ICON8: Newly diagnosed high risk early stage (FIGO stage IC/IIA, grade 3 or clear cell histology only) or advanced stage (FIGO stage IIB-IV, all grades and all histological types) epithelial ovarian, fallopian tube or primary peritoneal carcinoma. ICON8B:Patients with newly diagnosed, histologically confirmed high-risk stage III-IV ovarian cancer: FIGO (2013) stage IIIA-C disease with >1cm residual disease following IPS or those planned to undergo primary chemotherapy with or without DPS. Med
Conditions
Interventions
Trade Name: Carboplatin
Product Name: Carboplatin
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Carboplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equa
Sponsors
University College London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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): • Epithelial ovarian carcinoma • Primary peritoneal carcinoma of Müllerian histological type • Fallopian tube carcinoma • Ovarian carcinosarcoma (malignant mixed Müllerian tumour (MMMT) of the ovary) 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 • High grade serous carcinoma • Clear cell carcinoma • 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 • Absolute Neutrophil Count > 1.5 x 10^9/l • Platelets (Plt) > 100 x 10^9/l • Haemoglobin (Hb) > 9g/dl (can be post transfusion) 9. Adequate liver function (within 28 days prior to randomisation) • Serum bilirubin = 1.5 x ULN • 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: • Directly measured GFR (Glomerular Filtration Rate) = 30 ml/min, or • Calculated creatinine clearance = 60 ml/min NB. If the calculated creatinine clearance is 10mm in diameter, IIIB or IIIC disease i.With >1cm residual disease following IPS or ii.Planned to undergo primary chemotherapy with or without DPS •FIGO Stage IV disease: i.With any volume of residual disease following IPS or ii.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: •Absolute Neutrophil Count (ANC) ?1.5 x 109/l •Platelets (Plt) ?100 x 109/l •Haemoglobin (Hb) ?9g/dl (can be post transfusion) 8.Adequate liver function: •Serum bilirubin (BR) ?1.5 x ULN •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: •Directly measured GFR (Glomerular Filtration Rate) = 30 ml/min, or •Calculated creatinine clearance = 60 ml/min NB. If the calculated creatinine clearance is <60 ml/min the GFR should be directly measured using either a 24 hour urine collection or an isotopic evaluation 10.Adequate coagulation profile: •International normalised ratio (INR) =1.5 •Activated prothrombin time (APTT) =1.5xU
Exclusion criteria
Exclusion criteria: ICON8 Exclusion Criteria: 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: • adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous 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. 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 Additional Exclusion Criteria for ICON8B: 1.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. 2.Significant co-existing or previous medical conditions that are contra-indications to treatment with bevacizumab, including: a.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 b.Cardiovascular disease as follows: i.Uncontrolled hypertension, defined as sustained BP>150/100mmHg while receiving anti-hypertensive medication ii.Myocardial infarction or unstable angina within 6 months prior to randomization iii.New York Heart Association (NYHA) grade =2 congestive heart failure iv.Poorly controlled cardiac arrhythmia despite medication NB. Patients with rate-controlled atrial fibrillation are eligible v.Peripheral vascular disease grade =3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision c.History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication) d.Recent hi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives of the ICON8 Trials Programme are to test: 1.Whether dose-fractionated chemotherapy is more effective than standard 3-weekly treatment for women with FIGO stage IC-IV ovarian cancer. (ICON8) 2.Whether the combination of bevacizumab plus dose-fractionated chemotherapy will prolong progression-free survival compared to bevacizumab or dose-fractionation alone for women with high-risk stage III-IV ovarian cancer. If superiority of the combination is not shown, to assess evidence for the non-inferiority of dose-fractionated chemotherapy to standard 3-weekly chemotherapy + bevacizumab. (ICON8B) In ICON8 there are the three stages of trial analyses, each with different principal research objectives outlined below: 1. In stage 1, to determine the feasibility and safety of the two dose-fractionated carboplatin-paclitaxel regimens in the first-line treatment of ovarian cancer. This will be assessed in approximately the first 150 women entering the trial and addition;Secondary Objective: Secondary objectives in the 3rd stage analysis of ICON8 are: 1. To assess the impact of each of the dose-fractionated regimens on the safety and toxicity of carboplatin-paclitaxel combination chemotherapy compared to the standard treatment schedule. 2. To assess the impact of dose-fractionated chemotherapy on patients’ quality of life, both while receiving chemotherapy and during follow-up after its completion. 3. To evaluate the cost-effectiveness of the dose-fractionated regimens. Secondary objectives in the 2nd stage analysis of ICON8B are: 1. To assess the impact on the safety and toxicity of dose fractionated carboplatin-paclitaxel + bevacizumab regimens compared to the standard treatment schedule and dose-fractionated chemotherapy alone. 2. To assess the impact of dose-fractionated chemotherapy+bevacizumab on patients’ quality of life, both while receiving protocol defined treatment and during follow-up after its completion. 3. To | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The ICON8B analyses will compare the three randomised arms on the following outcome measures: -Overall survival (OS) | — |
Countries
Ireland, United Kingdom
Outcome results
None listed