Plain English Summary
Prof Heinrich Heimann
Mr Tony Coffey
North West Surgical Trials Centre
Cancer Research UK Liverpool Clinical Trials Unit
1-3 Brownlow Street
+44 151 794 8929
Neoadjuvant IntraviTreal Ranibizumab treatment in high-risk Ocular melanoma patients: a two-stage single-centre phase II single arm study (NITRO trial)
NITRO is a two stage phase II non-randomised single centre trial. The trial will recruit patients who require radical treatment (e-nucleation) due to tumour size. Participants will receive 0.5mg in 0.05ml ranibizumab as an intravitreal injection on day 1 of treatment. Tumour assessment will follow 28 days later and one of the following three decisions will be made.
1. If the tumour shows an increase in size, the patient will stop trial treatment and eye removal will be planned.
2. If the assessment shows a reduction in tumour size that may allow for eye sparing treatment (such as endoresection or radiotherapy), the patient will stop trial treatment and appropriate eye sparing treatment will be planned.
3. If a small response or the tumour size has remained stable, the patient may have a further dose of Ranibizumab. Up to 6 doses of trial treatment may be given.
All patients will be followed at 6 weeks, 3 months and 6 months following surgery/radiotherapy. Translational samples will be taken at first treatment (day 1) (blood sample, intravitreous fluid sample and tumour biopsy). A second tumour biopsy and intravitreous fluid sample will be taken at final surgery. A second translational blood sample will be taken at the 6 month follow-up.
The primary outcome of the trial is to determine the response rate of intravitreal Ranibizumab in high risk Ocular melanoma patients. The secondary outcomes are to explore relationships between ultrasonographic response, serum and intravitreous VEGF levels.
11/NW/0656; First MREC approval date 07/12/2011
Non-randomised; Interventional; Design type: Treatment
Primary study design
Secondary study design
Non randomised study
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet
Topic: National Cancer Research Network; Subtopic: Melanoma; Disease: Melanoma
Ranibizumab, Intravitreal injection of 0.5mg in 0.05ml Ranibizumab; Follow Up Length: 6 month(s); Study Entry: Registration only
14 patients will be recruited in the first stage of the trial. The trial will be paused after recruitment and treatment of patient 14. A further 11 patients will be recruited if there are any responders to treatment identified in the first stage.
Primary outcome measure
Response Rate; Timepoint(s): Response will be measured per patient every 28 days after treatment. Maximum of 6 treatments.
Secondary outcome measures
To explore relationships between ultrasonographic response, serum and intravitreous VEGF levels
Overall trial start date
Overall trial end date
Reason abandoned (if study stopped)
Participant recruitment issue
Participant inclusion criteria
1. Confirmed diagnosis of uveal melanoma requiring enucleation
2. Must have ultrasonographically documented measurable disease within 4 weeks of treatment according to the WHO criteria
3. Prior treatments with chemotherapeutic or antiangiogenic agents for other malignancies are allowed after 6 months of discontinuation
4. Age >=18 years
5. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
6. Platelets ≥100,000mm3
7. White cell count (WCC) ≥ 3.0 x 109/L
8. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
9. Bilirubin < twice normal, Alkaline Phosphatase < 5 x normal
10. International Normalized Ratio (INR) < 2
11. Cr ≤1.5 ULN
12. Normal blood pressure or controlled hypertension
13. No recent major surgical procedures (laparotomy or thoracotomy) within 4weeks
14. No thromboembolic event within 6 months
15. No known coagulopathy disorder
16. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and followup
schedule; those conditions should be discussed with the patient before registration in the trial
17. Before patient registration, written informed consent must be given according to ICH/GCP, and national regulations
18. Previous or present vascular intraocular diseases not requiring use of antiangiogenic agents will be allowed
19. Hb ≥ 10g/dl
Target number of participants
Planned Sample Size: 25; UK Sample Size: 25
Participant exclusion criteria
1. Serious underlying medical condition according to the judgement of the Principal Investigator
2. Pregnant or nursing patients
3. Inability to provide adequate informed consent
4. Hypersensitivity to the active substance or to any of the excipients
5. Active or suspected ocular or periocular infections
6. Active severe intraocular inflammation
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
Liverpool CR-UK Centre - Waterhouse Building
Royal Liverpool and Broadgreen University Hospitals NHS Trust (UK)
The Walton Centre for Neurology and Neurosurgery
Cancer Research UK (CRUK) (UK)
Funding Body Type
private sector organisation
Funding Body Subtype
Results and Publications
Publication and dissemination plan
To be submitted to an ophthalmology journal in June 2018.
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
A total of 7 patients were recruited to the study, with a median age of 66 years. There were 5 males and 2 females . Duration of symptoms was 6 months (mean, range 3-9 months). At baseline, the longest basal diameter was 15.1 mm (mean, range 10-20.4 mm) with a height measured by ultrasonography of 8.6 mm (mean, range 4-12.7mm). Exudative retinal detachment was present in one patient. Visual acuity was 87 letters (ETDRS) (mean, range 104 letters-counting fingers).
No patients achieved complete or partial response at any visit. The study was therefore abandoned and no further patients were recruited. 0/7 patients completed the 6 injections, all withdrew early due to either patient choice or objective progression judged clinically. The last tumour dimensions prior to enucleation were longest basal diameter 15.6 mm (mean, range 12.2-19.9 mm) and height 9.2 mm (mean, range 4.6-12.5).
All patients subsequently underwent enucleation with no complications. Histopathological analysis revealed mixed cell melanoma in 5/7 (71%) and spindle cell morphology in 2/7 (29%) with ciliary body involvement in 4/7 (57%) and the presence of closed loops also in 4/7 (57%). Genetic analysis demonstrated loss of chromosome 3 in 5/7 (71%) but abnormalities in chromosome 1,6 or 8 in all cases.