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

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

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.

Study Overview

• Status: Completed
• Conditions: Intraocular Retinoblastoma
• Intervention / Treatment: Drug: etoposide; Drug: carboplatin; Biological: filgrastim; Procedure: cryosurgery; Drug: liposomal vincristine sulfate; Procedure: laser surgery

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8032
      • Yale University
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Lombardi Comprehensive Cancer Center at Georgetown University
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (chemotherapy, surgery); 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: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: carboplatin; Given IV; Other Names: Carboplat; CBDCA; JM-8; Paraplatin; Paraplat; Biological: filgrastim; Given subcutaneously; Other Names: G-CSF; Neupogen; Procedure: cryosurgery; Application of extreme cold to destroy abnormal or diseased tissue.; Other Names: cryoablation; cryosurgical ablation; Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Procedure: laser surgery; Surgery using a laser (instead of a scalpel) to cut tissue; Other Names: conventional laser therapy; laser therapy, conventional; surgery, laser

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rima Jubran, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): April 16, 2007
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: November 4, 2003
• First Submitted That Met QC Criteria: November 5, 2003
• First Posted (Estimate): November 6, 2003

Study Record Updates

• Last Update Posted (Actual): July 30, 2021
• Last Update Submitted That Met QC Criteria: July 12, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Eye Diseases; Retinal Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Eye Diseases, Hereditary; Eye Neoplasms; Retinal Neoplasms; Retinoblastoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Carboplatin; Etoposide; Etoposide phosphate; Vincristine
• Other Study ID Numbers: ARET0231; U10CA098543 (U.S. NIH Grant/Contract); NCI-2009-00420 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CDR0000339627 (Other Identifier: Clinical Trials.gov); COG-ARET0231 (Other Identifier: Children's Oncology Group)