Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

NCT01783535 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: SJRET6NCI-2013-00409
• Study Type: interventional
• Target: 174
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this protocol is to evaluate the response rate of bilateral disease participants who have at least one eye with advanced intra-ocular retinoblastoma (stratum B) using upfront therapy with chemotherapy delivered directly to the eye. The main biology objective is to improve our understanding of the biology and tumorigenesis (how tumor develops) of retinoblastoma when biology specimens are available. As clinicians, the primary goal of the investigators for children with retinoblastoma is to provide optimal therapy using multiple treatment approaches \[chemotherapy (into the vein and directly into membrane of eyeball), cryotherapy (freeze and destroy tumor), thermotherapy (laser or heat to destroy tumor), radiation therapy, and surgical removal of eye if needed) in an attempt to preserve the eye and vision whenever possible, while still curing the disease. Therefore, all children with non-metastatic retinoblastoma at St. Jude will be offered enrollment on this study. PRIMARY OBJECTIVE:

• To evaluate the response (complete + partial response) rate of bilateral disease participants who have at least one eye with advanced intraocular retinoblastoma (Stratum B) to two upfront courses of therapy consisting of subconjunctival carboplatin and systemic topotecan. SECONDARY OBJECTIVES:
• To evaluate the ocular survival of eyes and event-free survival of participants by strata.
• To prospectively analyze intraocular disease tissue for participants with at least one eye undergoing enucleation in order to identify the mechanism of RB1 bi-allelic inactivation. Participants may undergo upfront enucleation (due to advanced disease at diagnosis) or may receive enucleation due to progressive disease during protocol therapy.

Conditions

Retinoblastoma

Keywords

intraocular retinoblastoma

Outcome Measures

Primary Outcomes (1)

• Response rate (complete or partial response)

  Stratum B patients, those Stratum B patients who had no significant subretinal seeding and received vincristine and topotecan are not evaluable for this primary objective.

  After two upfront courses of chemotherapy (approximately two months after patient enrollment)

Secondary Outcomes (3)

• ocular survival

  at end of study (approximately three years after the last patient enrollment)

• Event-free survival

  at end of study (approximately three years after the last patient enrollment)

• The mechanism (or frequencies) for each RB1 biallelic inactivation

  At end of study (approximately one year after the last patient is enrolled on study)

Study Arms (4)

Stratum A

EXPERIMENTAL

Participants with early bilateral or unilateral (unifocal or multifocal) retinoblastoma (R-E I-III, IC A-B; R-E IV with IC A or B; or IC C with limited sub-retinal seeding), and participants with bilateral disease in whom the advanced eye has been enucleated upfront (without any high risk histopathology) and the remaining eye has early stage disease (as defined above). Interventions (see detailed description): vincristine, carboplatin, topotecan, filgrastim or PEG-filgrastim, and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.

Drug: vincristine; Drug: topotecan; Drug: filgrastim; Drug: PEG-filgrastim; Drug: carboplatin; Other: focal therapy

Stratum B

EXPERIMENTAL

Participants considered candidates for conservative management including those: 1. Participants with bilateral retinoblastoma who have R-E IV-V and IC D in one eye 2. Participants with advanced unilateral (unifocal or multifocal) retinoblastoma (R-E IV-V and IC D-E) who demonstrate foveal sparing by the tumor during EUA. Due to foveal sparing, these patients have potential for vision preservation. Interventions (see Detailed Description): vincristine, topotecan, carboplatin, etoposide, filgrastim or PEG-filgrastim and focal therapy, including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.

Drug: vincristine; Drug: topotecan; Drug: filgrastim; Drug: PEG-filgrastim; Drug: carboplatin; Other: focal therapy; Drug: etoposide

Stratum C

EXPERIMENTAL

Participants with advanced (R-E IV-V and IC D-E) unilateral retinoblastoma who require upfront enucleation. Participants will be assessed and treated by low, intermediate or high risk. Interventions (see Detailed Description): vincristine, cyclophosphamide, MESNA, doxorubicin, etoposide, carboplatin, filgrastim or PEG-filgrastim, enucleation

Drug: vincristine; Drug: filgrastim; Drug: PEG-filgrastim; Drug: carboplatin; Drug: etoposide; Drug: cyclophosphamide; Drug: MESNA; Drug: doxorubicin; Procedure: enucleation

Stratum D

EXPERIMENTAL

Participants with bilateral retinoblastoma who may require upfront enucleation for one eye due to advanced disease (R-E IV-V and IC E). Interventions (see Detailed Description): vincristine, carboplatin, topotecan, etoposide, enucleation, filgrastim or PEG-filgrastim, focal therapy, including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation or proton beam radiation in select cases.

Drug: vincristine; Drug: topotecan; Drug: filgrastim; Drug: PEG-filgrastim; Drug: carboplatin; Other: focal therapy; Drug: etoposide; Procedure: enucleation; Radiation: external beam radiation or proton beam radiation

Interventions

vincristine DRUG

Given via minibag/gravity flow.

Also known as: VCR, Oncovin(R)

Stratum A; Stratum B; Stratum C; Stratum D

topotecan DRUG

Given IV over 30 minutes.

Also known as: TOPO, Hycamtin(R)

Stratum A; Stratum B; Stratum D

filgrastim DRUG

Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until absolute neutrophil count (ANC) is \>2,000/µL on one occasion after the expected nadir.

Also known as: G-CSF, Neupogen(R)

Stratum A; Stratum B; Stratum C; Stratum D

PEG-filgrastim DRUG

Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until ANC is \>2,000/µL on one occasion after the expected nadir.

Also known as: pegylated filgrastim, PEG filgrastim, SD-01, Neulasta(R)

Stratum A; Stratum B; Stratum C; Stratum D

carboplatin DRUG

Given IV over 60 minutes. Given periocular (subtenon/subconjunctival).

Also known as: CARBO, Paraplatin(R)

Stratum A; Stratum B; Stratum C; Stratum D

focal therapy OTHER

Focal treatments will be administered at the discretion of the treating team to strata A, B and D. In select cases of very early stage retinoblastoma (Stratum A), participants may receive focal therapies only and chemotherapy will be held at the discretion of the treating team. If there is any evidence of progression or unsatisfactory results, the participant will begin chemotherapy as per Stratum A. For selected participants an effort will be made to perform sequential chemo-thermotherapy. In these cases, carboplatin will be administered one or two hours prior to thermotherapy.

Also known as: cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy, thermo-chemotherapy, episcleral plaque brachytherapy

Stratum A; Stratum B; Stratum D

etoposide DRUG

Given IV. Participants who cannot tolerate etoposide may be given etoposide phosphate (Etopophos(R)).

Also known as: ETOP, VP-16, Vepesid(R), Etopophos(R)

Stratum B; Stratum C; Stratum D

cyclophosphamide DRUG

Given IV.

Also known as: CYCLO, Cytoxan(R)

Stratum C

MESNA DRUG

Given IV before CYCLO and at 3, 6 and 9 hours after CYCLO.

Also known as: Mesnex(R)

Stratum C

doxorubicin DRUG

Given IV on Day 1 of Cycles 2, 4 and 6 in Stratum C high-risk.

Also known as: DOXO, Adriamycin(R)

Stratum C

enucleation PROCEDURE

Eye removal due to advanced disease in Strata C and D participants.

Also known as: eye removal

Stratum C; Stratum D

external beam radiation or proton beam radiation RADIATION

EBRT or proton beam radiation will be administered to any eye in which the disease is considered to be not controllable with focal treatments alone, and in participants with enucleated eyes in which high risk of orbital and/or central nervous system disease is documented histologically (high-risk group with disease extension beyond the sclera or cornea, or beyond the cut end of the optic nerve). EBRT will be administered using standard techniques practices with the objective of limiting dose to normal tissues including the hypothalamic-pituitary unit, supratentorial brain, orbit, cochleae and contralateral eye when indicated. Participants will be evaluated on an individual basis to determine whether they might benefit from referral for proton therapy.

Also known as: EBRT

Stratum D

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed, untreated intraocular retinoblastoma. Participants previously diagnosed with unilateral retinoblastoma treated surgically, with focal therapy or needing chemotherapy who develop asynchronous involvement of the contralateral eye, or patients with unilateral retinoblastoma treated only with enucleation or focal therapy who develop asynchronous involvement of the contralateral eye, will be eligible for study.
• ECOG Performance Score must be ≤ 2 within two weeks prior to registration.
• Participants must have an adequate liver function, as defined by bilirubin ≤ to 3X upper limit of normal (ULN), and SGOT and SGPT ≤ to 3X ULN.
• Participants must have adequate renal function as defined by serum creatinine ≤ to 3X ULN for age.
• Legal guardians must sign an informed consent indicating that they are aware of this study, the possible benefits, and toxic side effects. Legal guardians will be given a signed copy of the consent form.

You may not qualify if:

• Previously treated participants.
• Presence of metastatic disease or gross (residual) orbital involvement
• Participants must not have an invasive infection at time of protocol entry.
• Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Retinoblastoma

Interventions

Vincristine; Topotecan; trioctyl phosphine oxide; Filgrastim; Granulocyte Colony-Stimulating Factor; pegfilgrastim; Carboplatin; Cryotherapy; Brachytherapy; Etoposide; Cyclophosphamide; Mesna; Doxorubicin; Eye Enucleation

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Retinal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases, Hereditary; Eye Diseases; Retinal Diseases

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Camptothecin; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Coordination Complexes; Organic Chemicals; Therapeutics; Radiotherapy; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Ophthalmologic Surgical Procedures; Surgical Procedures, Operative

Study Officials

• Carlos Rodriguez-Galindo, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2013
• First Posted: February 5, 2013
• Study Start: June 19, 2013
• Primary Completion: March 17, 2023
• Study Completion (Estimated): January 1, 2028
• Last Updated: April 16, 2024

Record last verified: 2024-03

Locations

US (1)