Condition category
Cancer
Date applied
27/05/2011
Date assigned
27/05/2011
Last edited
18/09/2015
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Miss Emma Kent

ORCID ID

Contact details

MRC Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
Aviation House
125 Kingsway
London
WC2B 6NH
United Kingdom

Additional identifiers

EudraCT number

2010-022209-16

ClinicalTrials.gov number

Protocol/serial number

9812

Study information

Scientific title

ICON8: An international phase III randomised trial of dose fractionated chemotherapy compared to standard three weekly chemotherapy, following immediate primary surgery or as part of delayed primary surgery, for women with newly diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancer
and
ICON8B: A phase III randomised trial investigating the combination of dose-fractionated chemotherapy and bevacizumab compared to either strategy alone for the first-line treatment of women with newly diagnosed high-risk stage III-IV epithelial ovarian, fallopian tube or primary peritoneal cancer

Acronym

ICON8 and ICON8B

Study hypothesis

Ovarian cancer is the most lethal gynaecological malignancy in the UK. Most patients respond well to firstline treatment, surgery and chemotherapy, but the majority go on to develop relapsed disease and the 5-year survival rate for patients with advanced disease is only 30%. There is a significant need to develop more effective first-line treatments.

ICON8:
Standard firstline chemotherapy is a combination of two drugs: carboplatin and paclitaxel, given once every 3 weeks for 6 cycles. However, giving these agents weekly may be more effective; this is called dose-fractionated chemotherapy. In ICON8 two dose-fractionated chemotherapy regimens are compared with standard carboplatin-paclitaxel.

The main outcome measures are whether dose-fractionated chemotherapy extends the time until ovarian cancer relapses (improved progression-free survival) and whether women who receive it live longer (improved overall survival). Secondary outcome measures are comparative toxicity, impact on quality of life and costeffectiveness. Two interim-analyses are planned: the first looking at feasibility and safety of the dose-fractionated regimens; and the second at their activity.

Women with newly diagnosed epithelial ovarian, fallopian tube or primary peritoneal cancers are eligible; including those with highrisk early stage (FIGO IC/IIA) or advanced (FIGO IIBIV) cancers. They can enter the trial either following primary surgery or with a plan to undergo delayed primary surgery between the 3rd and 4th cycles of chemotherapy. Women will be randomised to receive either: standard chemotherapy; or carboplatin given 3-weekly with weekly paclitaxel; or both carboplatin and paclitaxel weekly. Treatment duration in all three arms is 18 weeks.

ICON8B (added 12/08/2015):
As of 2014, the incorporation of bevacizumab and weekly dose dense paclitaxel respectively into the first-line management of ovarian cancer have shown improved survival in phase III clinical trials, hence both of these approaches can be considered new standards of care. They do however have markedly different economic implications for healthcare providers, and also place distinct burdens on patients with respect to treatment-related toxicity and duration of therapy. Hence there is an urgent need to compare these treatment approaches in a randomised trial. In ICON8B standard 3-weekly carboplatin-paclitaxel and bevacizumab will be compared to dose fractionated chemotherapy with or without bevacizumab in a randomised controlled trial.

The main outcome measures are to determine whether dose-fractionated chemotherapy with bevacizumab extends the time until ovarian cancer relapses (improved progression-free survival) and whether women who receive it live longer (improved overall survival). Secondary outcome measures are comparative toxicity, impact on quality of life and cost effectiveness. One interim analysis is planned after 50 delayed primary surgery patients have been randomised to each trial arm to establish the safety of bevacizumab in the neo-adjuvant treatment of patients undergoing delayed primary ovarian cancer surgery.

On 12/08/2015 the following changes were made to the trial record:
1. The overall trial end date was changed from 28/04/2014 to 01/05/2022.
2. The target number of participants was changed from 1485 to 2655.
3. Australia, New Zealand, Mexico, Korea and Ireland were added to the countries of recruitment.
4. The sponsor was updated; the previous sponsor for the trial was:
Medical Research Council (UK)
Cancer Division
222 Euston Road
London NW1 2DA
United Kingdom

Ethics approval

NRES Committee London - Chelsea, 08/04/2011, ref: 11/LO/0043

Study design

Randomised; Interventional; Design type: Treatment

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 email ICON8@ctu.mrc.ac.uk to request a patient information sheet

Condition

Ovarian/gynaecological cancer

Intervention

ICON8:
1. Dose-fractionated carb-pacl (carboplatin and paclitaxel given by intravenous infusion once every week)
2. The treatment course is 6 cycles with each cycle lasting 3 weeks
3. Dose-fractionated paclitaxel, carboplatin given by intravenous infusion once every 3 weeks at standard dose
4. Dose-fractionated paclitaxel given by intravenous infusion once every week
5. The treatment course is 6 cycles with each cycle lasting 3 weeks.
6. Standard treatment, carboplatin and paclitaxel given by intravenous infusion once every 3 weeks for 6 cycles.
7. Study entry: single randomisation only

ICON8B (added 12/08/2015):
1. Arm B1: (Control arm): Carboplatin (AUC5 by intravenous infusion over 30-60 minutes) and paclitaxel (175mg/m2 by intravenous infusion over 3 hours) plus bevacizumab (7.5mg/kg by intravenous infusion over 30-90 minutes) on day 1 of a 21-day cycle for 6 cycles followed by bevacizumab (7.5mg/kg by intravenous infusion over 30-90 minutes) as maintenance therapy to complete 18 cycles in total
2. Arm B2 (Control arm): Carboplatin (AUC55 by intravenous infusion over 30-60 minutes) on day 1 and dose-fractionated weekly paclitaxel (80mg/m2 by intravenous infusion over 1 hour) on day 1, 8 and 15 of a 21-day cycle for 6 cycles
3. Arm B3 (Research arm): Carboplatin (AUC55 by intravenous infusion over 30-60 minutes) on day 1 and dose-fractionated weekly paclitaxel (80mg/m2 by intravenous infusion over 1 hour) on day 1, 8 and 15 of a 21-day cycle plus bevacizumab (7.5mg/kg by intravenous infusion over 30-90 minutes) on day 1 of a 21-day cycle for 6 cycles followed by bevacizumab (7.5mg/kg by intravenous infusion over 30-90 minutes) as maintenance therapy to complete 18 cycles in total.
4. Study entry: Single randomisation only

Intervention type

Drug

Phase

Phase III

Drug names

Carboplatin, paclitaxel, bevacizumab

Primary outcome measures

ICON8:
Progression-free survival and overall survival in dose-fractionated arms. Timepoint(s): analyses will take place when the required number of events have occurred

ICON8B (added 12/08/2015):
Progression-free survival and overall survival in the experimental arm. Timepoint(s): analyses will take place when the required number of events have occurred

Secondary outcome measures

ICON8:
1. Activity of dose-fractionated arms; timepoint(s): after first 186 (approx) pts enter the trial and 9 months after randomisation
2. Feasibility and safety of dose-fractionated arms
3. Timepoint(s): when first 50 pts randomised to each arm could have completed 6 cycles of chemotherapy
4. Feasibility and safety of DPS dose-fractionated patients
Timepoint(s): when 1st 50 pts randomised each arm (with planned DPS) could have completed 6 cycles of chemotherapy

ICON8B (added 12/08/2015):
Safety of neo-adjuvant bevacizumab in patients undergoing DPS. Timepoint(s): when first 50 DPS pts randomised to each arm could have completed 6 cycles of chemotherapy

Overall trial start date

29/04/2011

Overall trial end date

01/05/2022

Reason abandoned

Eligibility

Participant inclusion criteria

ICON8:
1. Females aged 18 years and above
2. Signed informed consent and ability to comply with the protocol
3. Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis):
3.1. Epithelial ovarian carcinoma
3.2. Primary peritoneal carcinoma of Müllerian histological type
3.3. Fallopian tube carcinoma
4. FIGO stage IC or above, which may be based on clinical and radiological assessment in patients who have not undergone immediate primary surgery
5. Confirmed high-risk histological subtype for patients with FIGO stage IC/IIA disease, namely:
5.1. High grade serous carcinoma
5.2. Clear cell carcinoma
5.3. Other histological subtype considered poorly differentiated/grade 3
6. ECOG Performance Status (PS) 02
7. Life expectancy >12 weeks
8. Adequate bone marrow function:
8.1. Absolute Neutrophil Count > 1.5 x 10^9/l
8.2. Platelets (Plt) > 100 x 10^9/l
8.3. Haemoglobin (Hb) > 9g/dl (can be post transfusion)
9. Adequate liver function (within 28 days prior to randomisation)
9.1. Serum bilirubin = 1.5 x ULN
9.2. Serum transaminases = 3 x ULN in the absence of parenchymal liver metastases or = 5 x ULN in the presence of parenchymal liver metastases
10. Adequate renal function as defined by GFR (Glomerular Filtration Rate) = 30ml/min
11. Target gender: female
12. Lower age limit 18 years

ICON8B (added 12/08/2015):
1. Females aged ≥18 years
2. Signed informed consent and ability to comply with the protocol
3. Histologically confirmed, with core biopsy from a disease site as minimum requirement (cytology alone is insufficient for diagnosis):
3.1. Epithelial ovarian carcinoma
3.2. Primary peritoneal carcinoma of Müllerian histological type
3.3. Fallopian tube carcinoma
3.4. Ovarian carcinosarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary).
4. High-risk disease defined as
4.1. FIGO (2013) Stage IIIA1(ii), IIIA2 with positive retroperitoneal lymph nodes >10mm in diameter, IIIB or IIIC disease
4.1.1. With >1cm residual disease following IPS or
4.1.2. Planned to undergo primary chemotherapy with or without DPS
4.2. FIGO Stage IV disease
4.2.1. With any volume of residual disease following IPS or
4.2.2. Planned to undergo primary chemotherapy with or without DPS.
5. ECOG Performance Status (PS) 0-2
6. Life expectancy >12 weeks
7. Adequate bone marrow function:
7.1. Absolute Neutrophil Count (ANC) ≥1.5 x 109/l
7.2. Platelets (Plt) ≥100 x 109/l
7.3. Haemoglobin (Hb) ≥9g/dl (can be post transfusion).
8. Adequate liver function:
8.1. Serum bilirubin (BR) ≤1.5 x ULN
8.2. Serum transaminases ≤3 x ULN in the absence of parenchymal liver metastases or ≤5 x ULN in the presence of parenchymal liver metastases.
9. Adequate renal function as defined by:
9.1. Directly measured GFR (Glomerular Filtration Rate) ≥ 30 ml/min, or
9.2. Calculated creatinine clearance ≥ 60 ml/min.
10. Adequate coagulation profile:
10.1. International normalised ratio (INR) ≤1.5
10.2. Activated prothrombin time (APTT) ≤1.5xULN.
11. Able to start chemotherapy within 8 weeks after IPS (where applicable).

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

2655

Participant exclusion criteria

ICON8:
1. Non-epithelial ovarian cancer, including malignant mixed Müllerian tumours (carcinosarcomas)
2. Peritoneal cancer that is not of Müllerian origin, including mucinous histology
3. Borderline tumours (tumours of low malignant potential)
4. Prior systemic anticancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
5. Previous malignancies within 5 years prior to randomisation apart from: adequately treated carcinoma insitu of the cervix, breast ductal carcinoma insitu, nonmelanomatous skin cancer; or previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion
6. Preexisting sensory or motor neuropathy grade =2
7. Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at highrisk of treatment-related complications or prevent compliance with the trial protocol
8. Planned intraperitoneal cytotoxic chemotherapy
9. Any previous radiotherapy to the abdomen or pelvis
10. Sexually active women of childbearing potential not willing to use adequate contraception (eg. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards
11. Pregnant or lactating women
12. Treatment with any other investigational agent prior to protocol defined progression
13. Known hypersensitivity to carboplatin, paclitaxel or their excipients (including cremophor)
14. 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 brain or meningeal metastases are not eligible

ICON8B (added 12/08/2015):
1. Non-epithelial ovarian cancer
2. Peritoneal cancer that is not of Müllerian origin, including mucinous histology
3. Borderline tumours (i.e. tumours of low malignant potential)
4. Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
5. Previous malignancies within 5 years prior to randomisation apart from:
5.1. Adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or
5.2. Previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion.
6. Pre-existing sensory or motor neuropathy CTCAE grade ≥2
7. Proteinuria at baseline: >1gm protein/24h by a 24-hour urine collection. NB. Proteinuria should be initially assessed by urine dipstick. If urine protein is ≥2+ on urine dipstick, a 24-hour urine protein collection must be performed.
8. Significant co-existing or previous medical conditions that are contra-indications to treatment with bevacizumab, including:
8.1. Cerebrovascular disease, including transient ischaemic attacks (TIAs), cerebrovascular accident (CVA; i.e. stroke) and intracranial bleeds (i.e. intra-cerebral haemorrhage, sub-arachnoid haemorrhage or sub-dural haemorrhage) within 6 months before trial entry
8.2. Cardiovascular disease as follows:
8.2.1. Uncontrolled hypertension, defined as sustained BP>150/100mmHg while receiving anti-hypertensive medication. NB. Patients with a BP>150/100 mmHg prior to randomisation should be commenced on a calcium-channel blocker or other anti-hypertensive agent; or in the case of patients already on anti-hypertensives, medical therapy should be optimised. The BP should then be re-checked a few days later, if BP is controlled to ≤150/100mmHg the patient may be entered into the trial
8.2.2. Myocardial infarction or unstable angina within 6 months prior to randomization
8.3.3. New York Heart Association (NYHA) grade ≥2 congestive heart failure
8.3.4. Poorly controlled cardiac arrhythmia despite medication. NB. Patients with rate-controlled atrial fibrillation are eligible
8.3.5. Peripheral vascular disease grade ≥3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision
8.3. History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication)
8.4. Recent history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohns’ Disease and ulcerative colitis)
8.5. Previous gastrointestinal perforation.
9. Chronic daily use of high-dose aspirin, >325mg/day, within 10 days prior to study entry
10. Surgery (including open biopsy) or significant traumatic injury within 28 days prior to anticipated date of first dose of bevacizumab. NB. If IPS was performed within 28 days of planned start of treatment, patients are eligible but bevacizumab must be omitted from cycle 1.
11. Serious non-healing wound, worse than CTCAE Wound Complication or Wound Dehiscence grade 1
12. Active ulcer or bone fracture
13. Anticipated to require extensive dental work during protocol treatment
14. Evidence of any other disease/metabolic dysfunction that in the opinion of the investigator would put the subject at high-risk of treatment-related complications or prevent compliance with the trial protocol
15. Clinical symptoms or radiological evidence of bowel obstruction (including sub-acute obstruction) or extensive recto-sigmoid involvement on imaging related to ovarian cancer
16. Evidence of intra-abdominal free air not explained by paracentesis or recent surgical procedure
17. Symptomatic abdominal fistulae
18. 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 brain or meningeal metastases are not eligible
19. Sexually active women of childbearing potential not willing to use adequate contraception (e.g. oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards
20. Pregnant or lactating women who are currently breastfeeding
21. Known hypersensitivity to carboplatin, paclitaxel, bevacizumab or their excipients (including cremophor)
22. Planned intraperitoneal cytotoxic chemotherapy
23. Planned treatment with any other systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression
24. Any previous radiotherapy to the abdomen or pelvis
25. Treatment with any other investigational agent prior to protocol defined progression

Recruitment start date

29/04/2011

Recruitment end date

01/05/2019

Locations

Countries of recruitment

Australia, Ireland, Korea, South, Mexico, New Zealand, United Kingdom

Trial participating centre

MRC Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology Aviation House 125 Kingsway
London
WC2B 6NH
United Kingdom

Sponsor information

Organisation

MRC Clinical Trials Unit at UCL (UK)

Sponsor details

Institute of Clinical Trials & Methodology
Aviation House
125 Kingsway
London
WC2B 6NH
United Kingdom

Sponsor type

University/education

Website

http://www.mrc.ac.uk/index.htm

Funders

Funder type

Charity

Funder name

Cancer Research UK Clinical Trials Advisory and Awards Committee (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

For ICON8, results of the stage 1 feasibility and safety analysis will be published. After the stage 2 analysis, advice will be sought from the Trial Steering Committee with regards to publication of those results. The progression-free survival analysis is expected to occur 1 year after the last patient is randomised, and the overall survival analysis is expected to occur 3 years after the last patient is randomised. The results of the progression-free and overall survival analyses will be published separately, and as soon as possible after each analysis has occurred.

For the ICON8B cohort, results of the safety analysis in Delayed Primary Surgery patients will be published. The progression-free survival analysis is expected to occur 1 year after the last patient is randomised, and the overall survival analysis is expected to occur 3 years after the last patient is randomised. The results of the progression-free and overall survival analyses will be published separately, and as soon as possible after each analysis has occurred.

Data will be made available on request following the MRC CTU Data Sharing Policy. Data release applications will be reviewed by the Trial Management Group and Trial Steering Committee before final approval. Data sharing contracts will be put in place between the applicant and UCL.

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes