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

Phase 3

Completed

• Conditions: Intraocular Retinoblastoma
• Interventions: Drug: Carboplatin; Procedure: Cryosurgery; Procedure: Infrared Laser Therapy; Radiation: Iodine I-125; Radiation: Radiation Therapy; Radiation: Ruthenium Ru-106; Drug: Vincristine Sulfate

• Registration Number: NCT00079417
• Lead Sponsor: Children's Oncology Group

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2004-03-08
• Study First Submitted QC: 2004-03-09
• Study First Posted: 2004-03-10
• Study Start: 2005-12-26
• Primary Completion: 2010-01-01
• Results First Submitted: 2013-12-23
• Results First Submitted QC: 2013-12-23
• Results First Posted: 2014-02-14
• Study Completion: 2017-03-31
• Status Verified: 2023-01
• Last Update Submitted: 2023-02-14
• Last Update Posted: 2023-03-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemotherapy, surgery)	Vincristine Sulfate	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.
Treatment (chemotherapy, surgery)	Cryosurgery	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.
Treatment (chemotherapy, surgery)	Infrared Laser Therapy	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.
Treatment (chemotherapy, surgery)	Iodine I-125	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.
Treatment (chemotherapy, surgery)	Radiation Therapy	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.
Treatment (chemotherapy, surgery)	Ruthenium Ru-106	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.
Treatment (chemotherapy, surgery)	Carboplatin	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.

Primary Outcome Measures

Name	Time	Method
Event-free Survival	At 2 years	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.

Secondary Outcome Measures

Name	Time	Method
Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0	6 months after enrollment	Participants with Grade 3 and higher reported on protocol therapy
Response Rate (RR) at Patient Level After the First Course of Therapy	1 month after enrollment	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
Response Rate (RR) at Eye Levels After the First Course of Therapy	1 month after enrollment	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
Event-free Survival Rate (EFSR) Defined as the Need for Non-protocol Chemotherapy, Enucleation, or EBRT at the Patient Level	2 years after enrollment	EFSR will be estimated for patients who respond to vincristine and carboplatin after an initial 1 cycle of chemoreduction

Trial Locations

Locations (10)

Lurie Children's Hospital-Chicago; 🇺🇸 Chicago, Illinois, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Children's Oncology Group; 🇺🇸 Philadelphia, Pennsylvania, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Cincinnati Children's Hospital Medical Center; 🇺🇸 Cincinnati, Ohio, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States

Children's Hospital Los Angeles; 🇺🇸 Los Angeles, California, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States