Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
  • C07K16/2827—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• the present specification relates to a combination of an ATR inhibitor such as 4- ⁇ 4-[(3/?)-3- methylmorpholin-4-yl]-6-[l-((/?)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl ⁇ -lH-pyrrolo[2,3- b]pyridine (AZD6738, ceralasertib, Compound (I) below or a pharmaceutically acceptable salt thereof) and an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, where the combination is administered to a patient who has previously received immunotherapy.
• an ATR inhibitor such as 4- ⁇ 4-[(3/?)-3- methylmorpholin-4-yl]-6-[l-((/?)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl ⁇ -lH-pyrrolo[2,3- b]pyridine
• an immune checkpoint inhibitor such as durvalumab for
• the specification also relates to methods of treatment of melanoma involving the administration of an ATR inhibitor in combination with an immune checkpoint inhibitor to a patient who has previously received immunotherapy, the use of an ATR inhibitor in combination with an immune checkpoint inhibitor for the manufacture of a medicament for the treatment of melanoma in patients who have previously received immunotherapy.
• ATR is a serine/threonine protein kinase and member of the phosphatidylinositol 3-kinase related kinase (PIKK) family.
• PIKK phosphatidylinositol 3-kinase related kinase
• ATR is recruited at stalled replication forks, which can progress to double strand breaks if left unrepaired.
• ATR is also recruited to single strand DNA coated with Replication Protein A (RPA) following single strand DNA damage or the resection of double strand breaks.
• RPA Replication Protein A
• Recruitment and activation of ATR leads to cell cycle arrest in the S-phase while the DNA is repaired and the stalled replication fork resolved, or nuclear fragmentation and entry into programmed cell death (apoptosis).
• ATR inhibitors are expected to cause growth inhibition in tumour cells dependent upon ATR for DNA repair e.g. ATM-deficient tumours.
• ATR inhibitors are also predicted to potentiate the activity of cytotoxic DNA damaging agents and radiotherapy (through inhibition of ATR-dependent DNA repair processes) when used in combination.
• Example ATR inhibitors include AZD6738, a potent inhibitor of ATR with good selectivity against other PIKK family members first disclosed in WO2011/154737. This compound is being developed as an oral anti-tumour agent in patients with disease that is dependent upon ATR function for DNA repair, for example tumours that are deficient of the serine/threonine-specific protein kinase, ATM.
• AZD6738 is being investigated in clinical trials against various forms of cancer.
• the current standard of care for melanoma is based on first-line immunotherapy, for example using immune checkpoint inhibitors such as nivolumab or pembrolizumab.
• Patients with actionable mutations, such as those with BRAF mutations may receive targeted agents.
• Patients may receive several different lines of immunotherapy but once it is no longer effective, standard chemotherapy like doublet carboplatin and paclitaxel or single agent paclitaxel may be used to continue treatment.
• standard chemotherapy like doublet carboplatin and paclitaxel or single agent paclitaxel may be used to continue treatment.
• response to chemotherapy is often poor with about 20% responding to doublet chemotherapy and only around 5% of patients responding to taxanes. There is therefore a pressing need for additional approaches that can be used to treat resistant melanoma cancers which are no longer amenable to immunotherapy.
• ATR inhibitors such as AZD6738 in combination with immune checkpoint inhibitor such as durvalumab are effective in melanoma patients who have previously received treatment with immunotherapy, with a high proportion of such individuals responding to subsequent ATR inhibition and immunotherapy.
• the combination provides improved progression free survival, overall survival and improved duration of response. Responses were observed across all the melanoma subtypes enrolled, even in acral and mucosal melanoma which are known to be harder to treat.
• the combination was found to be effective in patients with primary resistance (as well as secondary resistance) which is usually harder to treat.
• Melanoma patients who have received prior immunotherapy have therefore been identified as a target population for treatment with a combination of ATR inhibitors such as AZD6738 and immune checkpoint inhibitors such as the PD-L1 inhibitor durvalumab.
• ATR inhibitors reset the immune profile of the melanoma, thereby sensitising the melanoma to further treatment with immunotherapy.
• a combination comprising an ATR inhibitor and an immune checkpoint inhibitor for use in the treatment of melanoma in a patient who has previously received immunotherapy.
• a method of treating melanoma in a human or animal patient, who has previously received immunotherapy, in need of such treatment comprising administering to said patient an effective amount of an ATR inhibitor in combination with an effective amount of an immune checkpoint inhibitor.
• an ATR inhibitor in combination with an immune checkpoint inhibitor, in the manufacture of a medicament for the treatment of melanoma, where the patient has previously received immunotherapy.
• a combination treatment comprising the administration of an effective amount of an ATR inhibitor, optionally together with a pharmaceutically acceptable diluent or carrier, in combination with an effective amount of an immune checkpoint inhibitor, optionally together with a pharmaceutically acceptable diluent or carrier to a human or animal patient in need of such therapeutic treatment that has received immunotherapy, for use in the treatment of melanoma.
• kits comprising a pharmaceutical composition comprising an ATR inhibitor and at least one pharmaceutically acceptable excipient, and a pharmaceutical composition comprising an immune checkpoint inhibitor, and instructions for the use of the pharmaceutical compositions in the treatment of melanoma, where the pharmaceutical compositions are administered to a patient who has previously received immunotherapy.
• Figure 1 Bar chart showing melanoma patient responses to combined AZD6738 and durvalumab treatment.
• Figure 2 Swimmer plot showing duration of AZD6738 and durvalumab treatment for melanoma patients along with patient response. The "x" on the bars corresponds to the date of first response with duration of response being calculated from x. Patient P30 had progressive disease (PD) and no bar is shown since the patient progressed after 10 days and therefore the start date of administration and the last date of administration were the same.
• PD progressive disease
• a or “an” mean “at least one”. In any embodiment where “a” or “an” are used to denote a given element, “a” or “an” may mean one. In any embodiment where “a” or “an” are used to denote a given element, “a” or “an” may mean 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
• “Comprising” means that a given material or element may contain other materials or elements. In any embodiment where “comprising” is mentioned the given material or element may be formed of at least 10% w/w, at least 20% w/w, at least 30% w/w, or at least 40% w/w of the material or element (or combination of materials or elements). In any embodiment where “comprising” is mentioned, “comprising” may also mean “consisting of” (or “consists of”) or “consisting essentially of” (or “consists essentially of”) a given material or element.
• Consisting of or “consists of” means that a given material or element is formed entirely of the material or element (or combination of materials or elements). In any embodiment where “consisting of” or “consists of” is mentioned the given material or element may be formed of 100% w/w of the material or element.
• Consisting essentially of or “consists essentially of” means that a given material or element consists almost entirely of that material or element (or combination of materials or elements).
• the given material or element may be formed of at least 50% w/w, at least 60% w/w, at least 70% w/w, at least 80% w/w, at least 90% w/w, at least 95% w/w or at least 99% w/w of the material or element.
• the element may be present in a suitable embodiment in any part of the specification, not just a suitable embodiment in the same section or textual region of the specification.
• the feature may be selected from a list consisting of the specified alternatives (i.e. a list of those alternatives and no others).
• a combination of an ATR inhibitor and an immune checkpoint inhibitor for use in the treatment of melanoma where the combination is administered to a patient who has previously received immunotherapy.
• a method of treatment of melanoma in a human or animal patient in need of such treatment comprising administering to said patient an effective amount of an ATR inhibitor in combination with an effective amount of an immune checkpoint inhibitor wherein the patient has previously received immunotherapy.
• an ATR inhibitor in combination with an immune checkpoint inhibitor, in the manufacture of a medicament for the treatment of melanoma, where the medicament is administered to a patient who has previously received immunotherapy.
• a combination may be simultaneously, separately and/or sequentially administered.
• a combination may be simultaneously administered.
• a combination may be separately administered.
• a combination may be sequentially administered.
• the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
• the ATR inhibitor may be administered before the immune checkpoint inhibitor.
• the ATR inhibitor may be administered 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, or 48 hours before the immune checkpoint inhibitor.
• the ATR inhibitor may be administered after the immune checkpoint inhibitor.
• the ATR inhibitor may be administered 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, or 48 hours after the immune checkpoint inhibitor.
• Immunotherapy Where a patient has "previously received immunotherapy", this includes patients who have been successfully or unsuccessfully treated with immunotherapy, such that their cancer responded or did not respond to treatment respectively. Patients who have previously received immunotherapy may have halted previous treatment due to treatment failure, where the cancer growth or health impact of the disease is not, or is no longer, positively managed by the immunotherapy. Where such a treatment has failed, the cancer may be described as resistant to immunotherapy. Primary resistance occurs when some inherent characteristic of the cancer prevents the immunotherapy from working whereas acquired resistance, also known as secondary resistance, occurs when the cancer becomes resistant during immunotherapy treatment. Some patients may receive immunotherapy as an adjuvant therapy. Patients who relapse on adjuvant immunotherapy may also be considered to have primary resistance to immunotherapy.
• the patient's cancer may be resistant to immunotherapy.
• the patient's cancer may be resistant to PD-1 inhibitor, PD-L1 inhibitor or CTLA-4 inhibitor immunotherapy.
• the patient's cancer may be resistant to PD-1 inhibitor immunotherapy.
• the patient's cancer may be resistant to PD-L1 inhibitor immunotherapy.
• the patient's cancer may be resistant to CTLA-4 inhibitor immunotherapy.
• the patient has primary resistance to immunotherapy. In some embodiments the patient has primary resistance to PD-1 inhibitor, PD-L1 inhibitor or CTLA-4 inhibitor immunotherapy. In some embodiments the patient has primary resistance to PD-1 inhibitor immunotherapy. In some embodiments the patient has primary resistance to PD-L1 inhibitor immunotherapy. In some embodiments the patient has primary resistance to CTLA-4 inhibitor immunotherapy. In one embodiment, primary resistance is defined according to the Society for Immunotherapy of Cancer (SITC) recommendations as having >6 weeks of immunotherapy drug exposure and a best response of progressive disease or stable disease for less than 6 months before progressing.
• SITC Society for Immunotherapy of Cancer
• the patient has acquired (or secondary) resistance to immunotherapy.
• the patient has acquired resistance to PD-1 inhibitor, PD-L1 inhibitor or CTLA- 4 inhibitor immunotherapy.
• the patient has acquired resistance to PD-1 inhibitor immunotherapy.
• the patient has acquired resistance to PD-L1 inhibitor immunotherapy.
• the patient has acquired resistance to CTLA-4 inhibitor immunotherapy.
• acquired resistance is defined according to SITC recommendations as having >6 weeks of immunotherapy drug exposure and a best response of complete response, partial response or stable disease for more than 6 months before progressing.
• "Immunotherapy" is the use of a patient's own immune system to treat disease, for example cancer.
• It includes stimulating the natural defences of a patient's immune system so it is better at finding and attacking harmful species in the body (for example cancer cells), as well as administering drugs that act like immune system components to restore or improve how the immune system works to defend the body (for example to find and attack cancer cells).
• the patient has received at least one form of immunotherapy for a minimum of 6 weeks prior to treatment with the combinations described herein.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor, chimeric antigen receptor T-cell therapy, treatment with a cytokine, treatment with an immunomodulator, treatment with a cancer vaccine, treatment with a monoclonal antibody and/or treatment with an oncolytic virus.
• Checkpoint inhibitors include any substance which blocks immune checkpoints: key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets, so checkpoint therapy is used that can block inhibitory checkpoints, restoring immune system function.
• Example checkpoint inhibitors include PD-1 inhibitors (for example pembrolizumab [Keytruda ® ], nivolumab [Opdivo ® ], cemiplimab [Libtayo ® ], spartalizumab [PDR001], camrelizumab [SHR1210], sintilimab [IBI308], tislelizumab [BGB-A317], toripalimab [JS 001], AMP-224 or AMP-514), PD-L1 inhibitors (for example atezolizumab [Tecentriq ® ], avelumab [Bavencio ® ], durvalumab [MEDI4736, Imfinzi ® ], KN035, CK-301, AUNP12, CA-170 or BMS-986189) and CTLA-4 inhibitors (for example ipilimumab [Yervoy ® ] or tremelimuma
• immunotherapy may comprise treatment with an immune checkpoint inhibitor.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor selected from a PD-1 inhibitor, a PD-L1 inhibitor and a CTLA-4 inhibitor.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor which is a PD-1 inhibitor.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor which is a PD-L1 inhibitor.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor which is a CTLA-4 inhibitor.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab and tremelimumab.
• an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, K
• immunotherapy may comprise treatment with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab and ipilimumab.
• an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab and ipilimumab.
• immunotherapy may comprise treatment with an immune checkpoint inhibitor selected from pembrolizumab and nivolumab.
• immunotherapy may comprise chimeric antigen receptor T-cell therapy.
• CAR T-cell therapy takes some T-cells from a patient's blood, mixes them with a special virus that makes the T-cells learn how to attach to tumour cells, and then gives the cells back to the patient so they can find, attach to, and kill cancer.
• immunotherapy may comprise treatment with a cytokine.
• Cytokines are small proteins that carry messages between cells and stimulate immune cells to attack cancer.
• immunotherapy may comprise treatment with an immunomodulator.
• immunomodulators are drugs that generally boost parts of the immune system to treat certain types of cancer.
• immunotherapy may comprise treatment with a cancer vaccine.
• cancer vaccines are substances put into the body to start an immune response against cancer. They can be used prophylactically or to increase a body's immune response, allowing more effective treatment.
• immunotherapy may comprise treatment with a monoclonal antibody.
• monoclonal antibodies mAbs or MoAbs are man-made versions of immune system proteins. Monoclonal antibodies can be designed to attack a very specific part of a cancer cell.
• immunotherapy may comprise treatment with an oncolytic virus.
• "Oncolytic virus” treatment uses viruses that have been modified in a lab to infect and kill certain tumour cells.
• immunotherapy may comprise treatment with one immunotherapy agent.
• immunotherapy may comprise treatment with more than one immunotherapy agent, for example, a PD-L1 or PD-1 antibody in combination with a CTLA-4 antibody, such as nivolumab in combination with ipilimumab.
• ATR Inhibitors for example, a PD-L1 or PD-1 antibody in combination with a CTLA-4 antibody, such as nivolumab in combination with ipilimumab.
• ATR inhibitor is any compound which attenuates the activity of the ATR enzyme in-vitro or in-vivo.
• ATR inhibitors may be selective or unselective, small molecules or biomolecules.
• Example ATR inhibitors include AZD6738, M6620 (berzosertib), BAY-1895344, EPT-46464, VE- 821 and VX-970.
• an ATR inhibitor may be selected from the group consisting of AZD6738, M6620, BAY-1895344, EPT-46464, VE-821 and VX-970.
• an ATR inhibitor may be AZD6738.
• AZD6738 may be Compound (I) or a pharmaceutically acceptable salt thereof.
• pharmaceutically acceptable is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients and/or has clinical or commercial precedence.
• An example list of pharmaceutically acceptable salts can be found in the "Handbook of Pharmaceutical Salts: Properties, Selection and Use", P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich: Wiley- VCH/VFiCA, 2002 or subsequent editions.
• AZD6738 may be Compound (I) in a salt-free form (for example in a neutral or zwitterionic form, or for example in a free base or free acid form).
• AZD6738 may be a pharmaceutically acceptable salt of Compound (I).
• a suitable pharmaceutically acceptable salt of Compound (I) is, for example, an acid-addition salt.
• An acid addition salt of Compound (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
• An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
• An acid addition salt may also be formed using an organic acid selected from citric acid, fumaric acid, maleic acid and methane sulfonic acid.
• a further suitable pharmaceutically acceptable salt of Compound (I) is, for example, a salt formed within the human or animal body after administration of Compound (I) to said human or animal body.
• an ATR inhibitor may be AZD6738 which is administered according to a two weeks on / two weeks off (14 days on / 14 days off) schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered for 14 consecutive days within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered on days 1 to 14 of a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered on days 15 to 28 of a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered according to a one week on / three weeks off (7 days on / 21 days off) schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered for 7 consecutive days within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered on days 1 to 7 of a 28-day cycle.
• a "28-day cycle” is a single treatment period which may be continuously repeated for a given patient, or may be repeated with a treatment gap (of for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 30 or 60 days) between discrete cycles.
• an ATR inhibitor may be AZD6738 which is administered in a total daily dose between 30 mg and 500 mg.
• an ATR inhibitor may be AZD6738 which is administered in a total daily dose of 40 mg, 60 mg, 80 mg, 160 mg, 240 mg, 320 mg or 480 mg.
• an ATR inhibitor may be AZD6738 which is administered in a total daily dose of 480 mg.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 240 mg doses (i.e. in a 480 mg total daily dose, administered in two separate tranches each consisting of 50% of the total daily dose, also referred to as 240 mg BID).
• an ATR inhibitor may be AZD6738 which is administered in a total daily dose of 320 mg.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses (i.e. in a 160 mg total daily dose, administered in two separate tranches each consisting of 50% of the total daily dose, also referred to as 160 mg BID).
• an ATR inhibitor may be AZD6738 which is administered twice daily on a two weeks on / two weeks off schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 240 mg doses on a two weeks on / two weeks off schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 240mg doses for 14 consecutive days within a 28 day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 240 mg doses on days 1 to 14 of a 28-day cycle. [0097] In some embodiments an ATR inhibitor may be AZD6738 which is administered twice daily in 240 mg doses on days 15 to 28 of a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses on a two weeks on / two weeks off schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses for 14 consecutive days within a 28 day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses on days 1 to 14 of a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses on days 15 to 28 of a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily on a one week on / three weeks off (7 days on / 21 days off) schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 240 mg doses on a one week on / three weeks off schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 240mg doses for 7 consecutive days within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered as a 240 mg dose twice daily on days 1 to 7 of a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses on a one week on / three weeks off schedule within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered twice daily in 160 mg doses for 7 consecutive days within a 28-day cycle.
• an ATR inhibitor may be AZD6738 which is administered as a 160 mg dose twice daily on days 1 to 7 of a 28-day cycle.
• a "checkpoint inhibitor” is defined in paragraphs [0044] and [0045]
• the immune checkpoint inhibitor administered in combination with the ATR inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor and a CTLA-4 inhibitor.
• the immune checkpoint inhibitor may be a PD-1 inhibitor.
• the immune checkpoint inhibitor may be a PD-L1 inhibitor.
• the immune checkpoint inhibitor may be a CTLA-4 inhibitor.
• the immune checkpoint inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab and tremelimumab.
• the immune checkpoint inhibitor may be the PD-L1 inhibitor durvalumab or an antigen-binding fragment thereof. In some embodiments the immune checkpoint inhibitor may be durvalumab.
• Durvalumab is a human monoclonal antibody directed against human PD-L1 that is capable of blocking the binding of PD-L1 to both the PD1 and CD80 receptors. Disclosure related to durvalumab can be found in U.S. Patent Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference. [00117] Durvalumab and antigen-binding fragments thereof for use in the treatments provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region.
• durvalumab or antigen-binding fragment thereof for use in the treatments provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 2.
• durvalumab or antigen-binding fragment thereof for use in the treatments provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3-5, and wherein the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.
• durvalumab or antigen-binding fragment thereof for use in the treatments provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as disclosed in U.S. Patent Nos. 8,779,108 and 9,493,565, which are herein incorporated by reference in their entirety.
• the immune checkpoint inhibitor may be durvalumab which is administered on every 4 weeks from cycle 1 day 1 .
• the immune checkpoint inhibitor may be durvalumab which is administered in an amount of 1500 mg.
• the immune checkpoint inhibitor may be durvalumab which is administered in an amount of 1500 mg once every 4 weeks (28 days) from cycle 1 day 1 (Q28D).
• the CTLA-4 inhibitor is tremelimumab or antigen-binding fragment thereof.
• Tremelimumab or antigen-binding fragment thereof for use in the treatments provided herein comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region.
• tremelimumab or antigen-binding fragment thereof for use in the treatments provided herein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:10.
• tremelimumab or antigen-binding fragment thereof for use in the treatments provided herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:ll-13, and wherein the light chain variable region comprises the Kabat- defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:14-16.
• the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:ll-13
• the light chain variable region comprises the Kabat- defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:14-16.
• tremelimumab or antigen-binding fragment thereof for use in the treatments provided herein comprises the variable heavy chain and variable light chain CDR sequences of the 11.2.1 antibody as disclosed in US 6,682,736, which is herein incorporated by reference in its entirety.
• antibody refers to a protein that is capable of recognizing and specifically binding to an antigen.
• Ordinary or conventional mammalian antibodies comprise a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light” chain (typically having a molecular weight of about 25 kDa) and one "heavy” chain (typically having a molecular weight of about 50-70 kDa).
• each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition.
• the carboxyl-terminal portion of each chain typically defines a constant domain responsible for effector function.
• a full- length heavy chain immunoglobulin polypeptide includes a variable domain (VH) and three constant domains (CHI, CH2, and CH3) and a hinge region between CHI and CH2, wherein the VH domain is at the amino-terminus of the polypeptide and the CH3 domain is at the carboxyl-terminus
• a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the V L domain is at the amino-terminus of the polypeptide and the C L domain is at the carboxyl-terminus.
• variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids.
• the variable regions of each light/heavy chain pair typically form an antigen-binding site.
• the variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs.
• the CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope.
• both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
• antigen-binding fragment refers to a portion of an intact antibody and/or refers to the antigenic determining variable domains of an intact antibody. It is known that the antigen binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single chain antibodies, diabodies, and multispecific antibodies formed from antibody fragments.
• Cancer is used synonymously with tumour and lesion in this specification. Cancer may include primary cancer as well as secondary cancers and metastases. The tumours may be detectable or non-detectable, e.g. micro metastases.
• treatment of melanoma encompass treating an existing melanoma cancer and/or preventing melanoma cancer.
• treatment may be conducted after one or more symptoms have developed.
• treatment may be conducted in the absence of symptoms.
• treatment of a susceptible individual may begin prior to the onset of symptoms (e.g. due to a history of disease and/or considering genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to present or delay their recurrence
• the treatment of melanoma or treating melanoma may mean treating and preventing melanoma.
• the treatment of melanoma or treating melanoma may mean treating melanoma.
• the treatment of melanoma or treating melanoma may mean preventing melanoma.
• Mucosal and acral melanoma are known to be particularly difficult histologic subtypes of melanoma to treat. Flowever, responses in these subtypes were observed in patients treated with the treatments described herein.
• melanoma may be cutaneous melanoma.
• melanoma may be cutaneous anal melanoma.
• melanoma may be acral melanoma.
• melanoma may be mucosal melanoma.
• melanoma may be early stage, actively progressing, advanced (for example locally advanced), invasive, metastatic and/or drug-resistant melanoma.
• melanoma may be locally advanced melanoma.
• melanoma may be advanced and/or metastatic melanoma.
• melanoma may be advanced melanoma.
• melanoma may be locally advanced and/or metastatic melanoma.
• melanoma may be metastatic melanoma.
• melanoma may be invasive melanoma.
• melanoma may be Stage IV melanoma.
• melanoma may be unresectable melanoma. In some embodiments melanoma may be Stage III unresectable melanoma.
• melanoma cancer may be ATM deficient.
• a melanoma cancer When a melanoma cancer is "ATM deficient", the cancer cells express less ATM protein than a normal, non-cancerous cell of the same type.
• the cancer cells may express ⁇ 5%, ⁇ 10%, ⁇ 20%, ⁇ 30%, ⁇ 40%, ⁇ 50%, ⁇ 60%, ⁇ 70%, ⁇ 80%, ⁇ 90% or ⁇ 100% of the total ATM protein expressed by a normal cell of the same type when analysed by IHC protein staining of the total ATM protein typically expressed by a normal cell of the same type when analysed by IHC protein staining.
• ATM deficient melanoma cancer cells may also comprise a biallelic deleterious mutation in their ATM gene.
• melanoma cancer may be ARID1A deficient.
• a melanoma cancer When a melanoma cancer is "ARID1A deficient", the cancer cells express less ARID1A protein than a normal, non-cancerous cell of the same type.
• the cancer cells may express ⁇ 5%, ⁇ 10%, ⁇ 20%, ⁇ 30%, ⁇ 40%, ⁇ 50%, ⁇ 60%, ⁇ 70%, ⁇ 80%, ⁇ 90% or ⁇ 100% of the total ARID1A protein typically expressed by a normal cell of the same type when analysed by IHC protein staining.
• ARID1A deficient melanoma cancer cells may also comprise a mutation in the ARID1A gene (for example a loss of function mutation such as a nonsense mutation).
• melanoma may be ATM deficient melanoma.
• melanoma may be ARID1A deficient melanoma.
• the combination described herein may be administered to patients as a second or third line of therapy.
• the combination is administered to a patient as second line therapy i.e. after the patient has failed on prior immunotherapy.
• the combination is administered to a patient as third line therapy. Patients receiving the combination as third line therapy may have received treatment with BRAF and MEK inhibitors, such as dabrafenib and trametinib, prior to treatment with immunotherapy.
• an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma
• an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma
• the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy and treatment with the combination achieves an objective response rate between 10% and 50%, between 10% and 40%, between 10% and 35%, between 20% and 35%, between 25% and 40%, between 30% and 35%, greater than 10%, greater than 20%, greater than 30%, greater than 40%, greater than 50%, greater than 60% or greater than 70%.
• Objective response rate is the percentage of patients with measurable disease at baseline and achieved at least 1 response, i.e. a complete or partial response to treatment according to RECIST.
• the "RECIST criteria” (for example the RECIST 1.1 criteria) are set out at the site https://recist.eortc.org/ and described in Eur. J. Cancer 2016, 62, Pages 132-137.
• an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, where the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy and treatment with the combination achieves a clinical benefit rate between 25% and 100%, between 25% and 90%, between 40% and 80% or between 50% and 70%.
• Chronic benefit rate is the objective response rate added to the % of patients whose best response was stable disease at the first scan, i.e. who had absence of disease progression at first scan (complete response + partial response + stable disease).
• an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, where the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy and treatment with the combination achieves a progression free survival of greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, preferably greater than 7 months.
• PFS progression free survival
• ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, where the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy and treatment with the combination achieves an overall survival of greater than 10 months, greater than 11 months, greater than 12 months, greater than 13 months, preferably greater than 14 months.
• an ATR inhibitor such as AZD6738 in combination with an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma, where the ATR inhibitor and the immune checkpoint inhibitor are administered to a patient who has previously received immunotherapy and treatment with the combination achieves a duration of response of at least 3 months, at least 4 months, at least 5 months, preferably at least 6 months.
• Duration of response or “DoR” is the length of time that a tumour continues to respond to treatment without the cancer growing or spreading.
• a combination of an ATR inhibitor such as AZD6738 and an immune checkpoint inhibitor such as durvalumab for use in the treatment of melanoma where the combination is administered to a patient who has previously received immunotherapy, and treatment with the combination does not cause any serious side-effects in a melanoma patient.
• serious side-effects may be defined as grade 4 or 5 adverse events.
• Grade 4 or 5 adverse events can be classified according to the common terminology criteria for adverse events (CTCAE).
• kits comprising: a) a first pharmaceutical composition comprising an ATR inhibitor and a pharmaceutically acceptable excipient; b) a second pharmaceutical composition comprising an immune checkpoint inhibitor and a pharmaceutically acceptable excipient; and c) instructions for the use of the use of the first and second pharmaceutical compositions in the treatment of melanoma in a patient who has previously received immunotherapy.
• the ATR inhibitor may AZD6738.
• the immune checkpoint inhibitor may be selected from a PD-1 inhibitor, a PD-L1 inhibitor and a CTLA-4 inhibitor.
• the immune checkpoint inhibitor may be selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab and tremelimumab.
• the immune checkpoint inhibitor may be durvalumab.
• the ATR inhibitor is AZD6738 and the immune checkpoint inhibitor is durvalumab.
• an ATR inhibitor for use in the treatment of melanoma, where the ATR inhibitor is AZD6738 which is administered in combination with an immune checkpoint inhibitor to a patient who has previously received therapy with an immune checkpoint inhibitor.
• an ATR inhibitor for use in the treatment of melanoma, where the ATR inhibitor is AZD6738 which is administered in combination with a PD-L1 inhibitor to a patient who has previously received therapy with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab and tremelimumab.
• an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, t
• an ATR inhibitor for use in the treatment of melanoma, where the ATR inhibitor is AZD6738 which is administered in combination with durvalumab to a patient who has previously received therapy with an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224, AMP-514, atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, BMS-986189, ipilimumab and tremelimumab.
• an immune checkpoint inhibitor selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tisleliz
• an ATR inhibitor for use in the treatment of melanoma, where the ATR inhibitor is AZD6738 which is administered in combination with durvalumab to a patient who has previously received therapy with an immune checkpoint inhibitor selected from pembrolizumab and nivolumab.
• Tumour evaluation using modified RECIST 1.1 was conducted at screening (within 28 days prior to first dose) and every 8 weeks relative to the date of first dose, up to week 40, then every 12 weeks until objective disease progression (within a window of +/- 7 days of the scheduled date). Study treatment was continued until objective disease progression (unless other criteria for treatment discontinuation are met). Patients may have continued AZD6738 plus durvalumab beyond progression (according to modified RECIST 1.1), at the discretion of the investigator if they were clinically benefiting from the treatment and they did not meet any other discontinuation criteria. Flowever, they were not permitted to continue either AZD6738 or durvalumab as monotherapy.
• modified RECIST 1.1 If a patient discontinued study treatment prior to disease progression, they should have continued to be assessed using modified RECIST 1.1 until disease progression and then followed up for survival. Assessments for survival were made every 8 weeks following objective disease progression. The details of first and subsequent therapies for cancer, after discontinuation of treatment, was collected. The imaging modalities used for modified RECIST 1.1 assessment was CT or MRI scans of chest, abdomen and pelvis. Modified RECIST 1.1 scans were analysed by the investigator on site. Patients were also requested to provide tumour samples from the primary or metastatic tumours on progression. Sample provision was not optional, subject to a specific consent, and will aid understanding of resistance mechanisms. However, if biopsy site was not feasible, the protocol allowed waiving the rebiopsy procedure.
• Target subject population There were two cohorts for this study although Cohort A is outside of the scope of the present specification:
• Cohort A Patients with refractory gastric cancer who had failed secondary chemotherapy treatments for advanced disease were enrolled. Patients must have had imaging confirmed progression on previous chemotherapy for gastric cancer treatment with at least one measurable lesion per modified RECIST 1.1. Previous adjuvant/neoadjuvant chemotherapy was allowed, if completed more than 6 months prior to starting the 1st line treatment. Prior exposure to AZD6738 was not allowed.
• Cohort B Patients with metastatic melanoma patients who had failed prior anti-PD(L)l were enrolled. Anti-PD(L)1 therapy should have been the immediate prior regimen before study entry.
• Duration of treatment Patients continued to receive study treatment, until they demonstrated objective disease progression (determined by modified RECIST 1.1) or until they met any other discontinuation criteria. There was no maximum duration of treatment with AZD6738 and durvalumab. Patients could continue with AZD6738 and durvalumab beyond objective disease progression (determined by modified RECIST 1.1) at the discretion of the investigator if they were clinically benefiting from the treatment and they did not meet any other discontinuation criteria.
• both durvalumab and AZD6738 were discontinued. If either durvalumab and/or AZD6738 were deemed intolerable (as judged by the investigator) so that discontinuation of either agent was deemed in the patient's best interest despite dose interruptions, dose modification and initiation of supportive treatments, both durvalumab and AZD6738 were discontinued and the patient withdrawn from the study. Patients were not permitted to continue either durvalumab or AZD6738 as monotherapy. There was no maximum duration of treatment with AZD6738 and durvalumab.
• AZD6738 was administered at 240 mg BD on days 15 to 28 in a 28-day cycle.
• Durvalumab was administered at 1500 mg every 4 weeks from cycle 1 day 1.
• Cohort A gastric cancer: The primary endpoint of the study was ORR (independently analyzed for cohort A and cohort B). The sample size was calculated by use of a two-stage minimax Simon's design to control the type I error at 5 % for null hypothesis that, for arm, the true response was 15 % or below and to have 90 % of power if the true response was 40 % or higher. 16 evaluable patients were to be treated in the first stage. If 2 or fewer response were observed in the first stage, the arm would have been stopped. If at least 3 responses were observed in the first stage, 11 additional evaluable patients were to be entered onto the second stage.
• Inclusion Criteria Patients were eligible to be included in the study only if all the following inclusion criteria and none of the exclusion criteria applied:
• Cohort A Confirmed histological or cytological diagnosis of gastric adenocarcinoma (including GEJ) that was at an advanced stage and that had progressed following who have failed secondary chemotherapy treatments (confirmed by imaging)
• Female patients of childbearing potential had a negative pregnancy test (urine or serum), were not breastfeeding and were using adequate contraceptive measures.
• barrier contraception i.e. condoms with all sexual partners.
• the sexual partner was a 'women of child-bearing potential' who was not using effective contraception
• Any gastrointestinal condition that would preclude adequate absorption of AZD6738 including but not limited to inability to swallow oral medication, refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, intestinal obstruction or CTCAE grade 3 or grade 4 upper Gl bleeding within 4 weeks before the enrollment.
• autoimmune or inflammatory disorders including IBD [e.g. Chohn's disease, ulcerative colitis or diverticulitis], SLE, sarcoidosis syndrome, tuberculosis, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, history of primary immunodeficiency or HIV infection, known hepatitis B or hepatitis C infection, history of organ transplant that requires use of immunosuppressives, glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis within the past 2 years prior to the start of treatment.
• IBD e.g. Chohn's disease, ulcerative colitis or diverticulitis
• SLE sarcoidosis syndrome
• tuberculosis e.g. Crohn's disease, ulcerative colitis or diverticulitis
• Wegener syndrome myasthenia gravis
• Graves' disease
• Any clinically important abnormalities in fhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block , third degree heart block, second degree heart block.
• Ophthalmological conditions as follows: Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intra-ocular pressure), Current or past history of central serous retinopathy or retinal vein occlusion
• Immunosuppressive medications including, but not limited to systemic corticosteroids at doses beyond 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumour necrosis factor alpha blockers were prohibited. Use of immunosuppressive medications for the management of study drug-related AEs and in patients with contrast allergies was acceptable. In addition, use of inhaled and intranasal corticosteroids was permitted. - Live attenuated vaccines within 30 days of durvalumab dosing (ie, 30 days prior to the first dose, during treatment with durvalumab and for 30 days post discontinuation of durvalumab). Inactivated viruses, such as those in the influenza vaccine, are permitted.
• Non-sterilized male partners of a female patient were to use male condom plus spermicide throughout this period.
• Cessation of birth control after this point should have been discussed with a responsible physician. Not engaging in sexual activity for the total duration of the drug treatment and the drug washout period was an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method were not acceptable methods of birth control.
• Female patients also refrained from breastfeeding throughout this period.
• Non-sterilized males who were sexually active with a female partner of childbearing potential were to use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + any drug combination therapy. Not engaging in sexual activity was an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method were not acceptable methods of contraception. Male patients refrained from sperm donation throughout this period.
• Females of childbearing potential were defined as those who were not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.
• Women were considered post-menopausal if they had been amenorrheic for 12 months without an alternative medical cause.
• the following age-specific requirements apply: Women ⁇ 50 years of age were considered post-menopausal if they had been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they had luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• the dose should only have been replaced if all of the intact tablets could be counted and then treatment resumed with the following scheduled dose.
• the scheduled dose could be taken up to 2 hours after the scheduled dose time. If greater than 2 hours, the missed dose should not have been taken and patient continued with next dose at allotted time.
• Contraceptives that were prone to drug-drug interactions may not have been effective due to a potential CYP3A4 interaction with AZD6738. Contraception used must therefore have included a condom and one of: o Medroxyprogesterone injections (eg, Depo-provera) o Intrauterine Device (IUD) o Levonorgestrol Intrauterine System (eg, Mirena) o Tubal occlusion o Vasectomised partner
• Modified RECIST 1.1 criteria was used to assess patient response to treatment by determiningPFS and ORR.
• the modified RECIST 1.1 guidelines for measurable, non-measurable, target and non-target lesions and the objective tumour response criteria (complete response, partial response, stable disease or progression of disease).
• the methods of assessment of tumour burden used at baseline, CT or MRI scans of chest, abdomen and pelvis must be used at each subsequent follow-up assessment. Following the baseline assessment, efficacy for all patients was assessed by objective tumour assessments every 8 weeks relative to date of first dose, until week 40, at which time assessments were carried out every 12 weeks until objective disease progression as defined by modified RECIST 1.1.
• tumour response assessment was based on the modified RECIST 1.1 criteria of response: CR (complete response), PR (partial response), SD (stable disease) and PD (progression of disease).
• Target lesion (TL) progression was calculated in comparison to when the tumour burden was at a minimum (i.e. smallest sum of diameters previously recorded on study).
• tumour response CR, PR, SD was calculated in comparison to the baseline tumour measurements obtained before starting treatment.
• any other sites at which new disease is suspected should also be appropriately imaged. If an unscheduled assessment was performed and the patient had not progressed, every attempt was to be made to perform the subsequent assessments at their scheduled visits. To achieve 'unequivocal progression' on the basis of non-target disease, there must have been an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumour burden had increased sufficiently to merit discontinuation of therapy. A modest 'increase' in the size of one or more non-target lesions is usually not sufficient to quality for unequivocal progression status.
• Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis were taken at the times indicated in the assessment schedules and as clinically indicated.
• Clinical laboratory safety tests including serum pregnancy tests, were to be performed in a licensed clinical laboratory according to local standard procedures. Sample tubes and sample sizes may vary depending on the laboratory method used and routine practice at the site. Pregnancy tests may be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal clinically significant laboratory results should have been repeated as soon as possible (preferably within 24 to 48 hours). Additional safety samples were collected if clinically indicated at the discretion of the Investigator. The date, time of collection, and results (values, units, and reference ranges) were recorded on the appropriate CRF. Other safety tests were performed at screening including assessment for hepatitis B surface antigen, hepatitis C antibodies, and HIV antibodies.
• APTT Activated partial thromboplastin time
• INR International normalised ratio
• LDH Lactic dehydrogenase
• Urinalysis was performed at screening and if clinically indicated. Microscopic analysis was performed by the hospital's local laboratory if required.
• ECG ECGs were performed at screening, baseline, once on combination treatment and as clinically indicated throughout the study and were as described in paragraph [00178]
• Concomitant Medications any medications (other than those excluded by the clinical trial protocol) that were considered necessary for the subject's welfare and would not interfere with the trial medication were to be given at the investigator's discretion. The investigator was to record all concomitant medication taken by subject during the trial, from the date of signature of informed consent, in the appropriate section of the CRF.
• Figures 1 and 2 present the clinical trial data of the AZD6738 and durvalumab combination in graphical form.
• Tables 1 and 2 set out the clinical characteristics and the resistance status of the patients in the clinical trials for the ceralasertib (AZD6738) and durvalumab combination. Responses were seen irrespective of whether patients had primary or secondary resistance. Furthermore, although it is known to be harder to treat patients with primary resistance, a greater proportion of responses were seen in the patients receiving ceralaserib and durvalumab who had primary resistance compared to patients with secondary resistance. Responses were seen in all the melanoma subtypes treated (acral, mucosal and cutaneous). Responses were also seen across patients with high/low baseline LDH (lactate dehydrogenase), low PD-L1 expression and regardless of BRAF mutant or wildtype.
• Table 1 Clinical Characteristics of the Patients immunotherapy; SD: stable disease; PD: progressive disease; PR: partial response; LDH: lactate dehydrogenase; ULN: upper limit of normal
• ORR objective response rate
• DCR disease control rate
• PFS progression free survival
• OS overal survival

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