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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03278717




Registration number
NCT03278717
Ethics application status
Date submitted
31/07/2017
Date registered
12/09/2017

Titles & IDs
Public title
Study Evaluating the Efficacy of Maintenance Olaparib and Cediranib or Olaparib Alone in Ovarian Cancer Patients
Scientific title
International Phase III Randomised Study to Evaluate the Efficacy of Maintenance Therapy With Olaparib and Cediranib or Olaparib Alone in Patients With Relapsed Ovarian Cancer Following a Response to Platinum-based Chemotherapy
Secondary ID [1] 0 0
UCL/14/0795
Universal Trial Number (UTN)
Trial acronym
ICON9
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Olaparib
Treatment: Drugs - Cediranib

Experimental: 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.

Active comparator: 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.


Treatment: Drugs: Olaparib
Olaparib is a PARP inhibitor, targeting DNA repair processes.

Treatment: Drugs: Cediranib
Cediranib is an inhibitor of vascular endothelial growth factor-A (VEGF), targeting angiogenesis.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression free survival (PFS) measured from the date of randomisation to the date of objective progression (investigator assessed using RECIST v1.1) or date of death from any cause (in the absence of progression)
Timepoint [1] 0 0
3 years
Secondary outcome [1] 0 0
Toxicity
Timepoint [1] 0 0
3 years
Secondary outcome [2] 0 0
PFS and OS measured from the time of starting chemotherapy
Timepoint [2] 0 0
3 years
Secondary outcome [3] 0 0
Adherence to maintenance therapy- compliance and dose reductions and interruptions
Timepoint [3] 0 0
3 years
Secondary outcome [4] 0 0
TSST (the time from randomisation to start of second subsequent therapy or death)
Timepoint [4] 0 0
3 years
Secondary outcome [5] 0 0
Quality of life using EORTC QLQ C30
Timepoint [5] 0 0
3 years
Secondary outcome [6] 0 0
Quality of life using EORTC QLQ OV28
Timepoint [6] 0 0
3 years
Secondary outcome [7] 0 0
Cost effectiveness using EQ-5D-5L for economic evaluation
Timepoint [7] 0 0
3 years
Secondary outcome [8] 0 0
VIII. Response rate (RECIST v1.1 and/or CA125) at 16 weeks of treatment in patients who had RECIST v1.1 measurable disease or elevated CA125 at randomisation. RECIST measurements will be based on investigator assessment not central review
Timepoint [8] 0 0
3 years
Secondary outcome [9] 0 0
Overall survival (OS) measured from the date of randomisation to the date of death from any cause
Timepoint [9] 0 0
3 years

Eligibility
Key inclusion criteria
Registration

1. Provision of informed consent prior to any study specific procedures and the ability to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations.
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.

Randomisation

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.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Non-epithelial ovarian cancer, carcinosarcoma, clear cell carcinoma and mucinous carcinomas.
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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
UNKNOWN
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
15/06/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2023
Actual
Sample size
Target
330
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,TAS
Recruitment hospital [1] 0 0
Calvary Mater Hospital - Sydney
Recruitment hospital [2] 0 0
Campbelltown Hospital - Sydney
Recruitment hospital [3] 0 0
Prince of Wales Hospital - Sydney
Recruitment hospital [4] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [5] 0 0
Border Medical Oncology - Albury
Recruitment hospital [6] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [7] 0 0
Pindara Private Hospital - Benowa
Recruitment hospital [8] 0 0
Chris O'Brien Lifehouse - Camperdown
Recruitment hospital [9] 0 0
Canberra Hospital - Canberra
Recruitment hospital [10] 0 0
Monash Health - Clayton
Recruitment hospital [11] 0 0
Gosford Hospital - Gosford
Recruitment hospital [12] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [13] 0 0
ICON Cancer Centre - South Brisbane
Recruitment hospital [14] 0 0
Mater Cancer Centre - South Brisbane
Recruitment hospital [15] 0 0
Townsville Hospital - Townsville
Recruitment hospital [16] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
- Sydney
Recruitment postcode(s) [2] 0 0
- Hobart
Recruitment postcode(s) [3] 0 0
- Albury
Recruitment postcode(s) [4] 0 0
- Bedford Park
Recruitment postcode(s) [5] 0 0
- Benowa
Recruitment postcode(s) [6] 0 0
- Camperdown
Recruitment postcode(s) [7] 0 0
- Canberra
Recruitment postcode(s) [8] 0 0
- Clayton
Recruitment postcode(s) [9] 0 0
- Gosford
Recruitment postcode(s) [10] 0 0
- Melbourne
Recruitment postcode(s) [11] 0 0
- South Brisbane
Recruitment postcode(s) [12] 0 0
- Townsville
Recruitment postcode(s) [13] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
Canada
State/province [1] 0 0
Edmonton
Country [2] 0 0
Canada
State/province [2] 0 0
Montréal
Country [3] 0 0
Canada
State/province [3] 0 0
Québec
Country [4] 0 0
Canada
State/province [4] 0 0
Toronto
Country [5] 0 0
Canada
State/province [5] 0 0
Vancouver
Country [6] 0 0
Canada
State/province [6] 0 0
Victoria
Country [7] 0 0
New Zealand
State/province [7] 0 0
Auckland
Country [8] 0 0
New Zealand
State/province [8] 0 0
Christchurch
Country [9] 0 0
United Kingdom
State/province [9] 0 0
Barrow In Furness
Country [10] 0 0
United Kingdom
State/province [10] 0 0
Belfast
Country [11] 0 0
United Kingdom
State/province [11] 0 0
Brighton
Country [12] 0 0
United Kingdom
State/province [12] 0 0
Cambridge
Country [13] 0 0
United Kingdom
State/province [13] 0 0
Canterbury
Country [14] 0 0
United Kingdom
State/province [14] 0 0
Cardiff
Country [15] 0 0
United Kingdom
State/province [15] 0 0
Cheltenham
Country [16] 0 0
United Kingdom
State/province [16] 0 0
Coventry
Country [17] 0 0
United Kingdom
State/province [17] 0 0
Dundee
Country [18] 0 0
United Kingdom
State/province [18] 0 0
Edinburgh
Country [19] 0 0
United Kingdom
State/province [19] 0 0
Glasgow
Country [20] 0 0
United Kingdom
State/province [20] 0 0
Guildford
Country [21] 0 0
United Kingdom
State/province [21] 0 0
Lancaster
Country [22] 0 0
United Kingdom
State/province [22] 0 0
London
Country [23] 0 0
United Kingdom
State/province [23] 0 0
Manchester
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Margate
Country [25] 0 0
United Kingdom
State/province [25] 0 0
Oxford
Country [26] 0 0
United Kingdom
State/province [26] 0 0
Portsmouth
Country [27] 0 0
United Kingdom
State/province [27] 0 0
Reading
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Southampton
Country [29] 0 0
United Kingdom
State/province [29] 0 0
Stevenage
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Swansea
Country [31] 0 0
United Kingdom
State/province [31] 0 0
Taunton
Country [32] 0 0
United Kingdom
State/province [32] 0 0
Truro
Country [33] 0 0
United Kingdom
State/province [33] 0 0
Wirral

Funding & Sponsors
Primary sponsor type
Other
Name
University College, London
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Ian Macdonald
Address 0 0
Country 0 0
Phone 0 0
+44 (0)20 7679 9808
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03278717