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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Rate of retinal toxicity of intravitreous administration of melphalan versus topotecan assessed by CTCAE v5.0
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Months 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Treatment 1a
IVitC melphalan (randomized) in case of vitreous relapse only
干预措施: Melphalan (Drug)
Treatment 1b
IVitC topotecan (randomized) in case of vitreous relapse only
干预措施: Topotecan (Drug)
Treatment 2a
IAC melphalan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
干预措施: Melphalan (Drug)
Treatment 2b
IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
干预措施: Topotecan (Drug)
Treatment 2b
IAC melphalan and topotecan (randomized) in case of retinal/diffuse subretinal relapse with no prior intra-arterial treatment
干预措施: Melphalan (Drug)
结局指标
主要结局
Rate of retinal toxicity of intravitreous administration of melphalan versus topotecan assessed by CTCAE v5.0
时间窗: 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
时间窗: at 2 years of follow-up
parameter: eye retention rate
次要结局
- Quality of vision assessed by visual acuity(at 5 years of age)
- Efficacy of intravitreous topotecan compared to intravitreous melphalan (number of injections to tumor clearance in vitreous)(at 3 or 6 months after last intravitreous injection)
- Ocular survival (eye salvage rate)(at 2 years since study entry)
- Number of participants with ocular (non retinal) and systemic toxicity assessed by CTCAE v5.0(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)
- 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(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(at 1 month after the last IAC)
- Incidence of the occurrence of secondary malignancies and/or metastases and long term sequelae(during a follow-up of at least 10 years)
研究者
Prof. Beck Popovic Maja
Head of pediatric hematology oncology unit
University of Lausanne Hospitals