Ocular Conservative Treatment for Retinoblastoma : Efficacy of the New Management Strategies and Visual Outcome

Study Overview
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Brief Summary
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This protocol includes 2 independent studies. Both studies are multicenter studies, evaluating different therapeutic approaches in two different populations of patients: Study 1, a randomized phase-II study evaluating the efficacy of Intra-Arterial Chemotherapy (IAC) with melphalan and topotecan versus melphalan alone, both in association with ophthalmologic treatments. Study 2, a minimally invasive interventional study evaluating the results on visual function following reference treatment with intravenous (IV) chemotherapy in association with ophthalmologic or local ophthalmological treatment without IV chemotherapy.

Detailed Description
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Primary objective of the studies: Study 1: To evaluate the efficacy of IAC in term of local control of the disease in patients eligible for IAC (randomized phase II study); Study 2: To assess the visual function, based on World Health Organization (WHO) criteria, in patients eligible for other conservative treatments (IV chemotherapy in association with local ophthalmologic trématent or local ophthalmological treatment without IV chemotherapy; this is a minimally invasive interventional study).

Official Title
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Ocular Conservative Treatment for Retinoblastoma: Efficacy of the New Management Strategies and Visual Outcome - RETINO 2018

Conditions
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Retinoblastoma

Intervention / Treatment
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* Drug: Melphalan or Melphalan + Topotecan
* Drug: etoposide, carboplatin and vincristine or local ophthalmological treatment without IV chemotherapy
* Drug: Carboplatin administered on Day 1
* Device: Thermotherapy (local treatment)
* Device: Cryotherapy (local treatment)
* Device: Iodine-125 plaques (local treatment)
* Drug: Intravitreal Melphalan chemotherapy injections (local treatment)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Overall study inclusion criteria: Newly diagnosed retinoblastoma (RB). Retinoblastoma with at least one eye eligible for conservative management. Patients likely to be compliant with the study requirements and visits, including late follow-up. Patients not previously treated with chemotherapy or radiotherapy for this or any other cancer. Patients with no contraindication to the proposed treatments. Informed consent signed by parents or legal representative. French Social Security System coverage. Study 1 inclusion criteria: 8.1. Children aged from 6 months to 6 years. 9. Retinoblastoma in at least one eye, deemed manageable with IAC in one side and without IV chemotherapy: Unilateral Retinoblastoma classified as group B, C (if vitreous seeds < 3 mm), D or E with no invasion of the anterior segment, and without massive tumor of more than 2/3 of the eye, eligible for conservative management, or Bilateral Retinoblastoma but with very unbalanced lesions between the two eyes: one eye group D or E without invasion of the anterior segment or massive tumor of more than 2/3 of the eye, eligible for IAC, and the other eye eligible for local treatment only (without IAC). Study 2 inclusion criteria: 8.2. Retinoblastoma eligible for conservative management although not manageable with IAC: Unilateral Retinoblastoma in children below 6 months of age, classified as Group A, B, C or D, with or without vitreous seeding, compatible with conservative management, or Bilateral Retinoblastoma classified as group A, B, C D, or E without invasion of the anterior segment, and/or massive tumors of more than 2/3 of the eye and eligible for conservative management. Exclusion Criteria: Overall study non-inclusion criteria: RB not eligible for conservative management : Extra-ocular extension of the disease, or Group E eyes with invasion of the anterior segment, and/or massive tumors of more than 2/3 of the eye. Patient older than 6 years of age. Patients with another associated disease contra indicating systemic chemotherapy. Previously treated retinoblastoma by chemotherapy. Patients already treated for another malignant disease. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Patients whose parents have not accepted the treatment regimen after explanation of it. Contraindication to study drug mentioned in SmPC (Summary of Products Characteristics) of the study drugs. Inclusion in another experimental anti-cancer drug therapy. Study 1 non-inclusion criteria: Any contraindication or concomitant disease that would preclude the Study 1 treatment procedure and could delay treatment. These patients should be eligible for Study 2.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study 1: Melphalan or Melphalan + Topotecan<br>Randomized phase-II study evaluating the efficacy of Intra-Arterial Chemotherapy (IAC) with melphalan and topotecan versus melphalan alone, both in association with ophthalmologic treatments. | Drug: Melphalan or Melphalan + Topotecan<br>* IAC: 2-6 cycles every 1 month (number based on the local tumor evolution), performed using radio-guided catheterization and delivery at the ostium of the ophthalmic artery, in neuroradiology operating room, and under General Anesthesia (GA). IAC will be administered at the Fondation Rothschild Hospital in collaboration with the Interventional Neuroradiology team.<br>* Other names: Alkeran, Topotecan Accord; Topotecan Hospira chemotherapy;Device: Thermotherapy (local treatment)<br>* Thermotherapy after carboplatin administered on Day 1<br>* Other names: Thermotherapy after carboplatin administered on Day 1;Device: Cryotherapy (local treatment)<br>* Cryotherapy (local treatment)<br>Device: Iodine-125 plaques (local treatment)<br>* Iodine-125 plaques (local treatment)<br>Drug: Intravitreal Melphalan chemotherapy injections (local treatment)<br>* Intravitreal Melphalan chemotherapy injections (local treatment)<br>|
| Other: Study 2: Etoposide, carboplatin and vincristine<br>Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments. | Drug: etoposide, carboplatin and vincristine or local ophthalmological treatment without IV chemotherapy<br>* 2 to 6 cycles of combined etoposide, carboplatin and vincristine or local ophthalmological treatment without IV chemotherapy : thermotherapy and/or cryotherapy and/or iodine-125 plaques and/or intravitreal chemotherapy injections<br>* Other names: etoposide, carboplatin and vincristine chemotherapy;Drug: Carboplatin administered on Day 1<br>* Chemothermotherapy : Intravenous injection by carboplatin<br>* Other names: platinum-based chemotherapy;Device: Thermotherapy (local treatment)<br>* Thermotherapy after carboplatin administered on Day 1<br>* Other names: Thermotherapy after carboplatin administered on Day 1;Device: Cryotherapy (local treatment)<br>* Cryotherapy (local treatment)<br>Device: Iodine-125 plaques (local treatment)<br>* Iodine-125 plaques (local treatment)<br>Drug: Intravitreal Melphalan chemotherapy injections (local treatment)<br>* Intravitreal Melphalan chemotherapy injections (local treatment)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study 1: Rate of eye preservation | Rate of eye preservation in the 2 treatments' arms | 24 months after randomization | 
| Visual function | Percentage of patients with major, mild or no impairment of visual function according to WHO criteria, i.e. normal bilateral visual acuity (≥ 6/10) or mild bilateral visual impairment (3/10 to 5/10) according to tumor location and extension | when patient is 6 years old and at least 24 months of follow-up after study inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ocular toxicity | Percentage of patients with at least one grade-3 or -4 toxicity (CTCAE v. 5.0) | Up to 24 months after inclusion in the study | 
| Systemic toxicity | Rate of specific grade 3-4 toxicity (CTCAE v. 5.0) | Up to 24 months after inclusion in the study | 
| Relapse | Percentage of patients with relapse within 24 months after inclusion, broken down into: Local relapse, Extra-ocular relapse | within 24 months after inclusion | 
| Second malignant tumor | Percentage of patients with second malignant tumor within 24 months after study inclusion | 24 months after study inclusion | 
| Additional assessment of visual function | Additional assessment of visual function at follow-up: Percentage of patients at each of the four levels of visual acuity according to WHO criteria | In the year patients turn 6 years of age and at least 24 months of treatment | 
| Retinal assessment | Optical Coherence Tomography (OCT) and Optical Coherence Tomography-Angiography (OCT-A) measures on retina | In the year patients turn 6 years of age and at least 24 months of treatment | 
| Integration at school | Rate of children able to attend the common primary school : without specific help or with the help of a dedicated person and/or with specific features to facilitate reading and writing | In the year patients turn 6 years of age and at least 24 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, Ocular conservative treatment in retinoblastoma