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

Phase 2

Recruiting

• Conditions: Retinoblastoma
• Interventions: Drug: Melphalan or Melphalan + Topotecan; Drug: etoposide, carboplatin and vincristine or local ophthalmological treatment without IV chemotherapy; Drug: Carboplatin administered on Day 1; Device: Cryotherapy (local treatment); Device: Thermotherapy (local treatment); Device: Iodine-125 plaques (local treatment); Drug: Intravitreal Melphalan chemotherapy injections (local treatment)

• Registration Number: NCT04681417
• Lead Sponsor: Institut Curie

Brief Summary

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

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).

Study Timeline

• Study First Submitted: 2020-12-17
• Study First Submitted QC: 2020-12-22
• Study First Posted: 2020-12-23
• Study Start: 2021-03-25
• Status Verified: 2023-11
• Last Update Submitted: 2024-01-10
• Last Update Posted: 2024-01-12
• Primary Completion: 2035-01-20
• Study Completion: 2036-01-20

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 225

Inclusion Criteria

Overall study inclusion criteria:

1. Newly diagnosed retinoblastoma (RB).
2. Retinoblastoma with at least one eye eligible for conservative management.
3. Patients likely to be compliant with the study requirements and visits, including late follow-up.
4. Patients not previously treated with chemotherapy or radiotherapy for this or any other cancer.
5. Patients with no contraindication to the proposed treatments.
6. Informed consent signed by parents or legal representative.
7. 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:

1. 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
2. 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:

1. 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
2. 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:

1. RB not eligible for conservative management :

   1. Extra-ocular extension of the disease, or
   2. Group E eyes with invasion of the anterior segment, and/or massive tumors of more than 2/3 of the eye.

2. Patient older than 6 years of age.

3. Patients with another associated disease contra indicating systemic chemotherapy.

4. Previously treated retinoblastoma by chemotherapy.

5. Patients already treated for another malignant disease.

6. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

7. Patients whose parents have not accepted the treatment regimen after explanation of it.

8. Contraindication to study drug mentioned in SmPC (Summary of Products Characteristics) of the study drugs.

9. Inclusion in another experimental anti-cancer drug therapy.

   Study 1 non-inclusion criteria:

10. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Study 1: Melphalan or Melphalan + Topotecan	Melphalan or Melphalan + Topotecan	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 1: Melphalan or Melphalan + Topotecan	Iodine-125 plaques (local treatment)	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: Etoposide, carboplatin and vincristine	etoposide, carboplatin and vincristine or local ophthalmological treatment without IV chemotherapy	Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments.
Study 2: Etoposide, carboplatin and vincristine	Intravitreal Melphalan chemotherapy injections (local treatment)	Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments.
Study 1: Melphalan or Melphalan + Topotecan	Cryotherapy (local treatment)	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: Etoposide, carboplatin and vincristine	Thermotherapy (local treatment)	Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments.
Study 2: Etoposide, carboplatin and vincristine	Carboplatin administered on Day 1	Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments.
Study 2: Etoposide, carboplatin and vincristine	Cryotherapy (local treatment)	Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments.
Study 1: Melphalan or Melphalan + Topotecan	Thermotherapy (local treatment)	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 1: Melphalan or Melphalan + Topotecan	Intravitreal Melphalan chemotherapy injections (local treatment)	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: Etoposide, carboplatin and vincristine	Iodine-125 plaques (local treatment)	Neoadjuvant chemotherapy involves 2 to 6 cycles of combined etoposide, carboplatin and vincristine in association with ophthalmologic treatments.

Primary Outcome Measures

Name	Time	Method
Visual function	when patient is 6 years old and at least 24 months of follow-up after study inclusion	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
Study 1: Rate of eye preservation	24 months after randomization	Rate of eye preservation in the 2 treatments' arms

Secondary Outcome Measures

Name	Time	Method
Systemic toxicity	Up to 24 months after inclusion in the study	Rate of specific grade 3-4 toxicity (CTCAE v. 5.0)
Ocular toxicity	Up to 24 months after inclusion in the study	Percentage of patients with at least one grade-3 or -4 toxicity (CTCAE v. 5.0)
Second malignant tumor	24 months after study inclusion	Percentage of patients with second malignant tumor within 24 months after study inclusion
Additional assessment of visual function	In the year patients turn 6 years of age and at least 24 months of treatment	Additional assessment of visual function at follow-up: Percentage of patients at each of the four levels of visual acuity according to WHO criteria
Retinal assessment	In the year patients turn 6 years of age and at least 24 months of treatment	Optical Coherence Tomography (OCT) and Optical Coherence Tomography-Angiography (OCT-A) measures on retina
Relapse	within 24 months after inclusion	Percentage of patients with relapse within 24 months after inclusion, broken down into: Local relapse, Extra-ocular relapse
Integration at school	In the year patients turn 6 years of age and at least 24 months of treatment	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

Trial Locations

Locations (28)

Bordeaux Chu; 🇫🇷 Bordeaux, France

MONTPELLIER CHU Hopital Arnaud De Villeneuve; 🇫🇷 Montpellier, France

Strasbourg Chu; 🇫🇷 Strasbourg, France

La Reunion - Chr Felix Guyon; 🇫🇷 Saint-Denis, La Réunion, France

BESANCON CHU Hopital Jean Minjoz; 🇫🇷 Besancon, France

Angers Chu; 🇫🇷 Angers, France

Amiens Chu; 🇫🇷 Amiens, France

BREST CHRU Hopital Morvan; 🇫🇷 Brest, France

CAEN CHU; 🇫🇷 Caen, France

CHU ESTAING Centre Régional de Cancérologie et Therapie Cellulaire Pediatrique (CRCTCP); 🇫🇷 Clermont-Ferrand, France

DIJON CHU Hopital François Mitterand; 🇫🇷 Dijon, France

Grenoble Chu; 🇫🇷 Grenoble, France

LILLE Centre Oscar Lambret; 🇫🇷 Lille, France

Limoges Chu; 🇫🇷 Limoges, France

LYON Centre Léon Bérard; 🇫🇷 Lyon, France

Marseille Chu; 🇫🇷 Marseille, France

NICE CHU Hopital Archet 2; 🇫🇷 Nice, France

PARIS Fondation Ophtalmologique Adolphe de Rothschild; 🇫🇷 Paris, France

NANTES CHU Hopital Mere-Enfant; 🇫🇷 Nantes, France

Institut Curie; 🇫🇷 Paris, France

Reims Chu; 🇫🇷 Reims, France

Rouen Chu; 🇫🇷 Rouen, France

Rennes Chu; 🇫🇷 Rennes, France

Saint Etienne Chu; 🇫🇷 Saint Etienne, France

Poitiers Chu; 🇫🇷 Poitiers, France

TOURS CHU Hopital Clocheville; 🇫🇷 Tours, France

Nancy Chu; 🇫🇷 Vandoeuvre Les Nancy, France

Toulouse Chu; 🇫🇷 Toulouse, France