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.
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
