• Age: Participants must be \< 8 years of age.

• Diagnosis and Treatment. Participants must have: Group D or earlier-stage intraocular retinoblastoma in which enucleation is a recommended therapy, OR Active residual or recurrent intraocular retinoblastoma in at least one eye following completion of first- line therapy (focal therapy for IIRC Group A eyes, or systemic or intra-arterial chemotherapy).

⁃ If both eyes require treatment, there will receive independent and individual treatment. Non-study eye will be treated by standard of care, with only focal therapy during the Study Period, if required.

• Must have demonstrated intraocular calcium in the tumor-containing eye by ophthalmic ultrasound or by neuroimaging as part of standard retinoblastoma diagnosis.

• Study eye must have vision potential, at least light perception vision in the tumor-bearing eye either with pupil response testing or demonstration of avoidance behavior to light presentation in the affected eye, and no clinical features suggestive of high risk of extraocular extension.

• Performance Level: Lansky ≥ 50 (\<16 years of age); Karnofsky performance scale of ≥50 (≥16 years of age).

• Organ Function Requirements:

‣ Adequate Bone Marrow Function defined as:

• Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3

∙ Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 Days prior to enrollment)

∙ Hemoglobin ≥ 8.0 g/dL at baseline (may receive RBC transfusions)

⁃ Adequate Renal Function defined as:

• Creatinine clearance or radioisotope GFR ≥70ml/min/1.73 m2 or

∙ A serum creatinine based on age/gender as follows:

‣ Age Maximum Serum Creatinine (mg/dL) Male Female

‣ 1 month to \< 6 months 0.4 0.4 6 months to \< 1 year 0.5 0.5

• to \< 2 years 0.6 0.6

‣ The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

⁃ Adequate Liver Function defined as:

• Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age.

∙ SGPT (ALT) ≤ 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

∙ Serum albumin ≥ 2 g/dL.

⁃ Pregnancy prevention. Females of reproductive potential must agree to the use of highly effective contraception during study participation and for an additional 40 days after the end of Episcleral Topotecan administration.

⁃ Informed consent. All participants and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign a written informed consent. Assent, where appropriate, will also be obtained.