E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed ovarian and endometrial clear cell carcinoma or relapsed other gynaecological cancers (endometriod (ovarian and endometrial), carcinosarcoma (ovarian and endometrial), cerviacal carcinoma (squamous and adenocarcinoma) |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed gynaecological cancers of rare subtypes, including clear cell (ovarian/uterus) and carcinosarcoma, cervical and endometrioid type. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073268 |
E.1.2 | Term | Ovarian clear cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009252 |
E.1.2 | Term | Clear cell endometrial carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073269 |
E.1.2 | Term | Ovarian endometrioid carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008224 |
E.1.2 | Term | Cervical adenocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062718 |
E.1.2 | Term | Endocervical squamous metaplasia |
E.1.2 | System Organ Class | 100000004872 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052204 |
E.1.2 | Term | Ovarian carcinosarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether AZD6738 has clinical activity as measured by RECIST 1.1 objective response rate as a single agent and in combination with olaparib in patients with ARID1A-deficient (‘loss’) and no loss relapsed gynaecological cancers. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the disease control rate using RECIST version 1.1 2. To evaluate the Progression Free Survival (PFS) 3. To evaluate the Time to Progression (TTP) 4. To evaluate the proportion of patients free of progression at 6 months 5. To assess the safety and tolerability of AZD6738 as monotherapy and in combination with olaparib in ARID1A loss and no loss relapsed gynaecological cancers 6. To evaluate Overall Survival (OS)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.1. Histologically confirmed progressive or recurrent gynaecological carcinomas of the following histological subtypes: • Ovarian and endometrial clear cell (>50% clear cell carcinoma with no serous differentiation) • Endometrioid • Cervical - adenocarcinomas and squamous • Carcinosarcomas 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 patients who have disease progression within 6 months of last dose of a platinum-containing regime, no more than two further lines of systemic therapy are permitted prior to trial entry 5. 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 6. ECOG performance status 0 or 1 with no deterioration over the previous 2 weeks 7. Life expectancy > 16 weeks 8. Adequate hepatic, bone marrow, coagulation and renal function as defined by the following values within 14 days prior to starting treatment: • Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 14 days • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L • Platelet count ≥ 100 x 109/L with no platelet transfusion in the past 28 days • Creatinine clearance ≥51 mL/min (estimated using Cockcroft-Gault equation or EDTA as appropriate); • Total bilirubin ≤1.5 x ULN (unless bilirubin rise >1.5 x ULN due to Gilbert’s syndrome a conjugated bilirubin < or = 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 9. No significant medical illness which in the opinion of the Investigator would preclude entry to ATARI 10. 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. 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 11. Patients with prior synchronous tumours or history of prior malignancy are eligible provided that there is biopsy evidence that the disease measurable on CT and/or MRI is of the histological subtypes stated in 1 12. Willingness to commit to scheduled visits, treatments plans, laboratory tests and study procedures 13. Able to swallow, absorb, retain oral medication 14. Able to provide written, informed consent
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E.4 | Principal exclusion criteria |
1. Prior treatment with ATR or PARP inhibitors, including AZD6738 and olaparib 2. Patients receiving, or having received: • cytotoxic treatment for their malignancy within 21 days prior to Cycle1 Day1 • 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 3. Treatment with any other investigational medicinal product within the 4 weeks prior to trial entry 4. Receiving, or having received, concomitant medications, herbal supplements and/or foods that are strong or moderate inhibitors or inducers of CYP3A4, sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index that significantly modulate CYP3A4 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 5. Pregnant or lactating women 6. Women of childbearing age and potential who are not willing to use two highly effective forms of contraception as detailed in Section 5.5 7. 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 8. Clinical/radiological evidence of bowel obstruction (e.g. hospitalisation) or symptoms of sub-acute bowel obstruction within 6 weeks prior to trial entry 9. Any clinically significant haematuria (as deemed by the investigator) 10. With the exception of alopecia, any unresolved toxicities from prior therapy should be no greater than CTCAE Grade 2 at trial entry 11. 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 12. Clinically relevant orthostatic hypotension 13. Patients who have a diagnosis of ataxia telangiectasia 14. Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access) or minor surgery (excluding tumour biopsies) within 2 weeks of entry into the study (excluding placement of vascular access) 15. Spinal cord compression, 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 16. Known hypersensitivity to investigational drugs or excipients 17. Receiving, or having received during the four weeks prior to registration, corticosteroids at a dose >10mg prednisone/day or equivalent for any reason 18. 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 19. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases e.g., severe hepatic impairment, interstitial lung disease [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 human immunodeficiency virus (HIV). Screening for chronic conditions is not required 20. 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 21. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of study drug 22. Patients with uncontrolled seizures 23. Active infection requiring systemic antibiotics, antifungal or antiviral drugs 24. Patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), or with features suggestive of MDS/AML 25. Concurrent severe and/ |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is confirmed overall objective response rate (complete or partial) as defined by RECIST version 1.1 for each cohort separately. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analyses of primary endpoint (stage 1 or final) will be triggered after a minimum follow-up of 16 weeks per patient, unless response status can be ascertained earlier e.g. due to progression or confirmed response. |
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E.5.2 | Secondary end point(s) |
1. Disease control rate 2. Duration of disease control 3. Progression free survival (PFS) 4. Time to progression (TTP) 5. Safety and toxicity 6. Overall Survival |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Disease control rate - proportion of patients experiencing complete or partial response, or stable disease lasting at least 16 weeks from start of treatment as assessed radiologically by RECIST v1.1 2. Duration of disease control - measured from the first documentation of RECIST complete/partial response or stable disease (whichever status recorded first) until first date that progressive disease is objectively documented. 3. PFS - from start of treatment until the first date of either progressive disease or death 4. TTP - measured from the date of registration until the date of progressive disease or clinical progression of disease. 5. Safety and toxicity - throughout treatment period and until 30 days post last dose 6. OS - from start of treatment until death from any cause |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The trial end date is deemed to be the date of last data capture. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 1 |