Clinical Trial Finder

Inclusion Criteria:

• - Patient must be < 18 years of age at enrollment.

• - Patient must have newly diagnosed intraocular (localized) retinoblastoma and meet one of the following criteria: - Unilateral Group D retinoblastoma with vitreous seeding; OR.

• - Bilateral retinoblastoma with worst eye Group D, with vitreous seeding present and the contralateral eye is Group A-C; OR.

• - Bilateral retinoblastoma with one Group D eye with vitreous seeding and one Group E eye where the Group E eye has been enucleated prior to any therapy.

Note exclusion for high-risk features.

• - Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2.

Use Karnofsky for patients > 16 years of age and Lansky for patients =<16 years of age.

• - Peripheral absolute neutrophil count (ANC) >= 750/uL (must be performed within 7 days prior to enrollment unless otherwise indicated) - Platelet count >= 75,000/uL (transfusion independent) (must be performed within 7 days prior to enrollment) - A serum creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment; must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment): - 1 month to < 6 months = 0.4 (male and female) - 6 months to < 1 year = 0.5 (male and female) - 1 to < 2 years = 0.6 (male and female) - 2 to < 6 years = 0.8 (male and female) - 6 to < 10 years = 1.0 (male and female) - 10 to < 13 years = 1.2 (male and female) - 13 to < 16 years = 1.5 (male) and 1.4 (female) - >= 16 years = 1.7 (male) and 1.4 (female) OR - a 24-hour urine Creatinine clearance >= 70 mL/min/1.73 m^2 OR - a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2.

GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard)

• - Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility.

• - For patients < 1 month of age, serum creatinine levels must be < 1.5 x the treating institution's creatinine upper limit of normal (ULN) for patients < 1 month of age or the creatinine clearance or radioisotope GFR must be >= 70 mL/min/1.73 m^2.

• - Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment; must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (must be performed within 7 days prior to enrollment; must be repeated prior to the start of protocol therapy if > 7 days have elapsed from their most recent prior assessment) - Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.

Exclusion Criteria:

• - Patients with evidence of metastatic or extra-orbital spread.

• - Patients must not have an invasive infection at time of protocol entry.

• - Patients must not have had any prior anti-cancer therapy to the study eye(s), including focal, local, or systemic chemotherapy or radiation therapy.

• - Note: A study eye is defined as being Group D with vitreous seeding.

Patients may have had enucleation of one eye as long as the remaining eye is Group D with vitreous seeds.

• - Patients with no reasonable expectation for any useful vision in the Group D eye as determined by the treating physician.

• - Patients with bilateral disease who undergo enucleation of a Group E eye prior to initiation of therapy and show evidence of high-risk histopathology features in the enucleated eye.

High-risk histopathology includes choroid involvement >= 3 mm, post lamina optic nerve involvement, full thickness scleral invasion or optic nerve invasion to the cut end.

• - Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs.

A pregnancy test is required for female patients of childbearing potential.

• - Lactating females who plan to breastfeed their infants.

• - Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

• - All patients and/or their parents or legal guardians must sign a written informed consent.

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

PRIMARY OBJECTIVE:

• I. To determine the feasibility of administering intravitreal melphalan by cycle 6 when given in combination with systemic carboplatin, vincristine, and etoposide (CVE) for the treatment of Group D retinoblastoma with vitreous seeding.

SECONDARY OBJECTIVES:

• I. To determine the safety and toxicity profile associated with intravitreal melphalan in combination with systemic CVE for the treatment of Group D retinoblastoma with vitreous seeding.

• II. To evaluate the efficacy of intravitreal melphalan in conjunction with systemic chemotherapy in Group D intraocular retinoblastoma with vitreous seeding.

EXPLORATORY OBJECTIVES:

• I. To determine if eyes that become eligible for injection at cycle 3 or later would have been eligible for injection at diagnosis by retrospective central review of examination under anesthesia (EUA) and ultrasound biomicroscopy (UBM) images from diagnosis.

• II. To validate and standardize the extraction, storage and collection protocols across multiple centers to demonstrate that aqueous humor from eyes undergoing therapy have high enough tumor-derived deoxyribonucleic acid (DNA) concentration for whole genome sequencing and RB1 testing.

• III. To explore the relationship between highly-recurrent retinoblastoma (RB) somatic copy number alterations (SCNAs) and ocular salvage as well as tumor fraction (% of tumor DNA) as a marker of minimal residual disease and risk of intraocular disease relapse.

• IV. To evaluate the effects of intravitreal melphalan therapy in the histopathology of enucleated eyes for progressive or recalcitrant retinoblastoma while on therapy.

• V. To evaluate the long-term visual potential of eyes salvaged using intravitreal therapy.

OUTLINE: CYCLES 1-2: Patients receive CVE regimen consisting of: carboplatin intravenously (IV) over 15-60 minutes on days 1 and 2 of each cycle, vincristine IV on day 1 of each cycle, and etoposide IV over 90-120 minutes on day 1 and 2 of each cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ultrasound biomicroscopy (UBM) and imaging of the eye during a procedure called examination under anesthesia (EUA) at baseline and prior to each cycle. NOTE: UBM is completed prior to cycle 1 only. CYCLES 3+: Patients receive CVE regimen as in cycles 1-2. Patients also undergo EUA prior to each cycle to determine eligibility to receive melphalan. If found eligible, patients receive intravitreal injection of melphalan once between days -14 to 14 of each cycle. Patients who are not eligible for melphalan for any cycle receive CVE only regimen for that cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients may be eligible to receive additional cycles of melphalan alone (maximum of 6 injections). After completion of study treatment, patients are followed up periodically until 5 years from study enrollment.

Arms

Experimental: Treatment (CVE, melphalan)

See Detailed Description

Interventions

Procedure: - Biospecimen Collection

Undergo correlative studies

Drug: - Carboplatin

Given IV

Drug: - Etoposide

Given IV

Procedure: - Examination Under Anesthesia

Undergo imaging of the eye during EUA

Drug: - Melphalan

Given I-VITRE

Procedure: - Ultrasound Biomicroscopy

Undergo UBM during EUA

Drug: - Vincristine

Given IV