A Study to Give Treatment Inside the Eye to Treat Retinoblastoma
Study Details
Study Description
Brief Summary
This phase II trial tests the safety and side effects of adding melphalan to standard chemotherapy in treating patients with retinoblastoma (RB). RB is a type of cancer that occurs in the eye. 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). The term, risk, refers to the chance of the cancer not responding to treatment or coming back after treatment. Chemotherapy drugs, such as melphalan, carboplatin, vincristine, and etoposide work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Melphalan is more commonly given later in therapy or in relapsed disease (cancer that has returned after treatment). Adding melphalan to standard chemotherapy early in treatment may improve the ability to treat vitreous seeds.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVE:
- 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:
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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.
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To evaluate the efficacy of intravitreal melphalan in conjunction with systemic chemotherapy in Group D intraocular retinoblastoma with vitreous seeding.
EXPLORATORY OBJECTIVES:
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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.
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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.
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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.
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To evaluate the effects of intravitreal melphalan therapy in the histopathology of enucleated eyes for progressive or recalcitrant retinoblastoma while on therapy.
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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 eligible, patients receive one intravitreal injection of melphalan during days -14 to 14 of each cycle. Patients who are not eligible for melphalan for any cycle receive CVE regimen only 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (CVE, melphalan) See Detailed Description |
Procedure: Biospecimen Collection
Undergo correlative studies
Other Names:
Drug: Carboplatin
Given IV
Other Names:
Drug: Etoposide
Given IV
Other Names:
Procedure: Examination Under Anesthesia
Undergo imaging of the eye during EUA
Drug: Melphalan
Given I-VITRE
Other Names:
Procedure: Ultrasound Biomicroscopy
Undergo UBM during EUA
Drug: Vincristine
Given IV
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Feasibility of intravitreal melphalan injection in combination with systemic chemotherapy [Up to cycle 6 (1 cycle = 28 days)]
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.
Secondary Outcome Measures
- Incidence of adverse events [Up to 30 days after last dose of study treatment]
Any eligible patient who receives protocol therapy will be considered as evaluable for toxicity. Percentage of patients with Grade 3 or higher toxicities in Common Terminology Criteria for Adverse Events (CTCAE) will be summarized.
- Event-free survival (EFS) [Up to 5 years]
Any eligible patient who receives protocol therapy will be considered as evaluable for EFS. EFS is defined as time from date of enrollment to the earliest occurrence of date of treatment failure, relapse, disease progression, SMN or death due to any cause. 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.
Other Outcome Measures
- Retrospective central review of examination under anesthesia (EUA) and ultrasound biomicroscopy (UBM) images: Cycle 3 to cycle 6 [Cycle 3 to cycle 6 (1 cycle = 28 days).]
Any eligible patient will receive intravitreal melphalan injection at cycle 3. Retrospective central review of exam under anesthesia at diagnosis, including retinal drawing, RETCAM, and Ultrasound Biomicroscopy (UBM) images, will determine if eyes that become eligible for injection at cycle 3 or later would have been eligible for injection at diagnosis. Will summarize the retrospective central review on images from diagnosis for eyes that are eligible for injection at cycle 3 or later.
- Retrospective central review of examination under anesthesia (EUA) and ultrasound biomicroscopy (UBM) images: Cycle 7 to cycle 11 [Cycle 7 to cycle 11 (1 cycle = 14-21 days)]
Any eligible patient following completion of cycle 6 will receive intravitreal melphalan injection at cycle 7. Retrospective central review of exam under anesthesia at diagnosis, including retinal drawing, RETCAM, and Ultrasound Biomicroscopy (UBM) images, will determine if eyes that are still eligible for injection at cycle 7 or later. Will summarize the retrospective central review on images from diagnosis for eyes that are eligible for injection at cycle 7 or later.
- Validate and standardize the aqueous humor extraction, storage, and collection protocols across multiple centers [Up to 5 years]
Extract tumor-derived deoxyribonucleic acid (DNA), from aqueous humor,for whole genome sequencing and RB1 testing.
- Highly-recurrent RB somatic copy number alterations (SCNAs) and ocular salvage [Up to 5 years]
Will explore the relationship between highly-recurrent RB SCNAs and ocular salvage as a marker of minimal residual disease and risk of intraocular disease relapse.
- Highly-recurrent RB somatic copy number alterations (SCNAs) and tumor fraction [Up to 5 years]
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.
- Proportion of enucleated eyes with histopathological characteristics that are known or suspected to affect prognosis adversely [Up to 5 years]
Will be calculated along with the 95% confidence interval. The number of evaluable eyes for this aim will depend on the ocular salvage rate.
- Long-term visual potential [Up to 5 years]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patient must be < 18 years of age at enrollment
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Patient must have newly diagnosed intraocular (localized) retinoblastoma and meet one of the following criteria:
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Unilateral Group D retinoblastoma with vitreous seeding; OR
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Bilateral retinoblastoma with worst eye Group D, with vitreous seeding present and the contralateral eye is Group A-C; OR
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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
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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
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Peripheral absolute neutrophil count (ANC) >= 750/uL (must be performed within 7 days prior to enrollment unless otherwise indicated)
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Platelet count >= 75,000/uL (transfusion independent) (must be performed within 7 days prior to enrollment)
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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):
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1 month to < 6 months = 0.4 (male and female)
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6 months to < 1 year = 0.5 (male and female)
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1 to < 2 years = 0.6 (male and female)
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2 to < 6 years = 0.8 (male and female)
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6 to < 10 years = 1.0 (male and female)
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10 to < 13 years = 1.2 (male and female)
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13 to < 16 years = 1.5 (male) and 1.4 (female)
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= 16 years = 1.7 (male) and 1.4 (female) OR - a 24-hour urine Creatinine clearance >= 70 mL/min/1.73 m2 OR - a glomerular filtration rate (GFR) >= 70 mL/min/1.73 m2. 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)
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Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility
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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
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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)
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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)
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Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
Exclusion Criteria:
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Patients with evidence of metastatic or extra-orbital spread
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Patients must not have an invasive infection at time of protocol entry
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Patients must not have had any prior anti-cancer therapy to the study eye(s), including focal, local, or systemic chemotherapy or radiation therapy
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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
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Patients with no reasonable expectation for any useful vision in the Group D eye as determined by the treating physician
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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
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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
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Lactating females who plan to breastfeed their infants
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Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
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All patients and/or their parents or legal guardians must sign a written informed consent
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All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Children's Oncology Group
Investigators
- Principal Investigator: Rachel C Brennan, Children's Oncology Group
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ARET2121
- NCI-2022-06082
- ARET2121
- ARET2121
- U10CA180886