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Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

Primary Purpose

Retinoblastoma

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
vincristine
topotecan
filgrastim
PEG-filgrastim
carboplatin
focal therapy
etoposide
cyclophosphamide
MESNA
doxorubicin
enucleation
external beam radiation or proton beam radiation
Sponsored by
St. Jude Children's Research Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Retinoblastoma focused on measuring intraocular retinoblastoma

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Newly diagnosed, untreated intraocular retinoblastoma. Participants previously diagnosed with unilateral retinoblastoma treated surgically, with focal therapy or needing chemotherapy who develop asynchronous involvement of the contralateral eye, or patients with unilateral retinoblastoma treated only with enucleation or focal therapy who develop asynchronous involvement of the contralateral eye, will be eligible for study.
  • ECOG Performance Score must be ≤ 2 within two weeks prior to registration.
  • Participants must have an adequate liver function, as defined by bilirubin ≤ to 3X upper limit of normal (ULN), and SGOT and SGPT ≤ to 3X ULN.
  • Participants must have adequate renal function as defined by serum creatinine ≤ to 3X ULN for age.
  • Legal guardians must sign an informed consent indicating that they are aware of this study, the possible benefits, and toxic side effects. Legal guardians will be given a signed copy of the consent form.

Exclusion Criteria:

  • Previously treated participants.
  • Presence of metastatic disease or gross (residual) orbital involvement
  • Participants must not have an invasive infection at time of protocol entry.
  • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Sites / Locations

  • St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Stratum A

Stratum B

Stratum C

Stratum D

Arm Description

Participants with early bilateral or unilateral (unifocal or multifocal) retinoblastoma (R-E I-III, IC A-B; R-E IV with IC A or B; or IC C with limited sub-retinal seeding), and participants with bilateral disease in whom the advanced eye has been enucleated upfront (without any high risk histopathology) and the remaining eye has early stage disease (as defined above). Interventions (see detailed description): vincristine, carboplatin, topotecan, filgrastim or PEG-filgrastim, and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.

Participants considered candidates for conservative management including those: Participants with bilateral retinoblastoma who have R-E IV-V and IC D in one eye Participants with advanced unilateral (unifocal or multifocal) retinoblastoma (R-E IV-V and IC D-E) who demonstrate foveal sparing by the tumor during EUA. Due to foveal sparing, these patients have potential for vision preservation. Interventions (see Detailed Description): vincristine, topotecan, carboplatin, etoposide, filgrastim or PEG-filgrastim and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.

Participants with advanced (R-E IV-V and IC D-E) unilateral retinoblastoma who require upfront enucleation. Participants will be assessed and treated by low, intermediate or high risk. Interventions (see Detailed Description): vincristine, cyclophosphamide, MESNA, doxorubicin, etoposide, carboplatin, filgrastim or PEG-filgrastim, enucleation

Participants with bilateral retinoblastoma who may require upfront enucleation for one eye due to advanced disease (R-E IV-V and IC E). Interventions (see Detailed Description): vincristine, carboplatin, topotecan, etoposide, enucleation, filgrastim or PEG-filgrastim, focal therapy, including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation or proton beam radiation in select cases.

Outcomes

Primary Outcome Measures

Response rate (complete or partial response)
Stratum B patients, those Stratum B patients who had no significant subretinal seeding and received vincristine and topotecan are not evaluable for this primary objective.

Secondary Outcome Measures

ocular survival
Ocular survival per eye will be defined as the time interval from study enrollment to date of enucleation or to date of last contact for eyes that have not been enucleated.
Event-free survival
Event-free survival per eye will be defined as the time interval from date on study to date of first event (where an event includes external beam radiation or enucleation) or to the date of last contact for eyes without events.
The mechanism (or frequencies) for each RB1 biallelic inactivation
The tumor tissue samples will be obtained from participant who has at least one eye undergoing enucleation.

Full Information

First Posted
January 31, 2013
Last Updated
March 6, 2023
Sponsor
St. Jude Children's Research Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01783535
Brief Title
Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
Official Title
Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 19, 2013 (Actual)
Primary Completion Date
March 2, 2023 (Actual)
Study Completion Date
January 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
St. Jude Children's Research Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The primary objective of this protocol is to evaluate the response rate of bilateral disease participants who have at least one eye with advanced intra-ocular retinoblastoma (stratum B) using upfront therapy with chemotherapy delivered directly to the eye. The main biology objective is to improve our understanding of the biology and tumorigenesis (how tumor develops) of retinoblastoma when biology specimens are available. As clinicians, the primary goal of the investigators for children with retinoblastoma is to provide optimal therapy using multiple treatment approaches [chemotherapy (into the vein and directly into membrane of eyeball), cryotherapy (freeze and destroy tumor), thermotherapy (laser or heat to destroy tumor), radiation therapy, and surgical removal of eye if needed) in an attempt to preserve the eye and vision whenever possible, while still curing the disease. Therefore, all children with non-metastatic retinoblastoma at St. Jude will be offered enrollment on this study. PRIMARY OBJECTIVE: To evaluate the response (complete + partial response) rate of bilateral disease participants who have at least one eye with advanced intraocular retinoblastoma (Stratum B) to two upfront courses of therapy consisting of subconjunctival carboplatin and systemic topotecan. SECONDARY OBJECTIVES: To evaluate the ocular survival of eyes and event-free survival of participants by strata. To prospectively analyze intraocular disease tissue for participants with at least one eye undergoing enucleation in order to identify the mechanism of RB1 bi-allelic inactivation. Participants may undergo upfront enucleation (due to advanced disease at diagnosis) or may receive enucleation due to progressive disease during protocol therapy.
Detailed Description
Participants will be stratified into four main treatment groups, depending on whether retinoblastoma is present in one or both eyes and disease grouping [early or advanced, Reese-Ellsworth (R-E) group I-V, and International Classification A-E]. Additionally, participants will be invited to participate in exploratory research objectives that address cognitive and functional development of children with retinoblastoma, the pharmacokinetics of topotecan in young children, and evaluation of ototoxicity, including genetic analysis. TREATMENT PLAN STRATUM A: Children ≥ or equal to 6 months old at time of enrollment - 8 courses of vincristine and carboplatin, given at 3-4 week intervals. Infants < 6 months old at time of enrollment - Therapy will consist of six courses of chemotherapy; three courses of vincristine and carboplatin, given at 3-4 week intervals, alternating with 3 cycles of vincristine and topotecan, given at 3-4 week intervals. Focal treatments will be administered at the discretion of the treating team. Focal therapies will include cryotherapy, laser photocoagulation, thermo-therapy and plaque radiotherapy. STRATUM B: Participants without extensive sub-retinal (SR) seeding, treatment will consist of two up-front courses of vincristine and topotecan, given at 3-4 week intervals. Participants without SR seeding: ≥ or equal to partial response after 2 cycles, will receive three additional courses of vincristine-topotecan (VT) and six courses of vincristine-carboplatin, given at 3-4 week intervals. Participants without SR seeding and < partial response after 2 cycles VT will receive 6 courses of vincristine-carboplatin-etoposide (VCE), given at 3-4 week intervals. Participants with extensive sub-retinal (SR) seeding will receive two up-front courses of subconjunctival (also called subtenon or periocular) CARBOplatin and systemic topotecan, given at 3-4 week intervals. Participants with SR seeding: > or equal to partial response after 2 cycles will receive three additional courses of vincristine-topotecan, and six courses of vincristine-carboplatin, given at 3-4 week intervals. Participants with SR seeding: < partial response after 2 cycles will receive 6 courses of VCE, given at 3-4 week intervals. Focal treatments will be administered at the discretion of the treating team. Focal therapies will include cryotherapy, laser photocoagulation, thermo-therapy and plaque radiotherapy. STRATUM C: Participants with unilateral (unifocal or multifocal) advanced (R-E IV-V and IC D-E) intraocular disease will undergo enucleation. Adjuvant therapy will be based on histopathology: low risk participants: Participants in whom the enucleated eye does not show extra-retinal disease (see definition of intermediate and high risk below); will not receive any additional treatment. intermediate risk participants: Participants in whom the enucleated eye shows presence of tumor in the anterior chamber, invasion of the ciliary body/iris, massive invasion of the choroid, and invasion of the optic nerve beyond the lamina cribrosa with concomitant invasion of the choroid, will receive 4 courses of adjuvant chemotherapy with vincristine-carboplatin-doxorubicin (VCD). high risk participants: Participants in whom the enucleated eye shows involvement of the sclera, or involvement of the optic nerve at the level of the cut-end, will be treated with 6 courses of chemotherapy, with alternating courses of VCE and VCD. High-risk participants with extra-ocular extension (i.e. tumor extending beyond the sclera/cornea or beyond the cut end of the optic nerve) will be candidates for external-beam radiation therapy (EBRT) to the entire orbit, including the optic nerve, administered after 2 or 3 courses of treatment. Patients with extra-ocular extension may be considered for enrollment on an alternative therapeutic protocol for metastatic retinoblastoma (or best clinical management). STRATUM D: Management of participants with bilateral retinoblastoma is often complex; and some participants will have one eye enucleated upfront due to advanced disease. The decision for enucleation will be made after thorough consideration by the treating team. The treatment of the remaining eye will depend on a combination of two factors: a) R-E group of the remaining eye, and b) Histology of the enucleated eye. Though we have accumulated some information regarding the use of vincristine, cyclophosphamide, and doxorubicin in the treatment of intraocular retinoblastoma, it is not considered standard of care. Therefore, participants with intermediate and high risk features will be treated with 6 courses of vincristine, carboplatin, and etoposide (VCE). Those participants in whom the enucleated eye shows only low risk histology will be eligible to proceed with either stratum A or stratum B therapy. For those receiving stratum B therapy, consideration of periocular carboplatin will be allowed. External beam or proton beam radiation therapy will be considered for patients with extra-ocular extension. Focal treatments will be administered at the discretion of the treating team. Focal therapies will include cryotherapy, laser photocoagulation, thermo-therapy and plaque radiotherapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Retinoblastoma
Keywords
intraocular retinoblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
174 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Stratum A
Arm Type
Experimental
Arm Description
Participants with early bilateral or unilateral (unifocal or multifocal) retinoblastoma (R-E I-III, IC A-B; R-E IV with IC A or B; or IC C with limited sub-retinal seeding), and participants with bilateral disease in whom the advanced eye has been enucleated upfront (without any high risk histopathology) and the remaining eye has early stage disease (as defined above). Interventions (see detailed description): vincristine, carboplatin, topotecan, filgrastim or PEG-filgrastim, and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.
Arm Title
Stratum B
Arm Type
Experimental
Arm Description
Participants considered candidates for conservative management including those: Participants with bilateral retinoblastoma who have R-E IV-V and IC D in one eye Participants with advanced unilateral (unifocal or multifocal) retinoblastoma (R-E IV-V and IC D-E) who demonstrate foveal sparing by the tumor during EUA. Due to foveal sparing, these patients have potential for vision preservation. Interventions (see Detailed Description): vincristine, topotecan, carboplatin, etoposide, filgrastim or PEG-filgrastim and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.
Arm Title
Stratum C
Arm Type
Experimental
Arm Description
Participants with advanced (R-E IV-V and IC D-E) unilateral retinoblastoma who require upfront enucleation. Participants will be assessed and treated by low, intermediate or high risk. Interventions (see Detailed Description): vincristine, cyclophosphamide, MESNA, doxorubicin, etoposide, carboplatin, filgrastim or PEG-filgrastim, enucleation
Arm Title
Stratum D
Arm Type
Experimental
Arm Description
Participants with bilateral retinoblastoma who may require upfront enucleation for one eye due to advanced disease (R-E IV-V and IC E). Interventions (see Detailed Description): vincristine, carboplatin, topotecan, etoposide, enucleation, filgrastim or PEG-filgrastim, focal therapy, including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation or proton beam radiation in select cases.
Intervention Type
Drug
Intervention Name(s)
vincristine
Other Intervention Name(s)
VCR, Oncovin(R)
Intervention Description
Given via minibag/gravity flow.
Intervention Type
Drug
Intervention Name(s)
topotecan
Other Intervention Name(s)
TOPO, Hycamtin(R)
Intervention Description
Given IV over 30 minutes.
Intervention Type
Drug
Intervention Name(s)
filgrastim
Other Intervention Name(s)
G-CSF, Neupogen(R)
Intervention Description
Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until absolute neutrophil count (ANC) is >2,000/µL on one occasion after the expected nadir.
Intervention Type
Drug
Intervention Name(s)
PEG-filgrastim
Other Intervention Name(s)
pegylated filgrastim, PEG filgrastim, SD-01, Neulasta(R)
Intervention Description
Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until ANC is >2,000/µL on one occasion after the expected nadir.
Intervention Type
Drug
Intervention Name(s)
carboplatin
Other Intervention Name(s)
CARBO, Paraplatin(R)
Intervention Description
Given IV over 60 minutes. Given periocular (subtenon/subconjunctival).
Intervention Type
Other
Intervention Name(s)
focal therapy
Other Intervention Name(s)
cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy, thermo-chemotherapy, episcleral plaque brachytherapy
Intervention Description
Focal treatments will be administered at the discretion of the treating team to strata A, B and D. In select cases of very early stage retinoblastoma (Stratum A), participants may receive focal therapies only and chemotherapy will be held at the discretion of the treating team. If there is any evidence of progression or unsatisfactory results, the participant will begin chemotherapy as per Stratum A. For selected participants an effort will be made to perform sequential chemo-thermotherapy. In these cases, carboplatin will be administered one or two hours prior to thermotherapy.
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
ETOP, VP-16, Vepesid(R), Etopophos(R)
Intervention Description
Given IV. Participants who cannot tolerate etoposide may be given etoposide phosphate (Etopophos(R)).
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CYCLO, Cytoxan(R)
Intervention Description
Given IV.
Intervention Type
Drug
Intervention Name(s)
MESNA
Other Intervention Name(s)
Mesnex(R)
Intervention Description
Given IV before CYCLO and at 3, 6 and 9 hours after CYCLO.
Intervention Type
Drug
Intervention Name(s)
doxorubicin
Other Intervention Name(s)
DOXO, Adriamycin(R)
Intervention Description
Given IV on Day 1 of Cycles 2, 4 and 6 in Stratum C high-risk.
Intervention Type
Procedure
Intervention Name(s)
enucleation
Other Intervention Name(s)
eye removal
Intervention Description
Eye removal due to advanced disease in Strata C and D participants.
Intervention Type
Radiation
Intervention Name(s)
external beam radiation or proton beam radiation
Other Intervention Name(s)
EBRT
Intervention Description
EBRT or proton beam radiation will be administered to any eye in which the disease is considered to be not controllable with focal treatments alone, and in participants with enucleated eyes in which high risk of orbital and/or central nervous system disease is documented histologically (high-risk group with disease extension beyond the sclera or cornea, or beyond the cut end of the optic nerve). EBRT will be administered using standard techniques practices with the objective of limiting dose to normal tissues including the hypothalamic-pituitary unit, supratentorial brain, orbit, cochleae and contralateral eye when indicated. Participants will be evaluated on an individual basis to determine whether they might benefit from referral for proton therapy.
Primary Outcome Measure Information:
Title
Response rate (complete or partial response)
Description
Stratum B patients, those Stratum B patients who had no significant subretinal seeding and received vincristine and topotecan are not evaluable for this primary objective.
Time Frame
After two upfront courses of chemotherapy (approximately two months after patient enrollment)
Secondary Outcome Measure Information:
Title
ocular survival
Description
Ocular survival per eye will be defined as the time interval from study enrollment to date of enucleation or to date of last contact for eyes that have not been enucleated.
Time Frame
at end of study (approximately three years after the last patient enrollment)
Title
Event-free survival
Description
Event-free survival per eye will be defined as the time interval from date on study to date of first event (where an event includes external beam radiation or enucleation) or to the date of last contact for eyes without events.
Time Frame
at end of study (approximately three years after the last patient enrollment)
Title
The mechanism (or frequencies) for each RB1 biallelic inactivation
Description
The tumor tissue samples will be obtained from participant who has at least one eye undergoing enucleation.
Time Frame
At end of study (approximately one year after the last patient is enrolled on study)

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Newly diagnosed, untreated intraocular retinoblastoma. Participants previously diagnosed with unilateral retinoblastoma treated surgically, with focal therapy or needing chemotherapy who develop asynchronous involvement of the contralateral eye, or patients with unilateral retinoblastoma treated only with enucleation or focal therapy who develop asynchronous involvement of the contralateral eye, will be eligible for study. ECOG Performance Score must be ≤ 2 within two weeks prior to registration. Participants must have an adequate liver function, as defined by bilirubin ≤ to 3X upper limit of normal (ULN), and SGOT and SGPT ≤ to 3X ULN. Participants must have adequate renal function as defined by serum creatinine ≤ to 3X ULN for age. Legal guardians must sign an informed consent indicating that they are aware of this study, the possible benefits, and toxic side effects. Legal guardians will be given a signed copy of the consent form. Exclusion Criteria: Previously treated participants. Presence of metastatic disease or gross (residual) orbital involvement Participants must not have an invasive infection at time of protocol entry. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlos Rodriguez-Galindo, MD
Organizational Affiliation
St. Jude Children's Research Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.stjude.org
Description
St. Jude Children's Research Hospital
URL
http://www.stjude.org/protocols
Description
Clinical Trials Open at St. Jude

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Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

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