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Elizabeth D. Alva

Jay Michael S. Balagtas

Sandra Luna-Fineman

Laura Sedig

Daniel Willis

Jessica M. Sun

Erin Wright

Rabi Hanna

Carlos Rodriguez-Galindo

Shannon M. Cohn

Daniel C. Bowers

Murali M. Chintagumpala

Najat C. Daw

Marianne B. Phillips

Rachana Shah

This phase II trial tests the safety and side effects of adding melphalan (by injecting it into the eye) to standard chemotherapy in early treatment of patients with retinoblastoma (RB). RB is a type of cancer that forms in the tissues of the retina (the light-sensitive layers of nerve tissue at the back of the eye). It may be hereditary or nonhereditary (sporadic). RB is considered harder to treat (higher risk) when there are vitreous seeds present. Vitreous seeds are RB tumors in the jelly-like fluid of the eye (called the vitreous humor). The term, risk, refers to the chance of the cancer not responding to treatment or coming back after treatment. Melphalan is in a class of medications called alkylating agents. It may kill cancer cells by damaging their deoxyribonucleic acid (DNA) and stopping them from dividing. Other chemotherapy drugs given during this trial include carboplatin, vincristine, and etoposide. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Adding melphalan to standard chemotherapy early in treatment may improve the ability to treat vitreous seeds and may be better than standard chemotherapy alone in treating retinoblastoma.

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.

A Study to Give Treatment Inside the Eye to Treat Retinoblastoma

Intravitreal Melphalan for Intraocular Retinoblastoma

In order to determine if eyes that become eligible for injection at cycle 3 or later would have been eligible for injection at diagnosis, the retrospective central review on images from diagnosis for eyes that are eligible for injection at cycle 3 or later will be summarized.

Extract tumor-derived deoxyribonucleic acid (DNA), from aqueous humor, for whole genome sequencing and retinoblastoma (RB)1 testing.

Will explore the relationship between highly-recurrent RB SCNAs and tumor fraction (% of tumor DNA) as a marker of minimal residual disease and risk of intraocular disease relapse.

Will explore the relationship between highly-recurrent RB 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.

Will be calculated along with the 95% confidence interval. The number of evaluable eyes for this aim will depend on the ocular salvage rate.

Eligible patients who retain the affected eye will be evaluated for visual acuity. The visual acuity will be evaluated prior to cycle 1 and at one year from end of therapy, if age-appropriate. The visual acuity data will be summarized by evaluation time points.

A patient will be considered to have experienced intravitreal injection feasibility success if intravitreal melphalan can be delivered by cycle 6. If the treating physician does not inject because the eye has a full complete response (CR) for vitreous seeds after 2 cycles of systemic chemotherapy, it will be counted as a success in the feasibility analysis. Any feasibility evaluable patient who does not experience feasibility success will be considered a feasibility failure. For a bilateral patient with two Group D eyes with vitreous seeds, he/she will be categorized based on the worse results with the intent of being conservative, i.e., if intravitreal melphalan can be delivered in one eye but not the other by cycle 6 for any reason other than a CR of vitreal seeds, the patient will be deemed as experiencing a failure.

Any eligible patient who receives protocol therapy will be considered as evaluable for toxicity.

Any eligible patient who receives protocol therapy will be considered as evaluable for EFS. Patients who need non-protocol chemotherapy, external beam radiotherapy, or enucleation will be considered as having a treatment failure and be considered as experiencing EFS events. The analysis will be conducted per patient level. The EFS along with the 95% confidence intervals will be estimated using the Kaplan-Meier method.

Children's Oncology Group

Spots Global Cancer Trial Database for group d retinoblastoma