ICON8 Trials Programme

ISRCTN	ISRCTN10356387
DOI	https://doi.org/10.1186/ISRCTN10356387
EudraCT/CTIS number	2010-022209-16
ClinicalTrials.gov number	NCT01654146
Secondary identifying numbers	9812

Submission date: 27/05/2011
Registration date: 27/05/2011
Last edited: 14/12/2023

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

http://cancerhelp.cancerresearchuk.org/trials/a-trial-looking-at-weekly-chemotherapy-for-ovarian-cancer-icon8
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-chemotherapy-with-or-without-bevacizumab-for-advanced-ovarian-cancer-icon8b
http://www.icon8trial.org/patients/icon8-trial-summary/

Study website

Contact information

Dr Andrew Clamp
Scientific

MRC Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
90 High Holborn, 2nd Floor
London
WC1V 6LJ
United Kingdom

Email	mrcctu.icon8and8b@ucl.ac.uk

Study information

Study design	Randomized; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please email mrcctu.icon8and8b@ucl.ac.uk to request a patient information sheet
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 standard three weekly chemotherapy and bevacizumab for the first-line treatment of women with newly diagnosed high-risk stage III-IV epithelial ovarian, fallopian tube or primary peritoneal cancer
Study 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.
Ethics approval(s)	1. Approved 06/06/2011, London- Chelsea (Research Ethics Committee (REC) London Centre, 2 Redman Place, London, E20 1JQ, United Kingdom; +44 (0)207 104 8150; chelsea.rec@hra.nhs.uk), ref: 11/LO/0043 2. NRES Committee London - Chelsea, 08/04/2011, ref: 11/LO/0043
Condition	Ovarian/gynaecological cancer
Intervention	Current interventions as of 01/10/2021: 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: 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 (Closed 05/05/2017) 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 Previous interventions: 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
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	Carboplatin, paclitaxel, bevacizumab
Primary outcome measure	Current primary outcome measure as of 01/10/2021: 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: Progression-free survival. Timepoint(s): analyses will take place when the required number of events have occurred Previous primary outcome measure: 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	Current secondary outcome measures as of 01/10/2021: 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: 1. 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 2. Overall Survival. Timepoints(s): analyses will take place only if a positive PFS result is observed. Previous 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 study start date	29/04/2011
Overall study end date	31/12/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Female
Target number of participants	1485 (ICON8); 590 (ICON8B)
Total final enrolment	2144
Participant inclusion criteria	Current ICON8 inclusion criteria as of 12/09/2018: 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. FIGO (1988) 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 (1988) 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) 0-2 7. Life expectancy >12 weeks 8. Adequate bone marrow function: 8.1. Absolute Neutrophil Count (ANC) ≥1.5 x 10(9)/l 8.2. Platelets (Plt) ≥100 x 10(9)/l 8.3. Haemoglobin (Hb) ≥9 g/dl (can be post transfusion) 9. Adequate liver function: 9.1. Serum bilirubin (BR) ≤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: 10.1. Directly measured GFR (Glomerular Filtration Rate) ≥ 30 ml/min, or 10.2. Calculated creatinine clearance ≥60 ml/min 11. Able to start chemotherapy within 8 weeks after immediate primary surgery (where applicable) Previous ICON8 inclusion criteria: 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 Current ICON8B inclusion criteria as of 12/09/2018: 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 >1 cm 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. No clinical symptoms or radiological evidence of bowel obstruction (including sub-acute obstruction), abdominal fistulae or extensive recto-sigmoid involvement on imaging related to ovarian cancer 7. No recent history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohn's Disease and ulcerative colitis) or any prior episode of gastrointestinal perforation. 8. Life expectancy >12 weeks 9. Adequate bone marrow function: 9.1. Absolute Neutrophil Count (ANC) ≥1.5 x 10(9)/l 9.2. Platelets (Plt) ≥100 x 10(9)/l 9.3. Haemoglobin (Hb) ≥9 g/dl (can be post transfusion) 10. Adequate liver function: 10.1. Serum bilirubin (BR) ≤1.5 x ULN 10.2. Serum transaminases ≤3 x ULN in the absence of parenchymal liver metastases or ≤5 x ULN in the presence of parenchymal liver metastases. 11 Adequate renal function as defined by: 11.1. Directly measured GFR (Glomerular Filtration Rate) ≥30 ml/min, or 11.2. Calculated creatinine clearance ≥60 ml/min. 12. Adequate coagulation profile: 12.1. International normalised ratio (INR) ≤1.5 12.2. Activated prothrombin time (APTT) ≤1.5xULN 13. Able to start chemotherapy within 8 weeks after IPS (where applicable) Previous ICON8B inclusion criteria (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 exclusion criteria	Current ICON8 exclusion criteria as of 12/09/2018: 1. Non-epithelial ovarian cancer 2. Peritoneal cancer that is not of Müllerian origin, including mucinous histology 3. Borderline tumours (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 grade ≥2 7. 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 8. Planned intraperitoneal cytotoxic chemotherapy 9. Planned maintenance treatment with systemic anti-cancer therapy following completion of protocol treatment and prior to protocol defined progression 10. Any previous radiotherapy to the abdomen or pelvis 11. 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 12. Pregnant or lactating women who are currently breastfeeding 13. Treatment with any other investigational agent prior to protocol defined progression 14. Known hypersensitivity to carboplatin, paclitaxel or their excipients (including cremophor) 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 brain or meningeal metastases are not eligible. Previous ICON8 exclusion criteria: 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 Current ICON8 exclusion criteria as of 12/09/2018: 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. Clinical symptoms or radiological evidence of bowel obstruction (including sub-acute obstruction) or extensive recto-sigmoid involvement on imaging related to ovarian cancer 5. Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy) 6. Previous malignancies within 5 years prior to randomisation apart from: 6.1. adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or 6.2. previous/synchronous early-stage endometrial cancer defined as stage IA (FIGO 2009) grade 1 or 2 endometrioid cancers with no lymphovascular space invasion 7. Pre-existing sensory or motor neuropathy CTCAE grade ≥2 8. Proteinuria at baseline: >1 g protein/24 h by a 24-hour urine collection 9. Significant co-existing or previous medical conditions that are contra-indications to treatment with bevacizumab, including: 9.1. 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 9.2. Cardiovascular disease as follows: 9.2.1. Uncontrolled hypertension, defined as sustained BP >150/100 mmHg 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 ≤150/100 mmHg the patient may be entered into the trial 9.2.2. Myocardial infarction or unstable angina within 6 months prior to randomization 9.2.3. New York Heart Association (NYHA) grade ≥2 congestive heart failure 9.2.4. Poorly controlled cardiac arrhythmia despite medication NB. Patients with rate-controlled atrial fibrillation are eligible 9.2.5. Peripheral vascular disease grade ≥3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision 9.3. History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication) 10. Chronic daily use of high-dose aspirin, >325 mg/day, within 10 days prior to study entry 11. Surgery (including open biopsy) or significant traumatic injury within 28 days prior to anticipated date of first dose of bevacizumab 12. Serious non-healing wound, worse than CTCAE Wound Complication or Wound Dehiscence grade 1 13. Active ulcer or bone fracture 14. Anticipated to require extensive dental work during protocol treatment 15. 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 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. Previous ICON8B exclusion criteria (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	08/04/2020

Locations

Countries of recruitment

Australia
England
Ireland
Korea, South
Mexico
New Zealand
Northern Ireland
Scotland
Switzerland
United Kingdom
Wales

Study participating centres

Aberdeen Royal Infirmary

Foresterhill Health Campus
Foresterhill Road
Aberdeen
AB25 2ZN
United Kingdom

Addenbrooke's Hospital

Hills Road
Cambridge
CB2 0QQ
United Kingdom

Airedale General Hospital

Skipton Road
Steeton
Keighley
BD20 6TD
United Kingdom

Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Bedford Hospital

Kempston Road
Bedford
MK42 9DJ
United Kingdom

Belfast City Hospital

51 Lisburn Road
Belfast
BT9 7AB
United Kingdom

Birmingham Heartlands Hospital

Bordesley Green E
Birmingham
B9 5SS
United Kingdom

Blackpool Victoria Hospital

Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Bradford Royal Infirmary

Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Bristol Haematology & Oncology Centre

Horfield Road
Avon
Bristol
BS2 8ED
United Kingdom

Broomfield Hospital

Court Road
Broomfield
Chelmsford
CM1 7ET
United Kingdom

Huddersfield Royal Infirmary

Acre Street
Huddersfield
HD3 3EA
United Kingdom

Castle Hill Hospital

Castle Road
Cottingham
HU16 5JQ
United Kingdom

Cheltenham General Hospital

Sandford Road
Cheltenham
GL53 7AN
United Kingdom

Christie Hospital

Wilmslow Road
Manchester
M20 4BX
United Kingdom

Churchill Hospital

Old Road
Oxford
OX3 7LE
United Kingdom

City Hospital

Dudley Road
Birmingham
B18 7QH
United Kingdom

The Clatterbridge Cancer Centre

Clatterbridge Road
Birkenhead
CH63 4JY
United Kingdom

County Hospital

151 Weston Road
Stafford
ST16 3SA
United Kingdom

Cumberland Infirmary

Newtown Road
Carlisle
CA2 7HY
United Kingdom

Diana, Princess of Wales Hospital

Scartho Road
Grimsby
DN33 2BA
United Kingdom

Doncaster Royal Infirmary

Thorne Road
Doncaster
DN2 5LT
United Kingdom

Dorset County Hispital

Williams Avenue
Dorchester
DT1 2JY
United Kingdom

Essex County Hospital

Lexden Road
Colchester
CO3 3NB
United Kingdom

Freeman Hospital

Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

George Eliot Hospital

College Street
Nuneaton
CV10 7DJ
United Kingdom

Glan Clwyd Hospital

Rhuddlan Road
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom

Gloucestershire Royal Hospital

Great Western Road
Gloucester
GL1 3NN
United Kingdom

Great Western Hospital

Marlborough Road
Swindon
SN3 6BB
United Kingdom

Guy's & St. Thomas' Hospital

Great Maze Pond
London
SE1 9RT
United Kingdom

Hammersmith Hospital

150 Du Cane Road
White City
London
W12 0HS
United Kingdom

Hereford County Hospital

Stonebow Road
Hereford
HR1 2BN
United Kingdom

Hinchingbrooke Hospital

Parkway
Hinchingbrooke
Huntingdon
PE29 6NT
United Kingdom

Ipswich Hospital

Heath Road
Ipswich
IP4 5PD
United Kingdom

James Cook University Hospital

Marton Road
Middlesbrough
TS4 3BW
United Kingdom

James Paget Hospital

Lowestoft Road
Gorleston-on-Sea
Great Yarmouth
NR31 6LA
United Kingdom

Leicester Royal Infirmary

Infirmary Square
Leicester
LE1 5WW
United Kingdom

Lincoln County Hospital

Greetwell Road
Lincoln
LN2 5QY
United Kingdom

Lister Hospital

Stevenage
SG1 4AB
United Kingdom

Liverpool Women's Hospital

Crown Street
Liverpool
L8 7SS
United Kingdom

Maidstone Hospital

Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom

Walsall Manor Hospital

Moat Road
Walsall
WS2 9PS
United Kingdom

Mount Vernon Hospital

Rickmansworth Road
Northwood
HA6 2RN
United Kingdom

Musgrove Park Hospital

Parkfield Drive
Taunton
TA1 5DA
United Kingdom

New Cross Hospital

Wolverhampton Road
Heath Town
Wolverhampton
WV10 0QP
United Kingdom

Ninewells Hospital

James Arrott Drive
Dundee
DD2 1SY
United Kingdom

Norfolk & Norwich University Hospital

Colney Lane
Norwich
NR4 7UY
United Kingdom

North Devon District Hospital

Raleigh Park
Barnstaple
EX31 4JB
United Kingdom

Northampton General Hospital

Cliftonville
Northampton
NN1 5BD
United Kingdom

Nottingham City Hospital

Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Peterborough City Hospital

Edith Cavell Campus
Bretton Gate
Peterborough
PE3 9GZ
United Kingdom

Pilgrim Hospital

Sibsey Road
Boston
PE21 9QS
United Kingdom

Dorset Cancer Centre

Poole Hospital NHS Foundation Trust
Longfleet Road
Poole
BH15 2JB
United Kingdom

Queen Alexandra Hospital

Portsmouth
PO6 3LY
United Kingdom

Queen Elizabeth, The Queen Mother Hospital

St Peter's Road
Margate
CT9 4AN
United Kingdom

Queen Elizabeth Hospital, King's Lynn

Gayton Road
King's Lynn
PE30 4ET
United Kingdom

Queen Elizabeth Hospital, Birmingham

Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Queen's Hospital, Burton-on-Trent

Belvedere Road
Burton-on-Trent
DE13 0RB
United Kingdom

Queen's Hospital, Romford

Rom Valley Way
Romford
RM7 0AG
United Kingdom

Royal Berkshire Hospital

21 Craven Road
Reading
RG1 5LE
United Kingdom

Royal Blackburn Hospital

Haslingden Road
Blackburn
BB2 3HH
United Kingdom

Royal Cornwall Hospital

Treliske
Truro
TR1 3LQ
United Kingdom

Royal Derby Hospital

Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Royal Devon & Exeter Hospital

Barrack Road
Exeter
EX2 5DW
United Kingdom

Royal Lancaster Infirmary

Ashton Road
Lancaster
LA1 4RP
United Kingdom

Furness General Hospital

Dalton Lane
Barrow-in-Furness
LA14 4LF
United Kingdom

The Royal Marsden Hospital

203 Fulham Road
Chelsea
London
SW3 6JJ
United Kingdom

The Royal Marsden Hospital (Sutton)

Downs Road
Sutton
SM2 5PT
United Kingdom

Royal Preston Hospital

Sharoe Green Lane North
Fulwood
Preston
PR2 9HT
United Kingdom

Royal Shrewsbury Hospital

Mytton Oak Road
Shrewsbury
SY3 8XQ
United Kingdom

Royal Stoke Hospital

Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom

Royal Surrey County Hospital

Egerton Road
Guildford
GU2 7XX
United Kingdom

Royal Sussex County Hospital

Barry Building
Eastern Road
Brighton
BN2 5BE
United Kingdom

Royal United Hospital

Combe Park
Avon
Bath
BA1 3NG
United Kingdom

Scunthorpe General Hospital

Cliff Gardens
Scunthorpe
DN15 7BH
United Kingdom

Singleton Hospital

Sketty Lane
Sketty
Swansea
SA2 8QA
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

Southend Hospital

Prittlewell Chase
Southend-on-Sea
SS0 0RY
United Kingdom

St Bartholomew's Hospital

W Smithfield
London
EC1A 7BE
United Kingdom

St George's Hospital

Blackshaw Road
London
SW17 0QT
United Kingdom

Whiston Hospital

Warrington Road
Rainhill
Prescot
L35 5DR
United Kingdom

St James's University Hospital

Beckett Street
Leeds
LS9 7TF
United Kingdom

Torbay Hospital

Newton Road
Torquay
TQ2 7AA
United Kingdom

University Hospital Coventry

Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom

Velindre Cancer Centre

Velindre Road
Cardiff
CF14 2TL
United Kingdom

Warwick Hospital

Lakin Road
Warwick
CV34 5BW
United Kingdom

West Cumberland Hospital

Homewood Road
Whitehaven
CA28 8JG
United Kingdom

Weston General Hospital

Grange Road
Weston-super-Mare
BS23 4TG
United Kingdom

Weston Park Hospital

Whitham Road
Sheffield
S10 2SJ
United Kingdom

Wexham Park Hospital

Wexham Street
Slough
SL2 4HL
United Kingdom

Worthing Hospital

Lyndhurst Road
Worthing
BN11 2DH
United Kingdom

Wrexham Maelor Hospital

Croesnewydd Road
Wrexham
LL13 7TD
United Kingdom

Yeovil District Hospital

Higher Kingston
Yeovil
BA21 4AT
United Kingdom

York Hospital

Wigginton Road
York
YO31 8HE
United Kingdom

Ysbyty Gwynedd Hospital

Bangor
LL57 2PW
United Kingdom

Good Hope Hospital

Rectory Road
Sutton Coldfield
B75 7RR
United Kingdom

Pinderfields General Hospital

Aberford Road
Wakefield
WF1 4DG
United Kingdom

Kantonsspital Frauenfeld

Pfaffenholzstrasse 4
Frauenfeld
CH-8501
Switzerland

Sponsor information

MRC Clinical Trials Unit at UCL (UK)
University/education

Institute of Clinical Trials & Methodology
90 High Holborn 2nd Floor
London
WC1V 6LJ
England
United Kingdom

Website	http://www.mrc.ac.uk/index.htm
"ROR"	https://ror.org/001mm6w73

Funders

Funder type

Charity

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

No information available

Results and Publications

Intention to publish date	30/09/2024
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
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 regard to the 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.
IPD sharing plan	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.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	ICON8 results	07/12/2019	04/12/2019	Yes	No
Results article	ICON8 quality-of-life results	01/07/2020	05/07/2020	Yes	No
Plain English results	ICON8	11/01/2018	25/01/2022	No	Yes
Results article	ICON8 overall survival and progression-free survival results	08/06/2022	13/06/2022	Yes	No
HRA research summary	ICON8		28/06/2023	No	No

Editorial Notes

14/12/2023: The outputs table has been updated to clarify which study the outputs relate to.
07/12/2023: The following changes were made to the study record:
1. Ethics approval details added.
2. The target number of participants was changed from 2655 to 1485 (ICON8); 590 (ICON8B).
3. The total final enrolment was changed from 1566 to 2144.
4. The recruitment end date was changed from 01/05/2019 to 08/04/2020.
5. Publication and dissemination plan updated.
6. The intention to publish date was changed from 30/09/2019 to 30/09/2024.
13/06/2022: Publication reference added.
25/01/2022: The Cancer Research UK lay results summary has been added.
01/10/2021: The following changes have been made:
1. The overall trial end date has been changed from 01/05/2022 to 31/12/2024.
2. The interventions have been updated.
3. The primary outcome measure has been updated.
4. The secondary outcome measures have been updated.
5. The participant information sheet contact email has been updated.
6. The trial participating centre "Kantonsspital Frauenfeld" has been added.
7. The ICON8B scientific title has been changed from "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" to "ICON8B: A phase III randomised trial investigating the combination of dose-fractionated chemotherapy and bevacizumab compared to standard three weekly chemotherapy and bevacizumab for the first-line treatment of women with newly diagnosed high-risk stage III-IV epithelial ovarian, fallopian tube or primary peritoneal cancer".
05/07/2020: Publication reference added.
04/12/2019: Publication reference and total final enrolment number added.
06/12/2018: The postcode for Lister Hospital has been corrected.
23/11/2018: As of today, all sites are open to recruitment for ICON8b only.
The following changes have been made to the trial record:
1. Emma Kent has been removed as a contact
2. Francesca Schiavone has been removed as a contact
3. Andrew Clamp has been added as a contact
4. MRC Clinical Trials Unit at UCL was removed as a trial participating centre
5. The following trial participating centres have been added: Aberdeen Royal Infirmary, Addenbrooke's Hospital, Airedale General Hospital, Beatson West of Scotland Cancer Centre, Bedford Hospital, Belfast City Hospital, Birmingham Heartlands Hospital, Blackpool Victoria Hospital, Bradford Royal Infirmary, Bristol Haematology & Oncology Centre, Broomfield Hospital, Huddersfield Royal Infirmary, Castle Hill Hospital, Cheltenham General Hospital, Christie Hospital, Churchill Hospital, City Hospital, Clatterbridge Cancer Centre, County Hospital, Cumberland Infirmary, Diana Princess of Wales Hospital, Doncaster Royal Infirmary, Dorset County Hospital, Essex County Hospital, Freeman Hospital, George Eliot Hospital, Glan Clwyd Hospital, Gloucestershire Royal Hospital, Great Western Hospital, Guy's & St. Thomas' Hospital, Hammersmith Hospital, Hereford County Hospital, Hinchingbrooke Hospital, Ipswich Hospital, James Cook University Hospital, James Paget Hospital, Leicester Royal Infirmary, Lincoln County Hospital, Lister Hospital, Liverpool Women's Hospital, Maidstone Hospital, Walsall Manor Hospital, Mount Vernon Hospital, Musgrove Park Hospital, New Cross Hospital, Ninewells Hospital, Norfolk & Norwich University Hospital, North Devon District Hospital, Northampton General Hospital, Nottingham City Hospital, Peterborough City Hospital, Pilgrim Hospital, Dorset Cancer Centre, Queen Alexandra Hospital, Queen Elizabeth The Queen Mother Hospital, Green Elizabeth Hospital King's Lynn, Queen Elizabeth Hospital Birmingham, Queen's Hospital Burton-on-Trent, Queen's Hospital Romford, Royal Berkshire Hospital, Royal Blackburn Hospital, Royal Cornwall Hospital, Royal Derby Hospital, Royal Devon & Exeter Hospital, Royal Lancaster Infirmary, Furness General Hospital, Royal Marsden Hospital, Royal Marsden Hospital (Sutton), Royal Preston Hospital, Royal Shrewsbury Hospital, Royal Stoke Hospital, Royal Surrey County Hospital, Royal Sussex County Hospital, Royal United Hospital, Scunthorpe General Hospital, Singleton Hospital, Southampton General Hospital, Southend Hospital, St Bartholomews Hospital, St George's Hospital, Whiston Hospital, St James's University Hospital, Torbay Hospital, University Hospital Coventry, Velindre Cancer Centre, Warwick Hospital, West Cumberland Hospital, Weston General Hospital, Weston Park Hospital, Wexham Park Hospital, Worthing Hospital, Wrexham Maelor Hospital, Yeovil District Hospital, York Hospital, Ysbyty Gwynedd Hospital, Good Hope Hospital, Pinderfields General Hospital
6. The intention to publish date has been added
13/09/2018: The trial website has been added.
12/09/2018: The following changes have been made:
1. Francesca Schiavone has been added as the public contact.
2. The NCT code has been added.
3. The participant inclusion criteria have been changed.
4. The participant exclusion criteria have been changed.
5. The Institute of Clinical Trials & Methodology address has been changed in the trial centres and sponsor details.
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