Systemic Chemotherapy and Subtenon Carboplatin, and Local Ophthalmic Therapy in Children With Intraocular Retinoblastoma

Study Overview
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Brief Summary
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Phase III trial to determine the effectiveness of combining systemic chemotherapy and subtenon carboplatin with ophthalmic therapy in treating children who have intraocular retinoblastoma. Drugs used in chemotherapy, such as vincristine, carboplatin, and etoposide, work in different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether systemic chemotherapy and subtenon (under the conjunctiva of the eye) carboplatin combined with ophthalmic therapy is effective in treating intraocular (within the eyeball) retinoblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the event-free survival at 12 months of pediatric patients' eyes with group D intraocular retinoblastoma treated with systemic chemotherapy comprising vincristine, carboplatin, and etoposide, subtenon carboplatin, and local ophthalmic therapy. (Event defined for each eye individually as needed for nonprotocol therapy including nonprotocol chemotherapy, enucleation or any external-beam radiation) SECONDARY OBJECTIVES: I. Determine the event-free survival at 12 months of pediatric patients' eyes with group C retinoblastoma treated with systemic chemotherapy comprising carboplatin, etoposide, vincristine, subtenon carboplatin, and local ophthalmic therapy. II. Determine the acute and long-term toxic effects of these regimens in these patients, including visual outcome and incidence of secondary malignancies. III. Determine the patterns of failure in patients treated with these regimens, in terms of vitreous vs retinal vs both as sites of recurrence. IV. Determine predictors of failure including findings at the on study examination under anesthesia and response status after six courses of chemotherapy. V. Determine the percentage of group C and D eyes separately that can be preserved without enucleation after failing protocol therapy. OUTLINE: This is a multicenter study. Patients receive vincristine IV over 1 minute on day 1 and carboplatin IV over 1 hour and etoposide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously daily beginning on day 3 and continuing until blood counts recover. Patients receive subtenon carboplatin to each group C or D eye on day 0 or 1 prior of courses 2-4 only. Treatment repeats every 28 days for 6 courses in the absence of occurrence of extraocular retinoblastoma or a second malignancy. Beginning with course 3 of systemic chemotherapy, patients undergo local ophthalmic therapy comprising local laser and/or cryotherapy on day 1. Patients are followed with ophthalmology exams every 4-12 weeks until 3 years of age, every 6 months until 5 years of age, and then annually for up to 10 years.

Official Title
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A Single Arm Trial of Systemic And Subtenon Chemotherapy For Groups C And D Intraocular Retinoblastoma

Conditions
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Intraocular Retinoblastoma

Intervention / Treatment
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* Drug: liposomal vincristine sulfate
* Procedure: cryosurgery
* Procedure: laser surgery
* Drug: carboplatin
* Drug: etoposide
* Biological: filgrastim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of bilateral retinoblastoma with at least 1 eye group C or D intraocular retinoblastoma by ophthalmologic examination, defined by the International Classification System for Intraocular Retinoblastoma as the following: Group C: Discrete localized disease with minimal subretinal and/or vitreous seeding Subretinal fluid, without prior or concurrent seeding, involving ≤ one quarter of the retina Local fine vitreous seeding may be present close to discrete tumor Local subretinal seeding < 3 mm from tumor Group D: Diffuse disease with significant vitreous and/or subretinal seeding Tumor(s) may be massive or diffuse Subretinal fluid, without prior or concurrent seeding, involving up to total retinal detachment Diffuse or massive vitreous disease may include greasy seeds or avascular tumor masses Diffuse subretinal seeding may include subretinal plaques or tumor nodules Prior enucleation of 1 eye allowed provided the remaining eye is group C or D No tumor present on histologic examination at the cut end of the optic nerve on any eye enucleated prior to study entry Evidence of choroidal and/or optic nerve invasion past the lumina cribrosa is allowed No extraocular retinoblastoma clinically or by MRI of brain and orbits with and without gadolinium or CT scan with and without contrast of brain and orbits No evidence of systemic metastases by bone marrow, lumbar puncture, bone scan, and/or any other additional test Performance status - Karnofsky 50-100% (over 16 years of age) Performance status - Lansky 50-100% (16 and under) Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age AST and ALT < 2.5 times ULN for age Creatinine adjusted according to age as follows: No greater than 0.4 mg/dL (≤ 5 months) No greater than 0.5 mg/dL (6 months -11 months) No greater than 0.6 mg/dL (1 year-23 months) No greater than 0.8 mg/dL (2 years-5 years) No greater than 1.0 mg/dL (6 years-9 years) No greater than 1.2 mg/dL (10 years-12 years) No greater than 1.4 mg/dL (13 years and over [female]) No greater than 1.5 mg/dL (13 years to 15 years [male]) No greater than 1.7 mg/dL (16 years and over [male]) Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min/1.73m^2 Not pregnant or nursing Fertile patients must use effective contraception Negative pregnancy test in postmenarchal females No prior chemotherapy No other concurrent chemotherapy No prior radiotherapy No other concurrent radiotherapy

Ages Eligible for Study
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Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, surgery)<br>Patients receive liposomal vincristine sulfate IV over 1 minute on day 1 and carboplatin IV over 1 hour and etoposide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously daily beginning on day 3 and continuing until blood counts recover. Patients receive subtenon carboplatin to each group C or D eye on day 0 or 1prior of courses 2-4 only. Treatment repeats every 28 days for 6 courses in the absence of occurrence of extraocular retinoblastoma or a second malignancy. Beginning with course 3 of systemic chemotherapy, patients undergo local ophthalmic therapy comprising local laser surgery and/or cryosurgery on day 1. | Drug: liposomal vincristine sulfate<br>* Given IV<br>* Other names: vincristine sulfate liposome injection;Procedure: cryosurgery<br>* Application of extreme cold to destroy abnormal or diseased tissue.<br>* Other names: cryosurgical ablation;Procedure: laser surgery<br>* Surgery using a laser (instead of a scalpel) to cut tissue<br>* Other names: surgery, laser;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Biological: filgrastim<br>* Given subcutaneously<br>* Other names: Neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Group D Eyes - Treatment Failure Within One Year | Each Group D eye will be classified as experiencing failure within one year after start of treatment: yes or no. The method of Rosner et al. (Biometrics v. 38, 105-114, 1982) will be used to model possible dependence between eyes from the same patient. The point estimate of the probability of treatment failure is reported as the Mean measure type. | One year | 
| Group C Eyes - Treatment Failure Within One Year | Each Group C eye will be classified as experiencing failure within one year after start of treatment: yes or no. The method of Rosner et al. (Biometrics v. 38, 105-114, 1982) will be used to model possible dependence between eyes from the same patient. The point estimate of the probability of treatment failure is reported as the Mean measure type. | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | Proportion of patients event free at 1 year following enrollment. Event free survival time is computed as the time to study entry until disease relapse/progression, secondary malignancy, or death. | One year after study enrollment | 
| Toxicity Associated With Chemotherapy | The number of patients that experience CTC Version 4 grade 3 or higher toxicities of any kind. | From date of enrollment until termination of protocol therapy assessed up to 72 weeks | 
| Patterns of Failure for Group C and Group D in Terms of Vitreous vs Patterns of Failure for Group C and Group D in Terms of Vitreous vs Retinal vs Both as Sites of Recurrence | Sites of disease recurrence for Group C and Group D eyes where treatment failure was detected | From the date of enrollment assessed up to 36 months | 
| Patterns of Treatment Failure vs. no Treatment Failure for Group C Eyes and Group D Eyes According to Initial Sites of Involvement | The association between the probability of experiencing treatment failure vs. no failure in a C eye and the presence of subretinal seeding (SRS), subretinal fluid (SRF), or vitreal seeding (VS) at the on study ophthalmological examination under anesthesia. The association between the probability of experiencing treatment failure vs. no failure in a D eye and the presence of subretinal seeding (SRS), subretinal fluid (SRF), or vitreal seeding (VS) at the on study ophthalmological examination under anesthesia. | From the date of enrollment assessed up to 12 months |