Neoadjuvant Carboplatin and Vincristine and Standard Local Ophthalmic Therapy in Treating Patients With Intraocular Retinoblastoma

Study Overview
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Brief Summary
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This phase III trial is studying how well giving carboplatin and vincristine together with standard local ophthalmic therapy works in treating children with intraocular retinoblastoma. Drugs used in chemotherapy, such as carboplatin and vincristine, work in different ways to stop tumor from dividing so they stop growing or die. It is not yet known whether neoadjuvant chemotherapy combined with standard local ophthalmic therapy is effective in treating intraocular retinoblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the 2-year event-free survival of patients with Group B intraocular retinoblastoma treated with neoadjuvant chemoreduction comprising carboplatin and vincristine and standardized local ophthalmic therapy. SECONDARY OBJECTIVES: I. Determine the response rate after one course of chemoreduction (before standardized local ophthalmic therapy) in these patients. II. Correlate response rate with event-free survival in patients treated with this regimen. III. Determine the incidence of toxic effects in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive chemoreduction comprising carboplatin IV over 60 minutes followed by vincristine IV over 1-2 minutes on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After the first course of chemoreduction, patients undergo standardized local ophthalmic therapy comprising local laser therapy, cryotherapy, and/or radioactive plaque comprising iodine I 125 or ruthenium Ru 106. Patients are followed every 3-4 weeks until there is no active tumor seen on a minimum of 3 ophthalmic exams under anesthesia, every 6-8 weeks until 3 years of age, every 4-6 months until 10 years of age, and then annually thereafter.

Official Title
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Trial of Systemic Neoadjuvant Chemotherapy for Group B Intraocular Retinoblastoma

Conditions
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Intraocular Retinoblastoma

Intervention / Treatment
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* Drug: Carboplatin
* Procedure: Cryosurgery
* Procedure: Infrared Laser Therapy
* Radiation: Iodine I-125
* Radiation: Radiation Therapy
* Radiation: Ruthenium Ru-106
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed Group B intraocular retinoblastoma meeting 1 of the following criteria: Group B tumor(s) in 1 eye Group B tumor(s) in both eyes Group A tumor in 1 eye and Group B tumor(s) in the other eye Group E tumor in 1 eye that has been enucleated and Group B tumor(s) in the remaining eye at the time of enucleation of the Group E tumor Defined by the International Classification System for Intraocular Retinoblastoma as follows: Group A: Small tumors (≤ 3 mm in greatest dimension) confined to the retina, away from foveola and disc meeting the following criteria: More than 3 mm from fovea More than 1.5 mm from optic disk Group B: Tumors more than 3 mm meeting the following criteria: Confined to the retina in any location not in Group A Tumor associated subretinal fluid < 3 mm from the tumor margin with no subretinal seeding Group E: Must have ≥ 1 of the following present: Tumor touching the lens Tumor anterior to anterior vitreous face involving ciliary body or anterior segment Diffuse infiltrating retinoblastoma Neovascular glaucoma Opaque media from hemorrhage Tumor necrosis with aseptic orbital cellulites Phthisis bulbi Confirmation of diagnosis by CT scan or MRI of the brain and orbits AND an ophthalmologic evaluation under anesthesia within the past 3 weeks No choroidal and/or optic nerve invasion past the lamina cribosa No evidence of extraocular retinoblastoma clinically or by head and orbital MRI and/or CT scan No tumor present on histological exam at the cut end of the optic nerve for any Group E eye enucleated before study entry Performance status - ECOG 0-2 Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age AST or ALT < 2.5 times ULN for age Creatinine clearance (based on Schwartz formula) or radioisotope glomerular filtration rate ≥ 70mL/min/1.73 m^2 No prior chemotherapy No other concurrent chemotherapy No prior radiotherapy No other concurrent radiotherapy, including intensity-modulated stereotactic, or proton beam radiotherapy Prior enucleation of one eye allowed provided the remaining eye is Group B No concurrent enucleation No prior local ophthalmic therapy for retinoblastoma No other prior therapy for retinoblastoma No local therapy during chemotherapy course 1

Ages Eligible for Study
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Maximum Age: 5 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 chemoreduction comprising carboplatin IV over 60 minutes followed by vincristine IV over 1-2 minutes on day 1. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. After the first course of chemoreduction, patients undergo standardized local ophthalmic therapy comprising local laser therapy, cryotherapy, and/or radioactive plaque comprising iodine I 125 or ruthenium Ru 106. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Procedure: Cryosurgery<br> <br> * Other names: cryosurgical ablation;Procedure: Infrared Laser Therapy<br> <br> Radiation: Iodine I-125<br>* Undergo radioactive therapy<br>* Other names: Iodine I 125;Radiation: Radiation Therapy<br>* Undergo radioactive therapy<br>* Other names: Therapy, Radiation;Radiation: Ruthenium Ru-106<br>* Undergo radioactive therapy<br>* Other names: Ruthenium Ru 106;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Proportion of patients with event free survival at 2 years. An event is defined as the need for non-protocol therapy, defined as additional on-protocol chemotherapy, enucleation or external beam radiation, among patients with Group B intraocular tumors with a schedule of neoadjuvant 2-agent (Vincristine/Carboplatin) chemotherapy (chemo-reduction) and standardized local ophthalmic therapy. | At 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) at Patient Level After the First Course of Therapy | RR will be estimated. The response after 1 course of chemotherapy will be used to better define response to this neoadjuvant systemic chemotherapy, prior to the use of local ophthalmic therapy. Response to subsequent courses will help define response to combined systemic chemotherapy and local ophthalmic therapy. Number of patients with Type I, II, III or IV response after first course of therapy | 1 month after enrollment | 
| Response Rate (RR) at Eye Levels After the First Course of Therapy | RR will be estimated. The response after 1 course of chemotherapy will be used to better define response to this neoadjuvant systemic chemotherapy, prior to the use of local ophthalmic therapy. Response to subsequent courses will help define response to combined systemic chemotherapy and local ophthalmic therapy. Number eyes with Type I, II, III or IV response after first course of therapy | 1 month after enrollment | 
| Event-free Survival Rate (EFSR) Defined as the Need for Non-protocol Chemotherapy, Enucleation, or EBRT at the Patient Level | EFSR will be estimated for patients who respond to vincristine and carboplatin after an initial 1 cycle of chemoreduction | 2 years after enrollment | 
| Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 | Participants with Grade 3 and higher reported on protocol therapy | 6 months after enrollment |