Bilateral RetinoblastomaPhase 2NCT05504291
A Study to Give Treatment Inside the Eye to Treat Retinoblastoma
A Phase 2 study testing Biospecimen Collection, Carboplatin and Etoposide in people with Bilateral Retinoblastoma and Childhood Intraocular Retinoblastoma, run by Children's Oncology Group at 20 sites in 3 countries.
Trial summary
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). Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Bilateral Retinoblastoma, Childhood Intraocular Retinoblastoma, Group D Retinoblastoma
- What is being tested?
- Biospecimen Collection, Carboplatin and Etoposide
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 20 sitesin 3 countries
- Study dates
- 4 Nov 2022to 31 Mar 2028
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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 Group D retinoblastoma with at least one eye with vitreous seeding; 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
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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 not been enucleated prior to any therapy at the discretion of the treating physician. Note exclusion for patients with evidence of metastatic or extra orbital spread
- 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/sex 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
- The threshold creatinine values were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Center for Disease Control (CDC)
- 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
Who cannot join
- 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 other than cryotherapy and/or laser therapy (green or infrared) to the study eye(s) and non-study eye, including systemic chemotherapy, intra-arterial chemotherapy, radioactive plaque, brachytherapy, 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 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
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- 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
Trial locations and contacts
20 sites in 3 countries. Contact the study team or a site near you to ask about taking part.
20 sites in 3 countries
United States17 sites, 16 recruiting
- Recruiting
Children's Hospital Medical Center of Akron
Akron, Ohio, 44308
Site Public Contact, 330-543-3193
Erin Wright
- Recruiting
C S Mott Children's Hospital
Ann Arbor, Michigan, 48109
Site Public Contact, 800-865-1125
Laura Sedig
- Recruiting
Children's Healthcare of Atlanta - Arthur M Blank Hospital
Atlanta, Georgia, 30329
Site Public Contact, 404-785-0232, Olivia.Floyd@choa.org
Sarah G. Mitchell
- Recruiting
Children's Hospital Colorado
Aurora, Colorado, 80045
Site Public Contact, 303-764-5056, josh.b.gordon@nsmtp.kp.org
Sandra Luna-Fineman
- Recruiting
Dell Children's Medical Center of Central Texas
Austin, Texas, 78723
Site Public Contact, 512-628-1902, TXAUS-DL-SFCHemonc.research@ascension.org
Shannon M. Cohn
- Recruiting
Children's Hospital of Alabama
Birmingham, Alabama, 35233
Site Public Contact, 205-638-9285, oncologyresearch@peds.uab.edu
Elizabeth D. Alva
- Recruiting
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Site Public Contact, 866-223-8100, TaussigResearch@ccf.org
Matteo M. Trucco
- Recruiting
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Site Public Contact, 214-648-7097, canceranswerline@UTSouthwestern.edu
Daniel C. Bowers
- Recruiting
Duke University Medical Center
Durham, North Carolina, 27710
Site Public Contact, 888-275-3853
Jessica M. Sun
- Recruiting
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, 77030
Site Public Contact, 713-798-1354, burton@bcm.edu
Murali M. Chintagumpala
- Recruiting
UT MD Anderson Cancer Center
Houston, Texas, 77030
Site Public Contact, 866-632-6789, askmdanderson@mdanderson.org
Najat C. Daw
- Recruiting
Children's Hospital Los Angeles
Los Angeles, California, 90027
Site Public Contact, 323-361-4110
Rachana Shah
- Recruiting
Saint Jude Children's Research Hospital
Memphis, Tennessee, 38105
Site Public Contact, 888-226-4343, referralinfo@stjude.org
Carlos Rodriguez-Galindo
- Recruiting
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53226
Site Public Contact, 414-955-4727, MACCCTO@mcw.edu
Kerri Becktell
- Recruiting
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, 94304
Site Public Contact, 800-694-0012, ccto-office@stanford.edu
Jay Michael S. Balagtas
- Withdrawn
Primary Children's Hospital
Salt Lake City, Utah, 84113
- Recruiting
Washington University School of Medicine
St Louis, Missouri, 63110
Site Public Contact, 800-600-3606, info@siteman.wustl.edu
Amy Armstrong
Australia2 sites
- Suspended
Royal Children's Hospital
Parkville, Victoria, 3052
- Suspended
Perth Children's Hospital
Perth, Western Australia, 6009
Canada1 site, 1 recruiting
- Recruiting
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, H3T 1C5
Site Public Contact, 514-345-4931, yvan.samson@umontreal.ca
Monia Marzouki
About this study
Official title: Intravitreal Melphalan for Intraocular Retinoblastoma
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.
Read the 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:
- 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:
- 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.
- 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, and urine sample collection at baseline and on study. 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. Additionally, patients undergo urine sample collection at baseline and on study for Cycles 3-6. NOTE: Patients may be eligible to receive additional cycles of melphalan alone (maximum of 6 injections).
Additionally, patients undergo magnetic resonance imaging and may undergo aqueous humor and tissue sample collection throughout the trial.
After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for 1 year, and then every 3-6 months for years 2-5.
- Conditions
- Bilateral Retinoblastoma, Childhood Intraocular Retinoblastoma, Group D Retinoblastoma, Stage I Retinoblastoma, Unilateral Retinoblastoma
- Being tested
- Biospecimen Collection, Carboplatin, Etoposide, Examination Under Anesthesia, Magnetic Resonance Imaging
- Medical subject headings
- Retinoblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection
Undergo aqueous humor, tissue, and blood sample collection
CarboplatinDrug
Also called Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino
Given IV
EtoposideDrug
Also called Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar
Given IV
Examination Under AnesthesiaProcedure or surgery
Undergo imaging of the eye during EUA
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
MelphalanDrug
Also called Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard
Given I-VITRE
Ultrasound BiomicroscopyProcedure or surgery
Also called Ultrasound Biomicroscopy (UBM)
Undergo UBM during EUA
VincristineDrug
Also called LCR, Leurocristine, VCR, Vincrystine
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Treatment (CVE, melphalan) | Experimental | See Detailed Description Receives: Procedure: Biospecimen Collection; Drug: Carboplatin; Drug: Etoposide; Procedure: Examination Under Anesthesia; Procedure: Magnetic Resonance Imaging; Drug: Melphalan; Procedure: Ultrasound Biomicroscopy; Drug: Vincristine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility success rate of intravitreal melphalan injection in combination with systemic chemotherapy
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.
Measured: Up to cycle 6 (1 cycle = 28 days)
Secondary outcomes (2)
Percentage of patients with grade 3 or higher toxicities
Any eligible patient who receives protocol therapy will be considered as evaluable for toxicity.
Measured: Up to 30 days after last dose of study treatment
Event-free survival (EFS)
Any eligible patient who receives protocol therapy will be considered as evaluable for EFS. Patients who need non-protocol chemotherapy for either the study eye or non-study eye, external beam radiotherapy for either the study eye or non-study eye, or enucleation for the study eye 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.
Measured: Up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Aug 2022
- Study start4 Nov 2022
- Primary completion31 Mar 2028 (estimated)
- Study completion31 Mar 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bilateral RetinoblastomaStudies of the same condition, open and under way.
- More trials run by Children's Oncology GroupThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Children's Oncology Group
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Rachana Shah, Principal investigator, Children's Oncology Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05504291
- Sponsor's protocol ID
- ARET2121
- Other IDs
- NCI-2022-06082, ARET2121, ARET2121, U10CA180886
- Status last verified
- Feb 2026
- First submitted
- 4 Aug 2022
- Last updated
- 25 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No