Study Evaluating the Efficacy of Maintenance Olaparib and Cediranib or Olaparib Alone in Ovarian Cancer Patients (ICON9)

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

ICON 9 will assess the efficacy, safety and tolerability of maintenance olaparib in combination with cediranib compared to maintenance olaparib alone following a response to platinum-based chemotherapy in women with relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer. Prognostic and predictive factors will be studied from tumour and blood samples.

Study Overview

• Status: Recruiting
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Olaparib; Drug: Cediranib

Detailed Description

ICON9 is an international multicentre randomised, phase III trial assessing maintenance treatment with olaparib and cediranib or olaparib alone in women with relapsed ovarian cancer whose disease progressed more than 6 months after first line chemotherapy. Women whose disease responds to platinum chemotherapy following 3 to 4 cycles can be registered for collection of germline BRCA test results if known, and somatic BRCA testing of archival tumour specimens or secondary debulking tissue if required. Patients who have completed treatment and whose disease has responded (partial or complete) to a minimum of 4 cycles of platinum based chemotherapy will be randomised to maintenance treatment of either olaparib and cediranib or olaparib alone.

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.

• Study Type: Interventional
• Enrollment (Anticipated): 330
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ian Macdonald; Phone Number: +44 (0)20 7679 9808; Email: ctc.ICON9@ucl.ac.uk
• Study Contact Backup: Name: Mandy Feeney; Phone Number: +44 (0)20 7679 9890; Email: ctc.ICON9@ucl.ac.uk

Study Locations

• Australia
  • Albury, Australia
    • Recruiting
    • Border Medical Oncology
    • Principal Investigator: Christopher Steer
  • Bedford Park, Australia
    • Recruiting
    • Flinders Medical Centre
  • Benowa, Australia
    • Recruiting
    • Pindara Private Hospital
    • Principal Investigator: Marco Matos
  • Camperdown, Australia
    • Recruiting
    • Chris O'Brien Lifehouse
    • Principal Investigator: Michelle Harrison
  • Canberra, Australia
    • Recruiting
    • Canberra Hospital
    • Principal Investigator: Alison Davies
  • Clayton, Australia
    • Recruiting
    • Monash Health
    • Principal Investigator: Kate Webber
  • Gosford, Australia
    • Recruiting
    • Gosford Hospital
    • Principal Investigator: Craig Kukard
  • Melbourne, Australia
    • Recruiting
    • Peter MacCallum Cancer Centre
  • South Brisbane, Australia
    • Recruiting
    • Icon Cancer Centre
    • Principal Investigator: Jim Coward
  • South Brisbane, Australia
    • Recruiting
    • Mater Cancer Centre
    • Principal Investigator: Catherine Shannon
  • Townsville, Australia
    • Recruiting
    • Townsville Hospital
    • Principal Investigator: Abhishek Joshi
  • Westmead, Australia
    • Recruiting
    • Westmead Hospital
  • New South Wales
    • Sydney, New South Wales, Australia
      • Recruiting
      • Calvary Mater Hospital
    • Sydney, New South Wales, Australia
      • Recruiting
      • Campbelltown Hospital
      • Principal Investigator: Felicia Roncolato
    • Sydney, New South Wales, Australia
      • Recruiting
      • Prince of Wales Hospital
      • Principal Investigator: Michael Friedlander
  • Tasmania
    • Hobart, Tasmania, Australia
      • Recruiting
      • Royal Hobart Hospital
      • Principal Investigator: Allison Black
• Canada
  • Edmonton, Canada
    • Recruiting
    • Cross Cancer Institute
  • Montréal, Canada
    • Recruiting
    • Centre Hospitalier de l'Université de Montréal
  • Québec, Canada
    • Recruiting
    • CHU de Québec
    • Principal Investigator: Vincent Castonguay
  • Toronto, Canada
    • Recruiting
    • Princess Margaret Cancer Centre
  • Toronto, Canada
    • Recruiting
    • Sunnybrook Hospital
    • Principal Investigator: Helen MacKay
  • Vancouver, Canada
    • Recruiting
    • Bc Cancer Vancouver
  • Victoria, Canada
    • Recruiting
    • BC Cancer Victoria
    • Principal Investigator: Jennifer Rauw
• New Zealand
  • Auckland, New Zealand
    • Recruiting
    • Auckland City Hospital
    • Principal Investigator: Michelle Wilson
  • Christchurch, New Zealand
    • Recruiting
    • Christchurch Hospital
    • Principal Investigator: Michelle Vaughan
• United Kingdom
  • Barrow In Furness, United Kingdom
    • Recruiting
    • Furness General Hospital
    • Principal Investigator: Sarah Moon
  • Belfast, United Kingdom
    • Terminated
    • Belfast City Hospital
  • Brighton, United Kingdom
    • Recruiting
    • Royal Sussex County Hospital
    • Principal Investigator: Rebecca Herbertson
  • Cambridge, United Kingdom
    • Recruiting
    • Addenbrookes Hospital
  • Canterbury, United Kingdom
    • Recruiting
    • Kent & Canterbury Hospital
    • Principal Investigator: Justin Waters
  • Cardiff, United Kingdom
    • Recruiting
    • Velindre Cancer Centre
    • Principal Investigator: Louise Hanna
  • Cheltenham, United Kingdom
    • Recruiting
    • Cheltenham General Hospital
    • Principal Investigator: Audrey Cook
  • Coventry, United Kingdom
    • Recruiting
    • University Hospital Coventry
    • Principal Investigator: Lucy McAven
  • Dundee, United Kingdom
    • Recruiting
    • Ninewells Hospital
  • Edinburgh, United Kingdom
    • Recruiting
    • Western General Hospital
  • Glasgow, United Kingdom
    • Recruiting
    • Beatson West of Scotland Cancer Centre
  • Guildford, United Kingdom
    • Recruiting
    • Royal Surrey County Hospital
    • Principal Investigator: Agnieszka Michael
  • Lancaster, United Kingdom
    • Recruiting
    • Royal Lancaster Infirmary
    • Principal Investigator: Sarah Moon
  • London, United Kingdom
    • Recruiting
    • University College London Hospital
    • Principal Investigator: Jonathan Ledermann
  • London, United Kingdom
    • Recruiting
    • Guy's Hospital
    • Principal Investigator: Ana Montes
  • London, United Kingdom
    • Recruiting
    • Royal Marsden NHS Foundation Trust
    • Principal Investigator: Susanna Banerjee
  • London, United Kingdom
    • Recruiting
    • Hammersmith Hospital
  • London, United Kingdom
    • Recruiting
    • Mount Vernon Cancer Centre
  • Manchester, United Kingdom
    • Recruiting
    • The Christie Hospital
    • Principal Investigator: Gordon Jayson
  • Margate, United Kingdom
    • Recruiting
    • Queen Elizabeth the Queen Mother Hospital
    • Principal Investigator: Justin Waters
  • Oxford, United Kingdom
    • Recruiting
    • Churchill Hospital
    • Principal Investigator: Shibani Nicum
  • Portsmouth, United Kingdom
    • Active, not recruiting
    • Queen Alexandra Hospital
  • Reading, United Kingdom
    • Recruiting
    • Royal Berkshire Hospital
    • Principal Investigator: Madhumita Battacharyya
  • Southampton, United Kingdom
    • Recruiting
    • Southampton General Hospital
  • Stevenage, United Kingdom
    • Recruiting
    • Lister Hospital
  • Swansea, United Kingdom
    • Recruiting
    • Singleton Hospital
    • Principal Investigator: Rachel Jones
  • Taunton, United Kingdom
    • Recruiting
    • Musgrove Park Hospital
  • Truro, United Kingdom
    • Recruiting
    • Royal Cornwall
  • Wirral, United Kingdom
    • Recruiting
    • Clatterbridge Cancer Centre
    • Principal Investigator: Danielle Shaw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Registration Inclusion Criteria:

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 Inclusion Criteria:

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:

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Olaparib; Olaparib is a PARP inhibitor, targeting DNA repair processes.; Drug: Cediranib; Cediranib is an inhibitor of vascular endothelial growth factor-A (VEGF), targeting angiogenesis.
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.	Drug: Olaparib; Olaparib is a PARP inhibitor, targeting DNA repair processes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Progression free survival (PFS) measured from the time of randomisation.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Toxicity (AEs) experienced by patients as assessed by the Common Terminology Criteria for Adverse Events v4.03	3 years
PFS and OS measured from the time of starting chemotherapy	PFS and OS measured from the time of starting chemotherapy	3 years
Adherence to maintenance therapy- compliance and dose reductions and interruptions	Adherence to maintenance therapy- compliance and dose reductions and interruptions	3 years
TSST (the time from randomisation to start of second subsequent therapy or death)	TSST (the time from randomisation to start of second subsequent therapy or death)	3 years
Quality of life using EORTC QLQ C30	Quality of life using EORTC QLQ C30	3 years
Quality of life using EORTC QLQ OV28	Quality of life using EORTC QLQ OV28	3 years
Cost effectiveness using EQ-5D-5L for economic evaluation	Cost effectiveness using EQ-5D-5L for economic evaluation	3 years
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	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	3 years
Overall survival (OS) measured from the date of randomisation to the date of death from any cause	Overall survival (death from any cause) measured from the time of randomisation.	3 years

Collaborators and Investigators

• Sponsor: University College, London

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2018
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: July 31, 2017
• First Submitted That Met QC Criteria: September 7, 2017
• First Posted (Actual): September 12, 2017

Study Record Updates

• Last Update Posted (Actual): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Olaparib; Cediranib
• Other Study ID Numbers: UCL/14/0795

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No