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Trial registered on ANZCTR


Registration number
ACTRN12618000498291
Ethics application status
Approved
Date submitted
21/03/2018
Date registered
6/04/2018
Date last updated
13/03/2019
Date data sharing statement initially provided
13/03/2019
Type of registration
Prospectively registered

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] 294403 0
NCT03278717
Secondary ID [2] 294404 0
UCL/14/0795
Secondary ID [3] 294408 0
ANZGOG 1415/2018
CTC 0133
Universal Trial Number (UTN)
Trial acronym
ICON9
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian Cancer 307133 0
Fallopian tube Cancer 307136 0
Peritoneal Cancer 307137 0
Condition category
Condition code
Cancer 306251 306251 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 twice daily and oral cediranib 20mg once daily.
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. Quality of life 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 twice daily.
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. Quality of life 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.

Strategies to monitor adherence to the intervention or active comparator include participant diaries.

Usual therapy would consist of observation therefore the experimental and active comparator arms are in addition to usual therapy.
Intervention code [1] 300692 0
Treatment: Drugs
Comparator / control treatment
Active comparator - Olaparib - Patients will receive oral olaparib 300mg twice daily.
Control group
Active

Outcomes
Primary outcome [1] 305255 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] 305255 0
3 years post randomisation.
Primary outcome [2] 305256 0
Overall survival (OS) measured from the date of randomisation to the date of death from any cause.
Timepoint [2] 305256 0
3 years post randomisation.

Secondary outcome [1] 344636 0
Toxicity - Toxicity experienced by patients as assessed by the Common Terminology Criteria for Adverse Events v4.03.
Timepoint [1] 344636 0
All adverse events will be collected that occur between informed consent and 30 days post last trial treatment administration.


Secondary outcome [2] 344637 0
PFS and OS measured from the time of starting second line chemotherapy.
Timepoint [2] 344637 0
3 years post randomisation.
Secondary outcome [3] 344638 0
Adherence to maintenance therapy using a participant diary - compliance and dose reductions and interruptions.
Timepoint [3] 344638 0
Participants are asked to complete a diary to record information on treatment (such as missed doses) and adverse events from randomisation to the discontinuation of trial treatment.
Secondary outcome [4] 344639 0
TSST (the time from randomisation to start of second subsequent therapy or death).
Timepoint [4] 344639 0
3 years post randomisation.
Secondary outcome [5] 344640 0
Quality of life using EORTC QLQ C30.
Timepoint [5] 344640 0
QOL questionnaires will be completed at baseline and each clinic visit out to 3 years post randomisation.
Secondary outcome [6] 344641 0
Quality of life using EORTC QLQ OV28.
Timepoint [6] 344641 0
QOL questionnaires will be completed at baseline and each clinic visit out to 3 years post randomisation.
Secondary outcome [7] 344642 0
Cost effectiveness using the health utility instrument EQ-5D-5L applicable to a wide range of health conditions and treatments. This tool provides a simple descriptive profile and a single index value for health status and can be used for economic evaluation.
Timepoint [7] 344642 0
The EQ-5D-5L questionnaires will be completed at baseline and each clinic visit out to 3 years post randomisation.


Secondary outcome [8] 344643 0
Progression free survival by CA125 - GCIG criteria.
Timepoint [8] 344643 0
3 years post randomisation.

Secondary outcome [9] 344644 0
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 [9] 344644 0
3 years post randomisation.

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 or older with previous histologically proven diagnosis of high grade serous or endometrioid carcinoma of the
- Ovary
- Fallopian tube
- or peritoneum,
progressing 6 months or greater 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 (RECIST v1.1) of disease or following surgical resection of recurrent disease.
Patients may be included post-secondary surgery if undertaken 6 months or greater after day 1 of the last cycle of first-line platinum-based chemotherapy.
3. Patients must have had CT or MRI proven relapsed disease (measureable by RECIST 1.1 or non-measureable abnormalities supported by GCIG CA125 criteria of progression), or have had debulking surgery for first relapse.
4. Patients showing response to chemotherapy mid-treatment (post 3 or 4 cycles), either by GCIG CA125 criteria or 'partial response' on CT/MRI scan, or no evidence of progression having undergone surgical debulking, should be approached for ICON9 trial registration to allow for BRCA mutation status to be assessed (germline and/or somatic).
5. Prior front-line maintenance therapy with bevacizumab is permitted.
6. ECOG performance status 0-1.
7. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer or from secondary debulking surgery must be available for central testing. For inclusion in i)
the genetic HRD Test and ii) the biomarker research, patients must complete the consent form.
8. Patients must have a life expectancy of at least 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:
- 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
- Or surgical sterilisation (bilateral oophorectomy or hysterectomy)

10. Adequately controlled blood pressure (systolic blood pressure [SBP] equal to or less than 140 mmHg; diastolic blood pressure [DBP] equal to or less than 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 1.1
'partial response' or 'complete response' for randomisation to take place.
3. In patients with non-measurable disease, who have not undergone debulking surgery,
there must have been a GCIG CA125 response to chemotherapy.
4. If CA125 has not normalised after chemotherapy then patients must have no evidence of
disease progression by GCIG criteria.
5. Patients who have had debulking surgery at first relapse must have no evidence of disease progression on imaging (CT or MRI) and by GCIG CA125 criteria.
6. Expected to be able to commence treatment within 7 days of post randomisation, and
within 4-8 weeks post day 1 of the last cycle of chemotherapy.
7. Adequate bone marrow function as defined below:
- Absolute Neutrophil Count (ANC) equal to or greater than 1.5 x 109/l
- Platelet (Plt) equal to or greater than 100 x 109/l
- Haemoglobin (Hb) equal to or greater 100g/l required and no packed blood transfusions in the 14 days prior to starting trial treatment
8. Adequate liver function as defined below:
- Serum bilirubin equal to or less than 1.5 x ULN (or equal to or less than 3 for cases of known Gilbert's syndrome)
- Serum transaminases equal to or less than 3 x ULN
- Serum transaminases equal to or less than 5 x ULN if liver metastasis present
9. Adequate renal function as defined below:
- Serum creatinine equal to or less than 1.5 x ULN and calculated glomerular filtration rate (GFR) equal to or greater than 50ml/min (calculated as per local practice)
10. Urine dipstick for proteinuria less than 2+. If urine dipstick is equal to or greater than 2+ on two occasions more than one week apart then a 24-hour urine must demonstrate equal to or less than 1 g of protein in 24 hours or protein/creatinine ratio of less than 1.5.
11. Germline and/or somatic BRCA mutation status must be known prior to randomisation.
Minimum age
18 Years
Maximum age
No limit
Gender
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 ischaemic 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.
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.
a. Myocardial infarct or unstable angina within the last 6 months
b. New York Health Association (NYHA) equal to or greater than grade 2 congestive heart failure
c. Cardiac ventricular arrhythmias requiring medication
d. History of 2nd or 3rd degree atrioventricular conduction defects
10. Resting ECG with QTcF greater than 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 greater than 30ml in a single episode within the last 3 months or any haemoptysis (greater than 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 equal to or greater than 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.
21. Concomitant use of known CYP3A4 inhibitors (such as ketoconazole, itraconazole, protease inhibitors boosted with ritonavir or cobicastat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir, telithromycin and clarithromycin or moderate CYP3A inhibitors (e.g. Ciprofloxacin, erthromycicn, 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 (e.g. 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)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation will be used to allocate patients to either treatment arm, with stratification factors as follows:
1. 6-12 versus >12 month progression free interval (defined by the time following completion of first line platinum based chemotherapy)
2. Surgery versus no surgery at relapse prior to chemotherapy
3. Prior bevacizumab therapy
4. BRCA status (germline and/or somatic)
5. Country
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size of 618, allows for 588 participants and a 5% drop out, this has 80% power to detect a hazard ratio of 0.75. Of the 618, we aim to recruit 350 BRCA wild-type patients (based on germline/somatic BRCA).

There are two primary endpoints, and two groups of patients. Which will be analysed using a fixed-sequence gatekeeping approach.
The gatekeeping approach will be performed in the following order, based on where we are most likely to detect a statistically significant difference:
1. PFS, all patients
2. PFS, BRCA wild type
3. OS, all patients
4. OS, BRCA wild type

The justification for this ordering is as follows:
PFS for all patients: we anticipate that the additional effect of cediranib will be seen particularly in BRCA wild-type patients where the beneficial effect of maintenance olaparib has been shown to be less than in patients with a BRCA mutation (Ledermann et al, 2014 and 2016). The PFS hazard ratios were: 0.35 all patients, 0.18 BRCA positive, and 0.54 BRCA wild type (where PFS was the primary trial endpoint). These effects are all much larger than our minimum target of 0.70 in ICON9 for PFS, hence we are being conservative.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 10427 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 10486 0
Gosford Hospital - Gosford
Recruitment hospital [3] 10572 0
Macarthur Cancer Therapy Centre - Campbelltown
Recruitment hospital [4] 10575 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 22133 0
3000 - Melbourne
Recruitment postcode(s) [2] 22201 0
2250 - Gosford
Recruitment postcode(s) [3] 22291 0
2560 - Campbelltown
Recruitment postcode(s) [4] 22294 0
2217 - Kogarah
Recruitment outside Australia
Country [1] 10234 0
United Kingdom
State/province [1] 10234 0

Funding & Sponsors
Funding source category [1] 299036 0
Government body
Name [1] 299036 0
Cancer Australia
Address [1] 299036 0
GPO Box 1756, Melbourne VIC 3001
Country [1] 299036 0
Australia
Funding source category [2] 299040 0
Commercial sector/Industry
Name [2] 299040 0
AstraZeneca
Address [2] 299040 0
Cambridge Biomedical Campus
1 Francis Crick Ave, Cambridge CB2 0RE
Country [2] 299040 0
United Kingdom
Funding source category [3] 299041 0
Government body
Name [3] 299041 0
Cancer Research UK
Address [3] 299041 0
Angel Building, 407 St John Street, London, EC1V 4AD
Country [3] 299041 0
United Kingdom
Primary sponsor type
University
Name
The University of Sydney
Address
NSW 2006
Country
Australia
Secondary sponsor category [1] 298274 0
None
Name [1] 298274 0
Address [1] 298274 0
Country [1] 298274 0
Other collaborator category [1] 280036 0
University
Name [1] 280036 0
University College of London
Address [1] 280036 0
Cancer Research UK & UCL Cancer Trials Centre
90 Tottenham Court Road
London
W1T 4TJ
United Kingdom
Country [1] 280036 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299971 0
Sydney Local Health District Human Research Ethics Committee - RPAH Zone
Ethics committee address [1] 299971 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 299971 0
Australia
Date submitted for ethics approval [1] 299971 0
21/02/2018
Approval date [1] 299971 0
20/03/2018
Ethics approval number [1] 299971 0
X18-0044 & HREC/18/RPAH/70

Summary
Brief summary
Study purpose
The purpose of the study is to investigate whether we can increase the effectiveness of treatment in ovarian cancer by adding one or two new anti-cancer drugs: cediranib and olaparib.

Who is it for?
You may be eligible for this study if you are a female aged over 18 years and have a histologically proven diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, which responded to platinum-based chemotherapy.

Study details
Participants will be randomly assigned (by chance) to one of two treatment groups. One group will receive two medications, called cediranib and olaparib taken once daily and twice daily respectively. The other group will receive olaparib twice daily. Participants will attend a number of hospital visits to give blood and answer questionnaires about their quality of life.

It is hoped that this research may help people in the future who have the same kind of cancer as you have.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82134 0
A/Prof Linda Mileshkin
Address 82134 0
c/o ICON9 Study Team
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown, NSW
1450
Country 82134 0
Australia
Phone 82134 0
+61 2 9562 5000
Fax 82134 0
Email 82134 0
Linda.mileshkin@petermac.org
Contact person for public queries
Name 82135 0
Miss ICON 9 Trial Coordinator
Address 82135 0
c/o ICON9 Study Team
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown, NSW
1450
Country 82135 0
Australia
Phone 82135 0
+61 2 9562 5000
Fax 82135 0
Email 82135 0
icon9@ctc.usyd.edu.au
Contact person for scientific queries
Name 82136 0
A/Prof Linda Mileshkin
Address 82136 0
c/o ICON9 Study Team
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown, NSW
1450
Country 82136 0
Australia
Phone 82136 0
+61 2 9562 5000
Fax 82136 0
Email 82136 0
icon9@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Contact the CTC for the data sharing policy.
What supporting documents are/will be available?
Informed consent form
Other
'Other' documents specified
Interim analysis outcome.
Summary results
No Results