ICON8B Eligibility criteria

Patients recruited onto the ICON8B trial were required to meet the following criteria:

Patient inclusion criteria

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):

• 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 IIIA1(ii), IIIA2 with positive retroperitoneal lymph nodes >10mm in diameter, IIIB or IIIC disease

1. With >1cm residual disease following IPS or
2. Planned to undergo primary chemotherapy with or without DPS

• FIGO Stage IV disease

1. With any volume of residual disease following IPS or
2. Planned to undergo primary chemotherapy with or without DPS.

 

5. The FIGO 2013 staging system should be used for women entering ICON8B (see Appendix 2 of protocol V5.0). Stage may be based on clinical and radiological assessment in patients who have not undergone IPS.

 

5. ECOG Performance Status (PS) 0-2

 

6. Life expectancy >12 weeks

 

7. Adequate bone marrow function:

• Absolute Neutrophil Count (ANC) >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) <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.

 

1. 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) ≤1.5xULN.

 

11. Able to start chemotherapy within 8 weeks after IPS (where applicable).

 

Patient Exclusion Criteria

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:

1. adequately treated carcinoma in-situ of the cervix, breast ductal carcinoma in-situ, non-melanomatous skin cancer; or
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.

 

1. 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:

 

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

 

1. Cardiovascular disease as follows:
   1. Uncontrolled hypertension, defined as sustained BP>150/100mmHg while receiving anti-hypertensive medication

 

1. 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

 

1. Myocardial infarction or unstable angina within 6 months prior to randomization

• New York Heart Association (NYHA) grade ≥2 congestive heart failure

1. Poorly controlled cardiac arrhythmia despite medication

 

1. Patients with rate-controlled atrial fibrillation are eligible

 

1. Peripheral vascular disease grade ≥3, i.e. symptomatic and interfering with activities of daily living requiring repair or revision

 

1. History or evidence of bleeding diathesis or coagulopathy (in patients not on therapeutic anti-coagulant medication)

 

1. Recent history of proven active peptic ulcer disease, diverticulitis or inflammatory bowel disease (Crohns’ Disease and ulcerative colitis)

 

1. 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

 

1. 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.