Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
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.
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.
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.