Condition category
Cancer
Date applied
22/03/2007
Date assigned
13/08/2007
Last edited
31/03/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Prof Jonathan Ledermann

ORCID ID

Contact details

University College London
Cancer Research UK and UCL Cancer Trials Centre
90 Tottenham Court Road
London
W1T 4TJ
United Kingdom

Type

Public

Additional contact

Ms Liz Clark

ORCID ID

Contact details

ICON6 Trial Manager
University College London
Cancer Research UK and UCL Cancer Trials Centre
90 Tottenham Court Road
London
W1T 4TJ
United Kingdom
-
elizabeth.clark@ucl.ac.uk

Additional identifiers

EudraCT number

2007-001346-41

ClinicalTrials.gov number

NCT00532194

Protocol/serial number

N/A

Study information

Scientific title

A double-blind, placebo-controlled, three-arm, randomised, multi-centre Gynaecologic Cancer InterGroup trial of cediranib (AZD2171), in combination with platinum-based chemotherapy and as a single agent maintenance therapy, in women with ovarian cancer relapsing more than 6 months following completion of first-line platinum-based treatment

Acronym

ICON6 (International Collaborative Ovarian Neoplasm 6)

Study hypothesis

Current hypothesis as of 13/03/2015:
That cediranib has an influence on progression-free survival when comparing patients receiving chemotherapy alone with patients receiving chemotherapy and cediranib (AZD2171).

Previous hypothesis:
Over three separate trial stages the study hypotheses are:

Stage 1:
That it is safe to add a once daily tablet of cediranib to standard platinum-based chemotherapy

Stage 2:
That cediranib has an influence on progression free survival when comparing patients receiving chemotherapy alone with patients receiving chemotherapy and cediranib (AZD2171)

Stage 3:
1. That cediranib has an effect on overall survival when taken at the same time as chemotherapy (placebo versus active), and when taken at the same time and then continued as a maintenance treatment (placebo versus active)
2. If the first Stage 3 assessments shows the product is effective, that cediranib has an effect on overall survival when taken at the same time as chemotherapy compared with at the same time and then continued as a maintenance treatment

Ethics approval

Oxfordshire Research Ethics Committee B, 16/07/2007, ref: 07/H0605/76

Study design

Randomised three-arm double-blind placebo-controlled multicentre phase III trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Relapsed platinum-sensitive ovarian cancer

Intervention

Current interventions as of 13/03/2015:
Patients in Arm A (the reference arm) will receive standard platinum-based chemotherapy plus a daily oral placebo tablet for the duration of the chemotherapy and then until protocol defined disease progression occurs.

Patients in Arm B (concurrent cediranib arm) will also receive standard chemotherapy plus daily oral cediranib during chemotherapy only, and then an oral daily placebo tablet until protocol defined disease progression or toxicity limiting treatment occurs.

Patients in Arm C (concurrent and maintenance cediranib arm) will also receive standard chemotherapy plus oral cediranib daily during chemotherapy and until protocol defined disease progression or toxicity limiting treatment occurs.

Previous interventions:
Patients in Arm A (the reference arm) will receive standard platinum-based chemotherapy plus a daily oral placebo tablet for the duration of the chemotherapy and then for up to 18 months from the time of randomisation, or until protocol defined disease progression occurs.

Patients in Arm B (concurrent cediranib arm) will also receive standard chemotherapy plus daily oral cediranib during chemotherapy only, and then an oral daily placebo tablet for up to 18 months from the time of randomisation, or until protocol defined disease progression or toxicity limiting treatment occurs.

Patients in Arm C (concurrent and maintenance cediranib arm) will also receive standard chemotherapy plus oral cediranib daily during chemotherapy and then continued for up to 18 months from the time of randomisation, or until protocol defined disease progression or toxicity limiting treatment occurs.

The starting dose of cediranib is 30 mg taken orally once daily. This will be down titrated if required on medical assessment to 20 mg and then 15 mg.

Intervention type

Drug

Phase

Phase III

Drug names

Cediranib (also known as AZD2171 and recentin)

Primary outcome measures

Current primary outcome measures as of 13/03/2015:
Progression-free survival (PFS) in arms A vs C

Previous primary outcome measures:
Stage 1: Safety
Stage 2: Progression free survival
Stage 3: Overall survival

Data for the outcomes above will be collected approximately 3 weekly during chemotherapy, 6 weekly after chemotherapy up to 18 months, 3 monthly up to 3 years, 6 monthly during years 4 and 5, then annually until protocol defined disease progression or death.

Secondary outcome measures

Current secondary outcome measures as of 13/03/2015:
1. Progression-free survival (PFS) across arms A, B and C
2. Overall survival (OS)
3. Toxicity
4. Quality of Life (QoL)

Previous secondary outcome measures:
Stage 1: None
Stage 2: Overall survival and toxicity
Stage 3: Progression free survival, toxicity and quality of life

Quality of life assessment will be made using EORTC QLQ-C30 version 3 and EORTC QLQ-OV28. This information will be supplemented by health questionnaire EQ-5D. Other outcome measures will be assessed by clinical interview, blood tests and CT scans.

Data for the outcomes above will be collected approximately 3 weekly during chemotherapy, 6 weekly after chemotherapy up to 18 months, 3 monthly up to 3 years, 6 monthly during years 4 and 5, then annually until protocol defined disease progression or death.

Overall trial start date

01/07/2007

Overall trial end date

31/12/2016

Reason abandoned

Eligibility

Participant inclusion criteria

1. Females aged 18 years or older with previous histologically proven diagnosis of:
1.1. Epithelial ovarian carcinoma
1.2. Fallopian tube carcinoma
1.3. Primary serous peritoneal carcinoma
Relapsing more than 6 months after completion of first-line platinum-based chemotherapy
2. Signed informed consent and ability to comply with the protocol
3. Ability to commence treatment within 2 weeks of randomisation
4. Computerised Tomography (CT) or Magnetic Resonance Imaging (MRI) proven relapsed disease, more than six months since completion of first-line platinum-based chemotherapy
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
6. Life expectancy more than 12 weeks
7. If there is a past history of a solid tumour, this must have been treated curatively more than five years ago with no evidence of recurrence
8. Adequate bone marrow function
8.1. Absolute Neutrophil Count (ANC) greater than or equal to 1.5 x 109/l
8.2. Platelets (Plt) greater than or equal to 100 x 109/l
8.3. Haemoglobin (Hb) greater than or equal to 9g/dl (can be post transfusion)
9. Adequate liver function (within 14 days before randomisation)
9.1. Serum bilirubin (BR) = 1.5 x Upper Limit of Normal (ULN)
9.2. Serum transaminases = 2.5 x ULN
10. Adequate renal function
10.1. Serum creatinine = 1.5 ULN
10.2. Urine dipstick for proteinuria less than 2+. If urine dipstick is greater than or equal to 2+ on two occasions more than one week apart then a 24 hour urine must demonstrate less than or equal to 1 g of protein in 24 hours

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

470

Participant exclusion criteria

1. Non-epithelial ovarian cancer, including malignant mixed Mullerian tumours and mucinous carcinoma of the peritoneum
2. Poorly controlled hypertension (persistently elevated >150/100 mmHg despite anti-hypertensive medication)
3. History of inflammatory bowel disease (Crohn's disease or ulcerative colitis)
4. Malignancies other than ovarian cancer within 5 years prior to randomisation, except for adequately treated carcinoma in situ of the cervix and/or basal cell skin cancer. Patients who have a past history of a solid tumour, treated curatively, more than five years prior to randomisation, with no evidence of recurrence, are still eligible to enter ICON6
5. Previous radiotherapy within 21 days prior to randomisation
6. Treatment with any other investigational agent within 30 days prior to entering this trial. Patients are still eligible for entry into ICON6 if they have received previous treatment for ovarian cancer with either bevacizumab, erlotinib, or a Cox-2 inhibitor as long as more than 30 days have elapsed since the last treatment
7. Arterial thrombotic event (including Transient Ischaemic Attack [TIA], cerebrovascular accident [CVA) and peripheral arterial embolus) within the previous 12 months
8. Gastrointestinal (GI) impairment that could affect ability to take, or adsorption of, oral medicines including sub acute or complete bowel obstruction
9. Known hypersensitivity to AZD2171 or other Vascular Endothelial Growth Factor (VEGF) inhibitors
10. Major surgery within 2 weeks before entry into the trial
11. Significant haemorrhage of >30 ml in a single episode within 3 months or any haemoptysis
12. Evidence of severe or uncontrolled cardiac disease
12.1. Myocardial Infarct (MI) or unstable angina within 12 months
12.2. New York Health Association (NYHA) = grade 2 Congestive Heart Failure (CHF)
12.3. Cardiac ventricular arrhythmias requiring medication
12.4. History of 2nd or 3rd degree atrioventricular conduction defects
13. Prolonged QTc (corrected) interval of >470 msec on electrocardiogram (ECG), or a family history of long QT syndrome
14. Persisting = Grade 2 CTC (Common Toxicity Criteria) toxicity (except alopecia and neuropathy) from previous anti-cancer treatment. If peripheral sensory or motor neuropathy = grade 2 then paclitaxel can be omitted from the chemotherapy at the discretion of the treating physician
15. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory in the case of suspected brain metastases. Spinal MRI is mandatory in the case of suspected spinal cord compression. Patients with unstable untreated brain or meningeal metastases are not eligible
16. Inability to attend or comply with treatment or follow-up scheduling
17. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
18. Fertile women of childbearing potential not willing to use adequate contraception for the duration of trial treatment and at least 6 months after
19. Any other severe uncontrolled medical condition or disease

Recruitment start date

29/11/2007

Recruitment end date

23/12/2011

Locations

Countries of recruitment

Australia, Canada, New Zealand, Spain, United Kingdom

Trial participating centre

University College Hospital
London
NW1 2BU
United Kingdom

Sponsor information

Organisation

Medical Research Council (UK)

Sponsor details

20 Park Crescent
London
W1B 1AL
United Kingdom

Sponsor type

Government

Website

http://www.mrc.ac.uk

Funders

Funder type

Industry

Funder name

Cancer Research UK (ref: C444/A6862)

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

AstraZeneca (ref: D8480C00037) (International)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

National Health and Medical Research Council

Alternative name(s)

NHMRC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

Australia

Results and Publications

Publication and dissemination plan

Primary outcome presented at European Cancer Congress 2013 (http://2013.europeancancercongress.org/Scientific-Programme/Abstract-search.aspx?abstractid=8897), full manuscript anticipated Q2 2015 in parallel with QoL data.
Mature OS analysis to be conducted when greater than 80% of deaths have occurred.

Intention to publish date

30/06/2015

Participant level data

Available on request

Results - basic reporting

Publication summary

2011 results in: http://www.ncbi.nlm.nih.gov/pubmed/21878941
2013 results in: Ledermann J, Perren T, Raja F, et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. Eur J Cancer 2013;49(Suppl. 3):S5 (LBA10).
2016 results in: http://www.ncbi.nlm.nih.gov/pubmed/27025186

Publication citations

Additional files

Editorial Notes

31/03/2016: Publication reference added. On 13/03/2015 the following changes were made to the trial record: 1. The study design was changed from 'Randomised three-arm three-stage double-blind placebo-controlled multicentre phase III trial' to 'Randomised three-arm double-blind placebo-controlled multicentre phase III trial' 2. The overall trial end date was changed from 31/07/2013 to 31/12/2016. 3. The target number of participants was changed from 2000 to 470. 4. Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Israel, Italy, Norway, Serbia and Sweden were removed from the countries of recruitment. 5. Medical Research Council (UK) and NHMRC (Cancer Australia) were added as funders.