ATr Inhibitor in Combination With Olaparib/Durvalumab (MEDI4736) in Gynaecological Cancers With ARId1A Loss or no Loss

Inclusion Criteria: 1. Histologically confirmed progressive or recurrent gynaecological carcinomas of the following histological subtypes: Cohorts 1A, 1B, 2 and 3: * Clear cell (Ovarian, endometrial or endometriosis-related, (\>50% clear cell carcinoma with no serious differentiation) * Endometrioid (ovarian, endometrial or endometriosis-related) * Cervical (adenocarcinomas or squamous) * Carcinosarcomas (ovarian or endometrial) Cohorts 4 and 5: • Endometrial carcinomas (serous, clear cell, endometrioid, carcinosarcoma) Note: patients who have an original diagnosis based on cytology only will not be eligible for entry into the study unless a biopsy confirming above histology is performed 2. Histological tissue specimen (tissue block or 8-10 unstained slides) must be available (specimen can be the sample at diagnosis or taken at relapse). Otherwise, a biopsy must be carried out to obtain sufficient tissue for histological assessment 3. Evidence of radiological disease progression since last systemic anti-cancer therapy and prior to trial entry 4. Patients who have progressed after ≥1 prior platinum containing regimen. Platinum-based therapy does not need to be the last treatment prior to study entry. For Cohorts 1A, 1B, 2 and 3, patients who have disease progression within 6 months of last dose of a platinum-containing regimen, no more than two further lines of systemic therapy are permitted prior to trial entry 5. Patients entering Cohorts 4 or 5 must have had prior anti-PD-1/anti-PD-L1/anti-CTLA-4 immunotherapy treatment, with a minimum duration of treatment is 6 weeks. Other previous immunotherapy treatments may be permissible following discussion with the Chief Investigator and ICR-CTSU. Patients who experienced toxicity leading to permanent discontinuation of prior immunotherapy are ineligible. * All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. * Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enrol if they are stably maintained on appropriate replacement therapy and are asymptomatic. * Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of \> 10 mg prednisone or equivalent per day. 6. Body weight \>30kg (Cohorts 4 and 5 only) 7. Measurable disease by RECIST criteria v1.1, which can be accurately assessed at baseline by CT (or MRI where CT is contradicted or unclear). Patients with CA125 progression in the absence of measurable disease will NOT be eligible 8. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks 9. Life expectancy \> 16 weeks 10. Adequate hepatic, bone marrow, coagulation and renal function as defined by the following values within 14 days prior to starting treatment: All cohorts: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; * Platelet count ≥ 100 x 109/L with no platelet transfusion in the past 28 days * Total bilirubin ≤1.5 x ULN (where bilirubin rise \> 1.5 x ULN due to Gilbert's syndrome a conjugated bilirubin ≤1.5 x ULN is required) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5 x ULN if no demonstrable liver metastases or ≤5 times ULN if patient has documented liver metastases Cohort 1A, Cohort 4 and Cohort 5: * Haemoglobin ≥9.0 g/dL with no blood transfusion in the past 14 days * Glomerular filtration rate (GFR) ≥45 mL/min (estimated using Cockcroft-Gault equation, MDRD, 24hr urine collection as appropriate) Cohort 1B, Cohort 2 and Cohort 3: * Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 14 days * Glomerular filtration rate ≥51 mL/min (estimated using Cockcroft-Gault equation, MDRD, 24hr urine collection as appropriate) 11. No significant medical illness which in the opinion of the Investigator would preclude entry to ATARI 12. Women of child-bearing potential who are confirmed NOT to be pregnant. This should be evidenced by a negative urine or serum pregnancy test within 72 hours prior to start of trial treatment (cohort 4 and 5 must be serum at screening). Patients will be considered to be not of child-bearing potential if they are: * Post-menopausal - defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, OR women under 50 years old who have been amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and have serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the post-menopausal range for the institution * Able to provide documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation * Radiation or chemotherapy-induced oophorectomy or menopause with \> 1 year since last menses 13. Patients with prior synchronous tumours or history of prior malignancy are eligible provided there is biopsy evidence that the disease measurable on CT and/or MRI is of the histological subtypes stated in 1 14. Willingness to commit to scheduled visits, treatments plans, laboratory tests and study procedures 15. Able to swallow, absorb, retain oral medication 16. Able to provide written, informed consent Exclusion Criteria 17. Patients receiving, or having received * Cohort 1A, Cohort 4 and Cohort 5: Prior treatment with ATR inhibitor * Cohort 1B, Cohort 2 and Cohort 3: Prior treatment with ATR or PARP inhibitors 18. Patients receiving, or having received: * cytotoxic treatment for their malignancy within 21 days prior to Cycle 1 Day 1 * exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1. The minimum washout for immunotherapy is 42 days * treatment with bevacizumab within 30 days prior to Cycle 1 Day 1 * palliative radiotherapy within 21 days prior to Cycle 1 Day 1 (with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study treatment). Patients can receive bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to commencing study treatment. 19. Treatment with any other investigational medicinal product within the 4 weeks prior to trial entry 20. Receiving, or having received, concomitant medications, herbal supplements and/or foods that are strong or moderate inhibitors or inducers of CYP3A4 and/or CYP1A2 for cohorts 1B, 2 and 3, and strong inhibitors or inducers of CYP3A4 and/or CYP1A2 for cohorts 1A, 4 and 5, sensitive CYP3A4 and/or CYP1A2 substrates or CYP3A4 and/or CYP1A2 substrates with a narrow therapeutic index that significantly modulate CYP3A4 and/or CYP1A2 or P-gp activity (washout period 5 half-lives or three weeks for St. John's Wort). Note these include common azole antifungals, macrolide antibiotics and other medications (Refer to Sections 22, 23 \& 24 and Appendix A6 for further details) 21. Pregnant or lactating women. 22. Women of childbearing age and potential who are not willing to use one highly effective form of contraception AND a condom as detailed in Section 5.5.1 23. Any other malignancy which has been active or treated within the past three years, with the exception of cervical intra-epithelial neoplasia and non-melanoma skin cancer 24. Clinical/radiological evidence of bowel obstruction (e.g. hospitalisation) or symptoms of sub-acute bowel obstruction within 6 weeks prior to trial entry 25. Any clinically significant haematuria (as deemed by the investigator) 26. With the exception of alopecia, any unresolved toxicities from prior therapy should be no greater than CTCAE Grade 2 at trial entry 27. Clinically significant cardiac disease currently or within the last 6 months including: a. Pre-existing arrhythmia: i. Mean resting QTc \>470 msec obtained from 3 electrocardiograms (ECGs) performed 2-5 minutes apart at study screening (within 14 days prior to Cycle 1 Day 1) using the Fredericia formula ii. Clinically important abnormalities in rhythm, conduction or morphology of resting ECG (including complete left bundle-branch block, third degree heart block) b. Any factor increasing the risk of QTc prolongation or arrhythmia, including: i. Hypokalaemia ii. Congenital long QT syndrome iii. Immediate family history of long QT syndrome or unexplained sudden death below the age of 40 years c. Unstable angina pectoris d. Acute myocardial infarction e. Unstable cardiac arrhythmias f. Cardiac failure i. Known reduced LVEF \<55% ii. New York Heart Association (NYHA) class II, III or IV cardiac failure g. Uncontrolled hypertension (≥ grade 2) requiring clinical intervention (Cohort 4 and Cohort 5 only) 28. Clinically relevant orthostatic hypotension 29. Patients who have a diagnosis of ataxia telangiectasia 30. Major surgery within 4 weeks prior to starting trial drug (excluding placement of vascular access) or minor surgery (excluding tumour biopsies) within 2 weeks of starting trial.Local surgery of isolated lesions for palliative intent is acceptable 31. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT) 32. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days 33. Known leptomeningeal involvement or brain metastases, unless asymptomatic, treated (with no evidence of progression since completion of CNS-directed therapy), presence of disease outside the CNS and stable off steroids for at least 4 weeks prior to registration 34. Known hypersensitivity to investigational drugs or excipients 35. Receiving, or having received during the four weeks prior to starting trial drug, corticosteroids at a dose \>10mg prednisolone/day or equivalent for any reason 36. Any haemopoietic growth factors (e.g., G-CSF, GM-CSF) and blood transfusions within 14 days prior to trial entry. Use of erytropoeitin is not permitted for 4 weeks prior to Cycle 1 Day 1 and for the duration of the study 37. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases that places the patient at unacceptable risk of toxicity or non-compliance e.g., severe hepatic impairment, extensive interstitial lung disease on high resolution CT scan (bilateral, diffuse, parenchymal lung disease), uncontrolled chronic renal diseases (glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis), current unstable or uncompensated respiratory or cardiac conditions, active bleeding diatheses or active infection including hepatitis B, hepatitis C, and immunocompromised patients e.g. patients who are known to be serologically positive for human immunodeficiency virus (HIV). Screening for chronic conditions is not required 38. Judgment by the Investigator that the patient is unsuitable to participate in the study and/or the patient is unlikely to comply with study procedures, restrictions and requirements 39. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of study drug 40. Patients with uncontrolled seizures 41. Active infection requiring systemic antibiotics, antifungal or antiviral drugs 42. Patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), or with features suggestive of MDS/AML 43. Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD, severe Parkinson's disease, active inflammatory bowel disease) or psychiatric condition (e.g. psychiatric disorder prohibiting obtaining informed consent) 44. Any contraindication to the combination anti-cancer agent (ceralasertib/olaparib or ceralasertib/durvalumab) as per local prescribing information 45. Patients unable to swallow orally administered medication 46. Patients in receipt of any live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study treatment. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug. 47. Patients with a confirmed COVID-19 infection by PCR test who have not made a full recovery In addition to the above and specific for Cohorts 4 and 5 only: 48. Any concurrent chemotherapy, IP, biological, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. 49. Persisting (\>4 weeks) severe pancytopenia due to previous therapy rather than disease (ANC \<0.5 x 109/L or platelets \<50 x 109/L) 50. History of organ transplant that requires use of immunosuppressive medications including, but not limited to systemic corticosteroids at doses \>10mg/day of prednisone or equivalent, methotrexate, azathioprine and tumour necrosis factor alpha (TNF-α) blockers. Use of immunosuppressive medications for the management of IMP-related AEs is acceptable 51. Active or prior documented autoimmune or inflammatory disease within the past 3 years (including, but not limited to inflammatory bowel disease \[e.g., Crohn's disease or colitis\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome, Hashimoto syndrome, hyperthyroidism, Sjogren's syndrome, glomerulonephritis, multiple sclerosis, vasculitis, rheumatoid arthritis, idiopathic pulmonary fibrosis, pneumonitis, organising pneumonitis, hepatitis, sarcoidosis, active tuberculosis. The following are exceptions to this criterion: * Patients with vitiligo or alopecia, patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy, patients without active disease in the last 5 years may be included but only after consultation with the ATARI Chief Investigator. Patients with celiac disease controlled by diet alone. 52\. History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of the study drug and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease 53. History of active primary immunodeficiency 54. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of durvalumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids or local steroid injections (e.g., intra articular injection) * Systemic corticoids at physiologic doses not to exceed 10mg/day of predisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan medication)