Difficulties in recruiting patients due to changing in treatment standards for the target population

While 95% of patients with retinoblastoma can be cured nowadays, treatment of relapse remains challenging, ending often in enucleation and/or radiotherapy. In the last 10 years, new treatment modalities have been developed to give the chance of cure also in relapse, avoiding enucleation which results in esthetic sequelae and orbital growth problems, and radiotherapy which significantly increases the risk of secondary cancers in hereditary retinoblastoma. The current protocol aims at covering all types of relapses in retinoblastoma, with treatments adapted to the site of relapse, at harmonizing the new eye- and vision-preserving treatment procedures, and evaluating their efficacy and toxicity.

The study aims at improving treatment of patients with recurrent Rb through a specific approach according to the site of relapse and a uniform and well-defined treatment schedule. A precise observation of early, intermediate and long-term toxic effects with treatment recommendation will be done. For intravitreal relapse, the trial will focus on a randomization between melphalan (standard) and topotecan (investigational). For retinal / diffuse subretinal relapse in patients not having received prior IAC, it will focus on a randomization between IAC melphalan only and IAC combining melphalan+topotecan. For vitreous and retinal relapse the treatment will be a sequential administration of intravitreous and intraarterial injections (observational patients).

The duration of patient recruitment is 3 years, the duration of patient follow-up for study purposes is until at least 2 years after end of current relapse treatment. A long-term follow-up of at least 10 years on a regular basis will be proposed at the end of the study, with the aim to record the occurrence of secondary malignancies, metastases and long term sequelae.

The overall objective is to provide a conservative eye-preserving treatment for pediatric patients with Rb who have failed prior standard treatments and have no other option than enucleation and/or EBR, to preserve functional vision and to limit general and ocular toxicity.

Primary objectives

A. To reduce the incidence of retinal toxicity in IVitC treatment while retaining similar efficacy of tumor control, in vitreous relapse.

B. To reduce further relapse by IAC with melphalan+topotecan compared to IAC with melphalan only in patients not having received prior IAC and presenting retinal / diffuse subretinal relapse.

The primary outcome, on which the sample size calculation is based, is the rate of retinal toxicity following IVitC treatment with melphalan as compared to topotecan. Currently a retinal toxicity rate of 40% is reported with melphalan. Topotecan is reportedly less toxic and the investigators expect a retinal toxicity of 10% or less. To have 90% power of detecting a reduction of 30% in retinal toxicity at the 5% level of significance, 43 patients are required in each arm. Allowing for a 5% drop out rate per year for 3 years, the investigators estimate that 50 patients are required in each of arm of this study. Concerning the second primary objective the investigators postulate that the eye salvage rate can be increased by adding topotecan to melphalan from overall 67% to 84% at 2 years. A randomized 2:1 (arm with association Topotecan-Melphalan and arm with Melphalan only, respectively) non comparative phase II will be performed. In the Topotecan and Melphalan arm, 67% (p0) or less of eye salvage rate is considered as ineffective, 84% (p1) as active. 64 patients will be included in the Topotecan and Melphalan arm, with a type one error of 7% and a type two error of 5%.

Inclusion Criteria:

1. Eye with recurrent Rb clinically defined as one or the combination of the following:

   • vitreous recurrence only
   • retinal / diffuse subretinal relapse only not amenable to focal treatment such as thermotherapy, cryotherapy or plaque
   • combined vitreous and retinal/diffuse subretinal relapse

2. Minimally required interval between study entry and time of the last treatment: 2 months (with a monthly follow-up), except for small retinal / subretinal tumors treated focally, not related to the current relapse

3. Photographic documentation of fundus at study entry

4. Registration into the study and start of treatment must occur no later than 14 days after diagnosis of recurrence

5. Mandatory ultrasound biomicroscopy (UBM) at 35 or 50 MHz in case of opaque media or insufficient pupillary dilatation for evaluation of the posterior chamber / pars plana

6. Age ≥3 months and < 11 years (10.99)

7. Weight ≥5 kg (in case of IAC eligibility or sequential IVitC/IAC eligibility)

8. Possibility of follow-up until at least 2 years after end of current relapse treatment

9. Written informed consent by parents or legal representative before enrolment

Exclusion Criteria:

1. Relapse with any uveal involvement and/or anterior chamber involvement

2. Indication for another treatment option according to investigator's judgement

3. Clinical/MRI signs of extraocular disease, including metastatic disease

4. Inadequate organ function (in case of IAC or sequential IVitC / IAC eligibility):

   • absolute neutrophils count <0.5 G/l
   • thrombocytes count <100 G/l
   • creatinine above normal value for age
   • ALAT more than 2x above upper normal limit
   • bilirubin above upper normal limit

5. Other (simultaneous) malignancies

6. Contraindication or known hypersensitivity to study drugs

7. Severe concomitant diseases (e.g. immune deficiency syndrome)

8. Current or recent (within 30 days prior to date of written informed consent) treatment with another investigational drug or participation in another interventional clinical trial