Trial Information

Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

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]. 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 any time after the second course of chemotherapy.
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.

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 and in whom the remaining eye is R-E IV-V, will still be eligible to
proceed with stratum B therapy, including consideration of periocular administration of
carboplatin.