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DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 1 July 2019 (2019-07-01), REDDY V P ET AL: "A preclinical PK/PD model based on a mouse glioblastoma survival model for AZD1390, a novel, brain-penetrant ATM kinase inhibitor, to predict the inhibition of DNA damage response induced by radiation and the human efficacious dose", XP002812550, Database accession no. EMB-628906361 *
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PIKE KURT: "Discovery of the clinical candidate AZD1390: A high-quality, potent and selective inhibitor of ATM kinase with the ability to cross the blood-brain barrier", ABSTRACTS OF PAPERS ; ACS NATIONAL MEETING & EXPOSITION, AMERICAN CHEMICAL SOCIETY, US, vol. 257, 31 March 2019 (2019-03-31), pages 226, XP002808220, ISSN: 0065-7727 *
QI LI: "A new wave of innovations within the DNA damage response", SIGNAL TRANSDUCTION AND TARGETED THERAPY, vol. 8, no. 1, 8 September 2023 (2023-09-08), XP093167112, ISSN: 2059-3635, Retrieved from the Internet <URL:https://www.nature.com/articles/s41392-023-01548-8> DOI: 10.1038/s41392-023-01548-8 *
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