SJRET6: Combination Chemotherapy in Treating Patients with Newly Diagnosed, Previously Untreated Intraocular Retinoblastoma

Protocol for the Study and Treatment of Participants with Intraocular Retinoblastoma

Categories:

Solid Tumor

Phase I/II

Diseases Treated:

Retinoblastoma

Eligibility Overview:

  • Newly diagnosed retinoblastoma that has not spread beyond the eye
  • Has not received previous treatment with chemotherapy or radiation therapy
  • Patients who have been diagnosed with retinoblastoma in one eye who did not receive chemotherapy, but then developed retinoblastoma in the opposite eye
  1. Brief Summary

    The primary objective of this protocol is to evaluate the response rate of bilateral disease participants who have at least 1 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.

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    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 2 upfront courses of therapy consisting of subconjunctival carboplatin and systemic topotecan.

    Trial Outline

    Participants will be stratified into 4 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.

    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 6 courses of chemotherapy; 3 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 at the discretion of the treating team. 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 2 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 3 additional courses of vincristine-topotecan (VT) and 6 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 2 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 3 additional courses of vincristine-topotecan, and 6 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.

    Focal treatments will be administered at the discretion of the treating team. Focal therapies will include cryotherapy, laser photocoagulation, thermo-therapy and plaque radiotherapy.

    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 1 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 2 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.

    Focal treatments will be administered at the discretion of the treating team. Focal therapies will include cryotherapy, laser photocoagulation, thermo-therapy and plaque radiotherapy.

    Study Arms

    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)
    • 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

    Vincristine, carboplatin, topotecan, filgrastim or PEG-filgrastim, and focal therapy - Strata A, 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 1 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

    Vincristine, topotecan, carboplatin, etoposide, filgrastim or PEG-filgrastim and focal therapy - Stratum B and D, 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

    Vincristine, cyclophosphamide, mesna, doxorubicin, etoposide, carboplatin, filgrastim or PEG-filgrastim, enucleation

    Experimental: Stratum D

    Participants with bilateral retinoblastoma who may require upfront enucleation for 1 eye due to advanced disease (R-E IV-V and IC E).

    Interventions

    Vincristine, carboplatin, topotecan, etoposide, enucleation, filgrastim or PEG-filgrastim, focal therapy - Stratum B and D, including cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy) and episcleral plaque brachytherapy, and external beam radiation therapy

    Eligibility

    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 2 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

    Study Design

    • Allocation: Non-Randomized
    • Endpoint Classification: Safety/Efficacy Study
    • Intervention Model: Parallel Assignment
    • Masking: Open Label
    • Primary Purpose: Treatment
  2. About this clinical trial

    SJRET6 is a Phase II clinical trial for children with newly diagnosed retinoblastoma that has not spread beyond the eye. Retinoblastoma is a rare cancer of the retina, which is the thin membrane on the inside back of the eye that is stimulated by light. This type of cancer is usually diagnosed before a child is 3 years old and can be passed down in families (inherited from parents). 

    The most important goal of retinoblastoma treatment at St. Jude Children’s Research Hospital is always to cure your child’s cancer and save your child’s life. Treatments are also focused on increasing the chances of saving your child’s eye and vision as much as possible, while still trying to completely destroy the cancer.

    Purpose of this clinical trial

    In this Phase II trial, St. Jude researchers want to find out how well giving chemotherapy directly to the eye with the first two cycles (six weeks) of treatment works in treating participants with retinoblastoma in one or both eyes with advanced tumors. Participants who do not have advanced tumors in one or both eyes will receive standard treatment.

    Treatment

    There are three parts to this study:

    • Staging– the first step is to find out how much tumor is in the eye and where it has spread.
    • Treatment – treatment can include surgery, chemotherapy, laser therapy or freezing/heat treatments directly to the eye and radiation therapy. The treatment is tailored specifically for your child depending on:
      • whether the tumor affects one eye or both eyes
      • how far the tumor has spread to  areas in and around the eye, or outside the eye
    • Follow-up – there will be regular follow-up visits for five years after treatment is completed.

    Eligibility overview

    • Newly diagnosed retinoblastoma that has not spread beyond the eye
    • Has not received previous treatment with chemotherapy or radiation therapy
    • Patients who have been diagnosed with retinoblastoma in one eye who did not receive chemotherapy, but then developed retinoblastoma in the opposite eye
  3. SJRET6   Quick View
    Sponsor St. Jude Children's Research Hospital
    Clinicaltrials.gov identifier NCT01783535
    Trial start date June 2013
    Estimated enrollment 155
    Study type Interventional
    Study phase Phase 2
    Condition Retinoblastoma
    Principal investigator Rachel C. Brennan, MD
    Study site St. Jude Children’s Research Hospital
    For a consultation or to discuss SJRET6 St. Jude Physician/Patient Referral Office
    1-888-226-4343
    referralinfo@stjude.org

Contact

Rachael C. Brennan, MD

St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Voice: 1-888-226-4343 or 901-595-4055
24-Hour Emergency Access Pager: 1-800-349-4334

Referring or consulting clinicians only: protocolinfo@stjude.org
For all other inquiries about St. Jude Children's Research Hospital studies: referralinfo@stjude.org

The above information is intended to provide only a basic description about a research protocol that may be currently active at St. Jude. The details made available here may not be the most up-to-date information on protocols used by St. Jude. To receive full details about a protocol and its status and or use at St. Jude, a physician must contact St. Jude directly.