Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma | RxWiki

Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

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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	Retinoblastoma
Intervention	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	Phase 2
Sponsor	St. Jude Children's Research Hospital
Responsible Party	St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier	NCT01783535
First Received	January 31, 2013
Last Updated	December 31, 2013
Last verified	December 2013

Tracking Information[ + expand ][ + ]

First Received Date	January 31, 2013
Last Updated Date	December 31, 2013
Start Date	June 2013
Estimated Primary Completion Date	June 2022
Current 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 subretinal seeding and received vincristine and topotecan are not evaluable for this primary objective.
Current 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.

Descriptive Information[ + expand ][ + ]

Brief Title	Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
Official Title	Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
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.
Detailed Description	Participants will be stratified into four main treatment groups, depending on whether retinoblastoma is present in one or both eyes and disease grouping [early or advanced, Reese-Ellsworth (R-E) group I-V, and International Classification A-E]. Additionally, participants will be invited to participate in exploratory research objectives that address cognitive and functional development of children with retinoblastoma, the pharmacokinetics of topotecan in young children, and evaluation of ototoxicity, including genetic analysis. TREATMENT PLAN STRATUM A: - Children > or equal to 6 months old at time of enrollment - 8 courses of vincristine and carboplatin, given at 3-4 week intervals. - Infants < 6 months old at time of enrollment - Therapy will consist of six courses of chemotherapy; three courses of vincristine and carboplatin, given at 3-4 week intervals, alternating with 3 cycles of vincristine and topotecan, given at 3-4 week intervals. Focal treatments will be administered any time after the second course of chemotherapy. Focal therapies will include cryotherapy, laser photocoagulation, thermo-therapy and plaque radiotherapy. STRATUM B: - Participants without extensive sub-retinal (SR) seeding, treatment will consist of two up-front courses of vincristine and topotecan, given at 3-4 week intervals. - Participants without SR seeding: > or equal to partial response after 2 cycles, will receive three additional courses of vincristine-topotecan (VT) and six courses of vincristine-carboplatin, given at 3-4 week intervals. - Participants without SR seeding and < partial response after 2 cycles VT will receive 6 courses of vincristine-carboplatin-etoposide (VCE), given at 3-4 week intervals. - Participants with extensive sub-retinal (SR) seeding will receive two up-front courses of subconjunctival (also called subtenon or periocular) CARBOplatin and systemic topotecan, given at 3-4 week intervals. - Participants with SR seeding: > or equal to partial response after 2 cycles will receive three additional courses of vincristine-topotecan, and six courses of vincristine-carboplatin, given at 3-4 week intervals. - Participants with SR seeding: < partial response after 2 cycles will receive 6 courses of VCE, given at 3-4 week intervals. STRATUM C: Participants with unilateral (unifocal or multifocal) advanced (R-E IV-V and IC D-E) intraocular disease will undergo enucleation. Adjuvant therapy will be based on histopathology: - low risk participants: Participants in whom the enucleated eye does not show extra-retinal disease (see definition of intermediate and high risk below); will not receive any additional treatment. - intermediate risk participants: Participants in whom the enucleated eye shows presence of tumor in the anterior chamber, invasion of the ciliary body/iris, massive invasion of the choroid, and invasion of the optic nerve beyond the lamina cribrosa with concomitant invasion of the choroid, will receive 4 courses of adjuvant chemotherapy with vincristine-carboplatin-doxorubicin (VCD). - high risk participants: Participants in whom the enucleated eye shows involvement of the sclera, or involvement of the optic nerve at the level of the cut-end, will be treated with 6 courses of chemotherapy, with alternating courses of VCE and VCD. - High-risk participants with extra-ocular extension (i.e. tumor extending beyond the sclera/cornea or beyond the cut end of the optic nerve) will be candidates for external-beam radiation therapy (EBRT) to the entire orbit, including the optic nerve, administered after 2 or 3 courses of treatment. Patients with extra-ocular extension may be considered for enrollment on an alternative therapeutic protocol for metastatic retinoblastoma (or best clinical management). STRATUM D: Management of participants with bilateral retinoblastoma is often complex; and some participants will have one eye enucleated upfront due to advanced disease. The decision for enucleation will be made after thorough consideration by the treating team. The treatment of the remaining eye will depend on a combination of two factors: a) R-E group of the remaining eye, and b) Histology of the enucleated eye. Though we have accumulated some information regarding the use of vincristine, cyclophosphamide, and doxorubicin in the treatment of intraocular retinoblastoma, it is not considered standard of care. Therefore, participants with intermediate and high risk features will be treated with 6 courses of vincristine, carboplatin, and etoposide (VCE). Those participants in whom the enucleated eye shows only low risk histology and in whom the remaining eye is R-E IV-V, will still be eligible to proceed with stratum B therapy, including consideration of periocular administration of carboplatin.
Study Type	Interventional
Study Phase	Phase 2
Study Design	Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Retinoblastoma
Intervention	Drug: vincristine Given via minibag/gravity flow. 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) 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 Names: 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 Names: eye removalRadiation: 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 Names: EBRT
Study Arm (s)	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, filgrastim or PEG-filgrastim, and focal therapy including cryotherapy, laser photocoagulation, thermo-therapy, plaque radiotherapy. 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. 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 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, filgrastim or PEG-filgrastim, focal therapy including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation therapy.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Recruiting
Estimated Enrollment	155
Estimated Completion Date	June 2022
Estimated Primary Completion Date	June 2020
Eligibility 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 ≤ 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. Exclusion Criteria: - 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.
Gender	Both
Ages	N/A
Accepts Healthy Volunteers	No
Contacts	Contact: Rachel C. Brennan, MD 866-278-5833 info@stjude.org
Location Countries	United States

Administrative Information[ + expand ][ + ]

NCT Number	NCT01783535
Other Study ID Numbers	SJRET6
Has Data Monitoring Committee	No
Information Provided By	St. Jude Children's Research Hospital
Study Sponsor	St. Jude Children's Research Hospital
Collaborators	Not Provided
Investigators	Principal Investigator: Rachel C. Brennan, MD St. Jude Children's Research Hospital
Verification Date	December 2013

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