Condition category
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
Publication status

Contact information



Primary contact

Prof Heinrich Heimann


Contact details

Liverpool University
United Kingdom



Additional contact

Mr Tony Coffey


Contact details

North West Surgical Trials Centre
Cancer Research UK Liverpool Clinical Trials Unit
Block C
Waterhouse Building
1-3 Brownlow Street
L69 3GL
United Kingdom
+44 151 794 8929

Additional identifiers

EudraCT number

2011-000961-10 number

Protocol/serial number


Study information

Scientific title

Neoadjuvant IntraviTreal Ranibizumab treatment in high-risk Ocular melanoma patients: a two-stage single-centre phase II single arm study (NITRO trial)



Study hypothesis

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.

Ethics approval

11/NW/0656; First MREC approval date 07/12/2011

Study design

Non-randomised; Interventional; Design type: Treatment

Primary study design


Secondary study design

Non randomised study

Trial setting


Trial type


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.

Intervention type



Phase II

Drug names


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

Participant type


Age group




Target number of participants

Planned Sample Size: 25; UK Sample Size: 25

Total final enrolment


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

United Kingdom

Trial participating centre

Liverpool CR-UK Centre - Waterhouse Building
L69 3GL
United Kingdom

Sponsor information


Royal Liverpool and Broadgreen University Hospitals NHS Trust (UK)

Sponsor details

The Walton Centre for Neurology and Neurosurgery
Prescot Street
L7 8XP
United Kingdom

Sponsor type

Hospital/treatment centre



Funder type


Funder name

Cancer Research UK (CRUK) (UK)

Alternative name(s)


Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit


United Kingdom

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)

See: (added 07/11/2019)

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.

Publication list

2019 results in: (added 07/11/2019)

Publication citations

Additional files

Editorial Notes

07/11/2019: The following changes were made to the trial record: 1. Publication reference added. 2. The total final enrolment was added. 07/06/2018: The following changes have been made: 1. The trial status and recruitment status have been changed to 'stopped'. 2. A publication and dissemination plan has been added. 3. An intention to publish date has been added. 4. Basic results have been added. 5. Tony Coffey has been added as a public contact and Lucy Delaney has been replaced as scientific contact by Prof Heinrich Heimann. 23/05/2016: No publications found, verifying study status with principal investigator.