A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma (EuRbG2018)

September 28, 2023 updated by: Prof. Beck Popovic Maja

A Phase II Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma, With Randomization Depending on the Site of Relapse or on Previous Treatment

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.

Study Overview

Status

Terminated

Intervention / Treatment

Detailed Description

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%.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Lausanne, Switzerland, 1011
        • CHUV Lausanne University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 months to 11 years (Child)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Treatment 1a
IVitC melphalan (randomized) in case of vitreous relapse only
intravitreal or intra-arterial administration of topotecan
Other Names:
  • alkeran
Experimental: Treatment 1b
IVitC topotecan (randomized) in case of vitreous relapse only
intravitreal or intra-arterial administration of topotecan
Other Names:
  • hycamtin
Active Comparator: Treatment 2a
IAC melphalan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
intravitreal or intra-arterial administration of topotecan
Other Names:
  • alkeran
Experimental: Treatment 2b
IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
intravitreal or intra-arterial administration of topotecan
Other Names:
  • alkeran
intravitreal or intra-arterial administration of topotecan
Other Names:
  • hycamtin
No Intervention: Treatment 2c
IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with prior intra-arterial treatment
No Intervention: Treatment 3a
sequential administration of IVitC melphalan and IAC melphalan in case of combined vitreous and retinal/diffuse subretinal relapse, if no pretreatment with intra-arterial treatment
No Intervention: Treatment 3b
sequential administration of IVitC melphalan and IAC melphalan and topotecan, in case of combined vitreous and retinal/diffuse subretinal relapse, if prior pretreatment with intra-arterial treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of retinal toxicity of intravitreous administration of melphalan versus topotecan assessed by CTCAE v5.0
Time Frame: at 1 month after treatment completion
parameters: salt and pepper retinopathy, choroidopathy, number of injections until toxicity
at 1 month after treatment completion
Relapse rate after IAC by melphalan only and IAC by melphalan + topotecan
Time Frame: at 2 years of follow-up
parameter: eye retention rate
at 2 years of follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of intravitreous topotecan compared to intravitreous melphalan (number of injections to tumor clearance in vitreous)
Time Frame: at 3 or 6 months after last intravitreous injection
Parameter: number of injections to tumor clearance in vitreous
at 3 or 6 months after last intravitreous injection
Ocular survival (eye salvage rate)
Time Frame: at 2 years since study entry
parameters: enucleation and EBR
at 2 years since study entry
Number of participants with ocular (non retinal) and systemic toxicity assessed by CTCAE v5.0
Time Frame: Weekly (IVitC) or monthly (IAC) during treatment, at end of treatment (1 month after last injection), at 6, 12 and 24 months, yearly until 60 months
parameter: number of participants
Weekly (IVitC) or monthly (IAC) during treatment, at end of treatment (1 month after last injection), at 6, 12 and 24 months, yearly until 60 months
Quality of vision assessed by visual acuity
Time Frame: at 5 years of age
parameters: Logmar values
at 5 years of age
Incidence of early (within 1 month), intermediate (2-12 months) and late (> 12 months) ocular and systemic general adverse events during regular ophthalmological and clinical examinationassessed by CTCAE v5.0
Time Frame: Weekly (IVitC) or monthly (IAC) during treatment, at end of treatment (1 month after last injection), at 6, 12 and 24 months, yearly until 60 months
parameter: incidence
Weekly (IVitC) or monthly (IAC) during treatment, at end of treatment (1 month after last injection), at 6, 12 and 24 months, yearly until 60 months
Quantification of the cumulative radiation exposure during the IAC procedures by routinely used devices (sub-study limited to Lausanne) by B three thermoluminescent dosimeters
Time Frame: at 1 month after the last IAC
parameter: B three thermoluminescent dosimeters
at 1 month after the last IAC
Incidence of the occurrence of secondary malignancies and/or metastases and long term sequelae
Time Frame: during a follow-up of at least 10 years
parameter: incidence
during a follow-up of at least 10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Maja Beck Popovic, Prof, Lausanne University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2021

Primary Completion (Actual)

May 22, 2023

Study Completion (Actual)

May 22, 2023

Study Registration Dates

First Submitted

April 24, 2020

First Submitted That Met QC Criteria

June 29, 2020

First Posted (Actual)

July 2, 2020

Study Record Updates

Last Update Posted (Actual)

October 3, 2023

Last Update Submitted That Met QC Criteria

September 28, 2023

Last Verified

September 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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