| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Newly diagnosed ovarian cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10016183 |
| E.1.2 | Term | Fallopian tube cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033159 |
| E.1.2 | Term | Ovarian epithelial cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052171 |
| E.1.2 | Term | Peritoneal carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective 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) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives in the 3rd stage analysis of ICON8:
1. Assess the impact of each of the dose-fractionated regimens on the safety and toxicity of carboplatin-paclitaxel combination chemotherapy vs the standard treatment schedule.
2. Assess the impact of dose-fractionated chemotherapy on patients' quality of life, both while receiving chemotherapy and during follow-up.
3. Evaluate the cost-effectiveness of the dose-fractionated regimens.
Secondary objectives in the 2nd stage analysis of ICON8B:
1. Assess the impact on the safety & toxicity of dose fractionated carboplatin-paclitaxel + bevaciumab regimens vs the standard treatment schedule & dose-fractionated chemotherapy alone.
2. Assess the impact of dose-fractionated chemotherapy + bevacizumab on patients' quality of life, both while receiving protocol defined treatment and during follow-up.
3. Evaluate the cost-effectiveness of the dose-fractionated regimens.
4. Prolonged overall survival.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Translational Research Substudy of ICON8 (TRICON8) and ICON8B (TRICON8B). Details of the substudy can be found in the ICON8 trials programme protocol. The aim of the TRICON8 programme is to establish a large, comprehensive biobank comprising tumour tissue, blood and serial plasma with associated clinical data which will be an invaluable resource for high-quality translational research in ovarian cancer. |
|
| E.3 | Principal 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 <60 ml/min the GFR should be directly measured using either a 24 hour urine collection or an isotopic evaluation
11. Able to start chemotherapy within 8 weeks after immediate primary surgery (where applicable)
ICON8B Inclusion Criteria:
1. Females aged 18 years or 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. High –risk disease defined as
• FIGO (2013) Stage IIA1(ii), IIA2 with positive retroperitoneal lymph nodes >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 10^9/l
• Platelets (Plt) ≥100 x 10^9/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 ≥60ml/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) ≤1.5 x ULN
11. Able to start chemotherapy within 8 weeks after IPS (where applicable)
|
|
| E.4 | Principal 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>150/100mgHg while receiving anti-hypertensive medication
ii. Myocardial infarction or unstable angina within 6 months prior to randomisation
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 history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohns’ Disease and ulcerative colitis)
e. Previous gastrointestinal perforation
3. Chronic daily use of high-dose aspirin, >325mg/day, within 10 days prior to study entry
4. 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.
5. Serious non-healing wound, worse than CTCAE Wound Complication or Wound Dehiscence grade 1
6. Active ulcer or bone fracture
7. Anticipated to require extensive dental work during protocol treatment
8. Clinical symptoms of radiological evidence of bowel obstruction (including sub-acute obstruction) or extensive rectosigmoid involvement on imaging related to ovarian cancer
9. Evidence of intra-abdominal free air not explained by paracentesis or recent surgical procedure
10. Symptomatic abdominal fistulae
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The ICON8 analyses will have 3 stages. The outcome measures for each stage are as follows:
Stage 1: Feasibility and safety
Stage 2: 9 month progression-free survival rate
Stage 3: Progression-free survival and overall survival (dual primary outcome measures)
The ICON8B analyses will compare the three randomised arms on the following outcome measures:
-Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ICON8:
1. In stage 1, feasibility and safety will be assessed in approximately the first 150 women entering the trial and additionally in approximately the first 150 women who enter the trial with a plan to undergo delayed primary surgery during chemotherapy.
2. In stage 2, 9 month PFS rate will be assessed in approximately the first 186 women to enter the trial.
3. In stage 3, PFS and OS will be assessed in terms of whether the dose fractionated regimens result in prolonged progression free survival and overall survival.
ICON8B:
1. In stage 1, safety of bevacizumab in combination with DPS will be assessed.
2. In stage 2, PFS and OS will be assessed. |
|
| E.5.2 | Secondary end point(s) |
The ICON8B analyses will compare the three randomised arms on the following outcome measures:
-Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| An Independend Data Monitoring Committee (IDMC) will review data, unblinded by treatment group, on patients in the trial. The IDMC will meet at least annually during the accrual period and around the time that the planned first and second stage analyses are performed. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Korea, Republic of |
| Mexico |
| New Zealand |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The trial will be considered closed for regulatory purposes after data on overall survival are sufficiently mature for the
primary publication. This is to ensure that the standard of follow up and data collection conforms to the trial protocol
until the primary outcome measures are reported. Further observational follow up of all patients enrolled in the trial
may continue indefinitely. This will initially be via hospitals and clinics, but in the longer term may exploit national
registers. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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