Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma - Full Text View

Purpose

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.

Condition	Intervention	Phase
Retinoblastoma	Drug: vincristine Drug: topotecan Drug: filgrastim Drug: PEG-filgrastim Drug: carboplatin Other: focal therapy Drug: etoposide Drug: cyclophosphamide Drug: MESNA Drug: doxorubicin Procedure: enucleation Radiation: external beam radiation	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

Resource links provided by NLM:

Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:

Response rate (complete or partial response) [ Time Frame: After two upfront courses of chemotherapy (approximately two months after patient enrollment) ] [ Designated as safety issue: No ]
Stratum B patients, those Stratum B patients who had no significant subtretinal seeding and received vincristine and topotecan are not evaluable for this primary objective.

Secondary Outcome Measures:

ocular survival [ Time Frame: at end of study (approximately three years after the last patient enrollment) ] [ Designated as safety issue: Yes ]
Ocular survival per eye will be defined as the time interval from study enrollment to date of enucleation or to date of last contact for eyes that have not been enucleated.
Event-free survival [ Time Frame: at end of study (approximately three years after the last patient enrollment) ] [ Designated as safety issue: No ]
Event-free survival per eye will be defined as the time interval from date on study to date of first event (where an event includes external beam radiation or enucleation) or to the date of last contact for eyes without events.
The mechanism (or frequencies) for each RB1 biallelic inactivation [ Time Frame: At end of study (approximately one year after the last patient is enrolled on study) ] [ Designated as safety issue: No ]
The tumor tissue samples will be obtained from participant who has at least one eye undergoing enucleation.

Estimated Enrollment:	155
Study Start Date:	February 2013
Estimated Study Completion Date:	February 2022
Estimated Primary Completion Date:	February 2020 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Stratum A 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, and focal therapy including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy.	Drug: vincristine Given IV push over 1 minute. Other Names: VCR Oncovin(R) Drug: topotecan Given IV over 30 minutes. Other Names: TOPO Hycamtin(R) Drug: filgrastim 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. Other Names: G-CSF Neupogen(R) Drug: PEG-filgrastim Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until ANC is >2,000/µL on one occasion after the expected nadir. Other Names: pegylated filgrastim PEG filgrastim SD-01 Neulasta(R) Drug: carboplatin Given IV over 60 minutes. Given periocular (subtenon/subconjunctival). Other Names: CARBO Paraplatin(R) Other: focal therapy Focal treatments will be administered any time after the second course of chemotherapy. In select cases of very early stage retinoblastoma, 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. In some participants, additional doses of carboplatin may be required after the completion of the 8 scheduled courses in order to achieve tumor control through thermotherapy. Other Names: cryotherapy laser photocoagulation thermo-therapy plaque radiotherapy thermo-chemotherapy episcleral plaque brachytherapy
Experimental: Stratum B Participants considered candidates for conservative management including those: Participants with bilateral retinoblastoma who have R-E IV-V and IC D in one eye 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 Given IV push over 1 minute. Other Names: VCR Oncovin(R) Drug: topotecan Given IV over 30 minutes. Other Names: TOPO Hycamtin(R) Drug: filgrastim 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. Other Names: G-CSF Neupogen(R) Drug: PEG-filgrastim Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until ANC is >2,000/µL on one occasion after the expected nadir. Other Names: pegylated filgrastim PEG filgrastim SD-01 Neulasta(R) Drug: carboplatin Given IV over 60 minutes. Given periocular (subtenon/subconjunctival). Other Names: CARBO Paraplatin(R) Other: focal therapy Focal treatments will be administered any time after the second course of chemotherapy. In select cases of very early stage retinoblastoma, 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. In some participants, additional doses of carboplatin may be required after the completion of the 8 scheduled courses in order to achieve tumor control through thermotherapy. Other Names: cryotherapy laser photocoagulation thermo-therapy plaque radiotherapy thermo-chemotherapy episcleral plaque brachytherapy Drug: etoposide Given IV. Participants who cannot tolerate etoposide may be given etoposide phosphate (Etopophos(R)). Other Names: ETOP VP-16 Vepesid(R) Etopophos(R)
Experimental: Stratum C 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 Given IV push over 1 minute. Other Names: VCR Oncovin(R) Drug: filgrastim 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. Other Names: G-CSF Neupogen(R) Drug: PEG-filgrastim Given subcutaneously 24-36 hours after chemotherapy for 7-10 days, until ANC is >2,000/µL on one occasion after the expected nadir. Other Names: pegylated filgrastim PEG filgrastim SD-01 Neulasta(R) Drug: carboplatin Given IV over 60 minutes. Given periocular (subtenon/subconjunctival). Other Names: CARBO Paraplatin(R) Drug: etoposide Given IV. Participants who cannot tolerate etoposide may be given etoposide phosphate (Etopophos(R)). Other Names: ETOP VP-16 Vepesid(R) Etopophos(R) Drug: cyclophosphamide Given IV. Other Names: CYCLO Cytoxan(R) Drug: MESNA Given IV before CYCLO and at 3, 6 and 9 hours after CYCLO. Other Name: Mesnex(R) Drug: doxorubicin Given IV on Day 1 of Cycles 2, 4 and 6 in Stratum C high-risk. Other Names: DOXO Adriamycin(R) Procedure: enucleation Eye removal due to advanced disease in Stratum D participants. Other Name: eye removal
Experimental: Stratum D 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, focal therapy including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation therapy.	Drug: vincristine Given IV push over 1 minute. Other Names: VCR Oncovin(R) Drug: topotecan Given IV over 30 minutes. Other Names: TOPO Hycamtin(R) Drug: carboplatin Given IV over 60 minutes. Given periocular (subtenon/subconjunctival). Other Names: CARBO Paraplatin(R) Other: focal therapy Focal treatments will be administered any time after the second course of chemotherapy. In select cases of very early stage retinoblastoma, 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. In some participants, additional doses of carboplatin may be required after the completion of the 8 scheduled courses in order to achieve tumor control through thermotherapy. Other Names: cryotherapy laser photocoagulation thermo-therapy plaque radiotherapy thermo-chemotherapy episcleral plaque brachytherapy Drug: etoposide Given IV. Participants who cannot tolerate etoposide may be given etoposide phosphate (Etopophos(R)). Other Names: ETOP VP-16 Vepesid(R) Etopophos(R) Procedure: enucleation Eye removal due to advanced disease in Stratum D participants. Other Name: eye removal Radiation: external beam radiation EBRT 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. Other Name: EBRT

Show Detailed Description

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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 < or equal to 3X upper limit of normal (ULN), and SGOT and SGPT < or equal to 3X ULN.
Participants must have adequate renal function as defined by serum creatinine < or equal 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.

Exclusion Criteria:

Previously treated participants.
Presence of metastatic disease or 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01783535

Contacts

Contact: Rachel C. Brennan, MD

866-278-5833

info@stjude.org

Locations

United States, Tennessee
St. Jude Children's Research Hospital	Not yet recruiting
Memphis, Tennessee, United States, 38105
Contact: Rachel C. Brennan, MD 866-278-5833 info@stjude.org
Principal Investigator: Rachel C. Brennan, MD

Sponsors and Collaborators

St. Jude Children's Research Hospital

Investigators

Principal Investigator:

Rachel C. Brennan, MD

St. Jude Children's Research Hospital

More Information

Additional Information:

St. Jude Children's Research Hospital This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:	NCT01783535 History of Changes
Other Study ID Numbers:	SJRET6
Study First Received:	January 31, 2013
Last Updated:	February 4, 2013
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration

Keywords provided by St. Jude Children's Research Hospital:

intraocular retinoblastoma

Additional relevant MeSH terms:

Retinoblastoma
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
Retinal Diseases
Mesna
Cyclophosphamide

Etoposide phosphate
Doxorubicin
Etoposide
Vincristine
Carboplatin
Topotecan
Lenograstim
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on May 23, 2013