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

Primary Purpose

Eye Cancer, Retinoblastoma

Status
Terminated
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Topotecan
Melphalan
Sponsored by
Prof. Beck Popovic Maja
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Eye Cancer, Retinoblastoma focused on measuring relapsed retinoblastoma, relapse of retinoblastoma

Eligibility Criteria

3 Months - 11 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • CHUV Lausanne University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

No Intervention

No Intervention

No Intervention

Arm Label

Treatment 1a

Treatment 1b

Treatment 2a

Treatment 2b

Treatment 2c

Treatment 3a

Treatment 3b

Arm Description

IVitC melphalan (randomized) in case of vitreous relapse only

IVitC topotecan (randomized) in case of vitreous relapse only

IAC melphalan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment

IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment

IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with prior intra-arterial treatment

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

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

Outcomes

Primary Outcome Measures

Rate of retinal toxicity of intravitreous administration of melphalan versus topotecan assessed by CTCAE v5.0
parameters: salt and pepper retinopathy, choroidopathy, number of injections until toxicity
Relapse rate after IAC by melphalan only and IAC by melphalan + topotecan
parameter: eye retention rate

Secondary Outcome Measures

Efficacy of intravitreous topotecan compared to intravitreous melphalan (number of injections to tumor clearance in vitreous)
Parameter: number of injections to tumor clearance in vitreous
Ocular survival (eye salvage rate)
parameters: enucleation and EBR
Number of participants with ocular (non retinal) and systemic toxicity assessed by CTCAE v5.0
parameter: number of participants
Quality of vision assessed by visual acuity
parameters: Logmar values
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
parameter: incidence
Quantification of the cumulative radiation exposure during the IAC procedures by routinely used devices (sub-study limited to Lausanne) by B three thermoluminescent dosimeters
parameter: B three thermoluminescent dosimeters
Incidence of the occurrence of secondary malignancies and/or metastases and long term sequelae
parameter: incidence

Full Information

First Posted
April 24, 2020
Last Updated
September 28, 2023
Sponsor
Prof. Beck Popovic Maja
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1. Study Identification

Unique Protocol Identification Number
NCT04455139
Brief Title
A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma
Acronym
EuRbG2018
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Terminated
Why Stopped
Difficulties in recruiting patients due to changing in treatment standards for the target population
Study Start Date
November 15, 2021 (Actual)
Primary Completion Date
May 22, 2023 (Actual)
Study Completion Date
May 22, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Prof. Beck Popovic Maja

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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%.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Eye Cancer, Retinoblastoma
Keywords
relapsed retinoblastoma, relapse of retinoblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment 1a
Arm Type
Active Comparator
Arm Description
IVitC melphalan (randomized) in case of vitreous relapse only
Arm Title
Treatment 1b
Arm Type
Experimental
Arm Description
IVitC topotecan (randomized) in case of vitreous relapse only
Arm Title
Treatment 2a
Arm Type
Active Comparator
Arm Description
IAC melphalan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
Arm Title
Treatment 2b
Arm Type
Experimental
Arm Description
IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
Arm Title
Treatment 2c
Arm Type
No Intervention
Arm Description
IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with prior intra-arterial treatment
Arm Title
Treatment 3a
Arm Type
No Intervention
Arm Description
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
Arm Title
Treatment 3b
Arm Type
No Intervention
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Topotecan
Other Intervention Name(s)
hycamtin
Intervention Description
intravitreal or intra-arterial administration of topotecan
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
alkeran
Intervention Description
intravitreal or intra-arterial administration of topotecan
Primary Outcome Measure Information:
Title
Rate of retinal toxicity of intravitreous administration of melphalan versus topotecan assessed by CTCAE v5.0
Description
parameters: salt and pepper retinopathy, choroidopathy, number of injections until toxicity
Time Frame
at 1 month after treatment completion
Title
Relapse rate after IAC by melphalan only and IAC by melphalan + topotecan
Description
parameter: eye retention rate
Time Frame
at 2 years of follow-up
Secondary Outcome Measure Information:
Title
Efficacy of intravitreous topotecan compared to intravitreous melphalan (number of injections to tumor clearance in vitreous)
Description
Parameter: number of injections to tumor clearance in vitreous
Time Frame
at 3 or 6 months after last intravitreous injection
Title
Ocular survival (eye salvage rate)
Description
parameters: enucleation and EBR
Time Frame
at 2 years since study entry
Title
Number of participants with ocular (non retinal) and systemic toxicity assessed by CTCAE v5.0
Description
parameter: number of participants
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
Title
Quality of vision assessed by visual acuity
Description
parameters: Logmar values
Time Frame
at 5 years of age
Title
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
Description
parameter: incidence
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
Title
Quantification of the cumulative radiation exposure during the IAC procedures by routinely used devices (sub-study limited to Lausanne) by B three thermoluminescent dosimeters
Description
parameter: B three thermoluminescent dosimeters
Time Frame
at 1 month after the last IAC
Title
Incidence of the occurrence of secondary malignancies and/or metastases and long term sequelae
Description
parameter: incidence
Time Frame
during a follow-up of at least 10 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Months
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 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 Photographic documentation of fundus at study entry Registration into the study and start of treatment must occur no later than 14 days after diagnosis of recurrence 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 Age ≥3 months and < 11 years (10.99) Weight ≥5 kg (in case of IAC eligibility or sequential IVitC/IAC eligibility) Possibility of follow-up until at least 2 years after end of current relapse treatment Written informed consent by parents or legal representative before enrolment Exclusion Criteria: Relapse with any uveal involvement and/or anterior chamber involvement Indication for another treatment option according to investigator's judgement Clinical/MRI signs of extraocular disease, including metastatic disease 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 Other (simultaneous) malignancies Contraindication or known hypersensitivity to study drugs Severe concomitant diseases (e.g. immune deficiency syndrome) 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maja Beck Popovic, Prof
Organizational Affiliation
Lausanne University Hospital
Official's Role
Study Director
Facility Information:
Facility Name
CHUV Lausanne University Hospital
City
Lausanne
ZIP/Postal Code
1011
Country
Switzerland

12. IPD Sharing Statement

Learn more about this trial

A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma

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