Eye Cancer, RetinoblastomaPhase 2EuRbG2018NCT04455139
A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma
A Phase 2 study testing Topotecan and Melphalan in people with Eye Cancer, Retinoblastoma, run by Prof. Beck Popovic Maja at 1 site in Switzerland.
Trial 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… Read more about this study
- Who is it for?
- Ages 3 months to 11 years
- Conditions the study is for
- Eye Cancer, Retinoblastoma
- What is being tested?
- Topotecan and Melphalan
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 1 siteSwitzerland
- Study dates
- 15 Nov 2021to 22 May 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 months to 11 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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
- To reduce the incidence of retinal toxicity in IVitC treatment while retaining similar efficacy of tumor control, in vitreous relapse.
- 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%.
- Conditions
- Eye Cancer, Retinoblastoma
- Keywords
- relapsed retinoblastoma, relapse of retinoblastoma
- Medical subject headings
- Retinoblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TopotecanDrug
Also called hycamtin
intravitreal or intra-arterial administration of topotecan
MelphalanDrug
Also called alkeran
intravitreal or intra-arterial administration of topotecan
| Study group | Role | What they receive |
|---|---|---|
| Treatment 1a | Active comparator | IVitC melphalan (randomized) in case of vitreous relapse only Receives: Drug: Melphalan |
| Treatment 1b | Experimental | IVitC topotecan (randomized) in case of vitreous relapse only Receives: Drug: Topotecan |
| Treatment 2a | Active comparator | IAC melphalan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment Receives: Drug: Melphalan |
| Treatment 2b | Experimental | IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment Receives: Drug: Topotecan; Drug: Melphalan |
| Treatment 2c | No intervention | IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with prior intra-arterial treatment |
| Treatment 3a | No intervention | 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 |
| Treatment 3b | No intervention | 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 being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: at 1 month after treatment completion
Relapse rate after IAC by melphalan only and IAC by melphalan + topotecan
parameter: eye retention rate
Measured: at 2 years of follow-up
Secondary outcomes (7)
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
Measured: at 3 or 6 months after last intravitreous injection
Ocular survival (eye salvage rate)
parameters: enucleation and EBR
Measured: at 2 years since study entry
Number of participants with ocular (non retinal) and systemic toxicity assessed by CTCAE v5.0
parameter: number of participants
Measured: 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
parameters: Logmar values
Measured: 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
parameter: incidence
Measured: 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
parameter: B three thermoluminescent dosimeters
Measured: at 1 month after the last IAC
Incidence of the occurrence of secondary malignancies and/or metastases and long term sequelae
parameter: incidence
Measured: during a follow-up of at least 10 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jul 2020
- Study start15 Nov 2021
- Primary completion22 May 2023
- Study completion22 May 2023
Why it stopped: Difficulties in recruiting patients due to changing in treatment standards for the target population
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Eye Cancer, RetinoblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- Prof. Beck Popovic Maja
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Prof. Beck Popovic Maja, University of Lausanne Hospitals
- Investigators
- Maja Beck Popovic, Prof, Study director, University of Lausanne Hospitals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04455139
- Sponsor's protocol ID
- 2018-01967
- Other IDs
- 2018
- Acronym
- EuRbG2018
- Status last verified
- Sep 2023
- First submitted
- 24 Apr 2020
- Last updated
- 3 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04455139
- Acronym / sponsor ID
- EuRbG2018 / 2018-01967
- Conditions
- Eye Cancer, Retinoblastoma
- Keywords
- relapsed retinoblastoma, relapse of retinoblastoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Difficulties in recruiting patients due to changing in treatment standards for the target population
- Enrolment
- 2 participants (actual)
- Lead sponsor
- Prof. Beck Popovic MajaUniversity, hospital or other
- Study start
- 15 Nov 2021 (actual)
- Primary completion
- 22 May 2023 (actual)
- Study completion
- 22 May 2023 (actual)
- First posted
- 2 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- To reduce the incidence of retinal toxicity in IVitC treatment while retaining similar efficacy of tumor control, in vitreous relapse.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Treatment 1a | Active comparator | Drug: MelphalanIVitC melphalan (randomized) in case of vitreous relapse only |
| Treatment 1b | Experimental | Drug: TopotecanIVitC topotecan (randomized) in case of vitreous relapse only |
| Treatment 2a | Active comparator | Drug: MelphalanIAC melphalan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment |
| Treatment 2b | Experimental | Drug: Topotecan, Drug: MelphalanIAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment |
| Treatment 2c | No intervention | –IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with prior intra-arterial treatment |
| Treatment 3a | No intervention | –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 |
| Treatment 3b | No intervention | –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 |
Who may qualify
- Ages
- 3 months to 11 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (12 listed)
- Eye with recurrent Rb clinically defined as one or the combination of the following:
- 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
Key exclusion criteria (13 listed)
- 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):
- Other (simultaneous) malignancies
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TopotecanAlso: hycamtinintravitreal or intra-arterial administration of topotecan | Drug | Treatment 1b, Treatment 2b |
| MelphalanAlso: alkeranintravitreal or intra-arterial administration of topotecan | Drug | Treatment 1a, Treatment 2a, Treatment 2b |
Primary outcome
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
Relapse rate after IAC by melphalan only and IAC by melphalan + topotecan
Time frame: at 2 years of follow-up
parameter: eye retention rate
7 secondary outcomes
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
Ocular survival (eye salvage rate)
Time frame: 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
Quality of vision assessed by visual acuity
Time frame: 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
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
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
Results and safety
The study was stopped early (reason given: Difficulties in recruiting patients due to changing in treatment standards for the target population). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maja Beck Popovic, Prof study director
University of Lausanne Hospitals
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Topotecan and Melphalan in people with Eye Cancer, Retinoblastoma, run by Prof. Beck Popovic Maja at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 3 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Difficulties in recruiting patients due to changing in treatment standards for the target population). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of retinal toxicity of intravitreous administration of melphalan versus topotecan assessed by CTCAE v5.0 (time frame: at 1 month after treatment completion). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2023.