Study Evaluating the Efficacy of Maintenance Olaparib and Cediranib or Olaparib Alone in Ovarian Cancer Patients
NCT ID: NCT03278717
Last Updated: 2022-09-27
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE3
330 participants
INTERVENTIONAL
2018-06-15
2023-12-31
Brief Summary
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Detailed Description
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The maintenance regimen may be continued beyond radiological progression until trial closure if the patient is deemed to still be deriving clinical benefit, but must be discontinued once subsequent treatment is instituted.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Olaparib and Cediranib
Patients will receive oral olaparib 300mg BD and oral cediranib 20mg OD.
Patients will attend hospital for a 2 weekly review for the first 8 weeks, then 4 weekly for year 1 and 8 weekly for year 2 onwards until discontinuation of all trial drugs. Treatment may continue beyond progression until the next line of treatment if the patient is deemed to still be deriving clinical benefit. QOL instruments will be collected at baseline, every clinic visit and continue to be completed after relapse.
Olaparib
Olaparib is a PARP inhibitor, targeting DNA repair processes.
Cediranib
Cediranib is an inhibitor of vascular endothelial growth factor-A (VEGF), targeting angiogenesis.
Olaparib
Patients will receive oral olaparib 300mg BD.
Patients will attend hospital for a 2 weekly review for the first 8 weeks, then 4 weekly for year 1 and 8 weekly for year 2 onwards until discontinuation of all trial drugs. Treatment may continue beyond progression until the next line of treatment if the patient is deemed to still be deriving clinical benefit. QOL instruments will be collected at baseline, every clinic visit and continue to be completed after relapse.
Olaparib
Olaparib is a PARP inhibitor, targeting DNA repair processes.
Interventions
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Olaparib
Olaparib is a PARP inhibitor, targeting DNA repair processes.
Cediranib
Cediranib is an inhibitor of vascular endothelial growth factor-A (VEGF), targeting angiogenesis.
Eligibility Criteria
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Inclusion Criteria
2. Females aged ≥ 18 years with previous histologically proven diagnosis of high grade serous or endometrioid carcinoma of the
* Ovary
* Fallopian tube
* or peritoneum, progressing \>6 months after day 1 of the last cycle of first-line platinum-based chemotherapy and requiring treatment with platinum-based chemotherapy on the basis of radiological evidence of disease or following surgical resection of recurrent disease.
3. Patients must have had CT or MRI proven relapsed disease (measureable or non-measureable abnormalities supported by GCIG CA125 criteria of progression), or have had debulking surgery for first relapse.
4. Patients showing evidence of response to chemotherapy mid-treatment (post 3 or 4 cycles), either by CA125 or CT/MRI scan, should be approached for ICON9 trial registration to allow for BRCA mutation status to be assessed (germline and/ or somatic). Patients who underwent surgical debulking must show no evidence of disease progression by the assessments above (CA125 and CT/MRI scan) in order to be approached for registration.
5. Prior front-line maintenance therapy with bevacizumab is permitted.
6. ECOG performance status 0-1.
7. Formalin fixed, paraffin embedded (FFPE) archival/diagnostic tumour sample or from secondary debulking surgery with adequate neoplastic cell content (\>30%), must be available for central BRCA testing. For inclusion in i) the genetic HRD Test and ii) the biomarker research, patients must complete the consent form. Translational blood samples are also required, see Laboratory Manual for further details.
8. Patients should have a life expectancy ≥ 16 weeks.
9. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days prior to study treatment and confirmed prior to treatment on day 1.
Postmenopausal is defined as age ≥60 years, or:
* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
* Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50
* Radiation-induced oophorectomy with last menses \>1 year ago
* Chemotherapy-induced menopause with \>1 year interval since last menses
* Surgical sterilisation (bilateral oophorectomy or hysterectomy)
10. Adequately controlled blood pressure (systolic blood pressure \[SBP\] ≤140 mmHg; diastolic blood pressure \[DBP\] ≤ 90mmHg) on maximum of 2 antihypertensive medications.
11. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction.
1. Patients must have received at least 4 cycles, and a maximum of 6 cycles of second-line platinum-based chemotherapy.
2. In patients with measurable disease, end of treatment scans must have a RECIST v1.1 'partial response' or 'complete response' and meet one of the following CA125 requirements:
1. If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required.
2. If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by ≥ 15% then the patient will not be eligible.
3. In patients with non-measurable disease, who have not undergone debulking surgery, they must have had a GCIG CA125 response to chemotherapy and meet one of the following CA125 requirements:
1. If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required.
2. If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by ≥ 15% then the patient will not be eligible.
4. Patients who have had debulking surgery at first relapse must have no evidence of disease progression on imaging (CT or MRI) and meet one of the following CA125 requirements:
1. If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required.
2. If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by ≥ 15% then the patient will not be eligible.
5. Expected to be able to commence treatment within 7 days post randomisation, and within 4-8 weeks post day 1 of the last cycle of chemotherapy.
6. Adequate bone marrow function as defined below:
* Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/l
* Platelet (Plt) ≥ 90 x 109/l
* Haemoglobin (Hb) ≥ 100g/l required and no packed blood transfusions in the 14 days prior to starting trial treatment
7. Adequate liver function as defined below:
* Serum bilirubin ≤ 1.5 x ULN (or ≤ 3 for cases of known Gilbert's syndrome)
* Serum transaminases ≤3 x ULN
* Serum transaminases ≤ 5 x ULN if liver metastasis present
8. Adequate renal function as defined below:
• Serum creatinine ≤ 1.5 x ULN and calculated glomerular filtration rate (GFR) ≥50ml/min (calculated as per local practice using Wright or Cockroft-gault formula)
9. Urine dipstick for proteinuria \<2+. If urine dipstick is ≥ 2+ on two occasions more than one week apart then a 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours or protein/creatinine ratio \< 1.5.
10. Adequately controlled blood pressure (systolic blood pressure \[SBP\] ≤140 mmHg; diastolic blood pressure \[DBP\] ≤ 90mmHg) on maximum of 2 antihypertensive medications.
11. Germline and/or somatic BRCA mutation status must be known prior to randomisation.
Exclusion Criteria
2. Arterial thrombotic event (including transient ischemic attack, cerebrovascular accident, and peripheral arterial embolus) within the last 12 months.
3. Patients unable to swallow orally administered medication and patients with gastrointestinal impairment that could affect ability to take, or absorption of oral medicines including sub-acute or complete bowel obstruction.
4. Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment.
5. History of intra-abdominal abscess within 3 months prior to starting treatment (randomisation).
6. History of GI perforation. Patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting treatment, and patient is deemed to be at low risk of recurrent fistula.
7. Symptomatic or clinically significant inflammatory bowel disease (Crohn's disease or ulcerative colitis).
8. Patients with an ileostomy will be excluded.
9. Evidence of severe or uncontrolled cardiac disease.
1. Myocardial infarct or unstable angina within the last 6 months
2. New York Health Association (NHYA) ≥ grade 2 congestive heart failure
3. Cardiac ventricular arrhythmias requiring medication
4. History of 2nd or 3rd degree atrioventricular conduction defects
10. Resting ECG with QTcF \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
11. Evidence of active bleeding or bleeding diathesis.
Significant haemorrhage of \>30ml in a single episode within the last 3 months or any haemoptysis (\>5ml fresh blood in last 4 weeks).
12. Malignancy treated within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, Stage 1, grade 1 endometrial carcinoma.
13. Previous treatment with VEGFR tyrosine kinase inhibitors or PARP inhibitors are not permitted.
14. Patients with a known hypersensitivity to excipients of cediranib or olaparib.
15. Persisting ≥ grade 2 CTCAE toxicity (except alopecia and neuropathy) from previous anti-cancer treatment.
16. Major surgery within 14 days before anticipated start of treatment and patients must have recovered from any effects of major surgery.
17. Inability to attend or comply with treatment or follow-up scheduling.
18. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicated the use of an investigation drug or puts the patients at high risk for treatment-related complications.
19. Pregnant or breast-feeding women are excluded. Women of childbearing potential will be excluded unless effective methods of contraception are used from signing of the informed consent, throughout the period of taking study treatment and for at least 6 weeks after last dose of trial drug(s).
20. Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment (randomisation).
21. Concomitant use of known strong CYP3A4 inhibitors (such as systemic ketoconazole, itraconazole, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir, telithromycin and clarithromycin or moderate CYP3A inhibitors (e.g. systemic Ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
22. Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
23. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
24. Other psychological, psychiatric, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
25. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids.
26. Immunocompromised patients e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
27. Patients with symptomatic uncontrolled brain or meningeal metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment.
28. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
29. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
18 Years
FEMALE
No
Sponsors
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University College, London
OTHER
Responsible Party
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Locations
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Calvary Mater Hospital
Sydney, New South Wales, Australia
Campbelltown Hospital
Sydney, New South Wales, Australia
Prince of Wales Hospital
Sydney, New South Wales, Australia
Royal Hobart Hospital
Hobart, Tasmania, Australia
Border Medical Oncology
Albury, , Australia
Flinders Medical Centre
Bedford Park, , Australia
Pindara Private Hospital
Benowa, , Australia
Chris O'Brien Lifehouse
Camperdown, , Australia
Canberra Hospital
Canberra, , Australia
Monash Health
Clayton, , Australia
Gosford Hospital
Gosford, , Australia
Peter MacCallum Cancer Centre
Melbourne, , Australia
ICON Cancer Centre
South Brisbane, , Australia
Mater Cancer Centre
South Brisbane, , Australia
Townsville Hospital
Townsville, , Australia
Westmead Hospital
Westmead, , Australia
Cross Cancer Institute
Edmonton, , Canada
Centre Hospitalier de L'Universite de Montreal
Montreal, , Canada
CHU de Quebec
Québec, , Canada
Princess Margaret Cancer Centre
Toronto, , Canada
Sunnybrook Hospital
Toronto, , Canada
BC Cancer Vancouver
Vancouver, , Canada
BC Cancer Victoria
Victoria, , Canada
Auckland City Hospital
Auckland, , New Zealand
Christchurch Hospital
Christchurch, , New Zealand
Furness General Hospital
Barrow in Furness, , United Kingdom
Belfast City Hospital
Belfast, , United Kingdom
Royal Sussex County Hospital
Brighton, , United Kingdom
Addenbrookes Hospital
Cambridge, , United Kingdom
Kent & Canterbury Hospital
Canterbury, , United Kingdom
Velindre Cancer Centre
Cardiff, , United Kingdom
Cheltenham General Hospital
Cheltenham, , United Kingdom
University Hospital Coventry
Coventry, , United Kingdom
Ninewells Hospital
Dundee, , United Kingdom
Western General Hospital
Edinburgh, , United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, , United Kingdom
Royal Surrey County Hospital
Guildford, , United Kingdom
Royal Lancaster Infirmary
Lancaster, , United Kingdom
Guy's Hospital
London, , United Kingdom
Hammersmith Hospital
London, , United Kingdom
Mount Vernon Cancer Centre
London, , United Kingdom
Royal Marsden NHS Foundation Trust
London, , United Kingdom
University College London Hospital
London, , United Kingdom
The Christie Hospital
Manchester, , United Kingdom
Queen Elizabeth the Queen Mother Hospital
Margate, , United Kingdom
Clatterbridge Cancer Centre
Metropolitan Borough of Wirral, , United Kingdom
Churchill Hospital
Oxford, , United Kingdom
Queen Alexandra Hospital
Portsmouth, , United Kingdom
Royal Berkshire Hospital
Reading, , United Kingdom
Southampton General Hospital
Southampton, , United Kingdom
Lister Hospital
Stevenage, , United Kingdom
Singleton Hospital
Swansea, , United Kingdom
Musgrove Park Hospital
Taunton, , United Kingdom
Royal Cornwall
Truro, , United Kingdom
Countries
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Central Contacts
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References
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Gaitskell K, Rogozinska E, Platt S, Chen Y, Abd El Aziz M, Tattersall A, Morrison J. Angiogenesis inhibitors for the treatment of epithelial ovarian cancer. Cochrane Database Syst Rev. 2023 Apr 18;4(4):CD007930. doi: 10.1002/14651858.CD007930.pub3.
Elyashiv O, Ledermann J, Parmar G, Farrelly L, Counsell N, Feeney A, El-Khouly F, Macdonald I, Neto A, Arthur-Darkwa E, Burnett E, Jayson GC, Mileshkin L, Gourley C, Nicum S. ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy. Int J Gynecol Cancer. 2021 Jan;31(1):134-138. doi: 10.1136/ijgc-2020-002073. Epub 2020 Oct 23.
Other Identifiers
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UCL/14/0795
Identifier Type: -
Identifier Source: org_study_id
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