Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma

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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 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 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.

      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 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 will be eligible to proceed with either stratum A or stratum B therapy.
      For those receiving stratum B therapy, consideration of periocular carboplatin will be
      allowed. External beam or proton beam radiation therapy will be considered for patients with
      extra-ocular extension.

      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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Response rate (complete or partial response)

Secondary Outcome

 ocular survival

Condition

Retinoblastoma

Intervention

vincristine

Study Arms / Comparison Groups

 Stratum A
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

147

Start Date

June 19, 2013

Completion Date

June 2022

Primary Completion Date

November 2021

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

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Rachel C. Brennan, MD, 866-278-5833, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01783535

Organization ID

SJRET6

Secondary IDs

NCI-2013-00409

Responsible Party

Sponsor

Study Sponsor

St. Jude Children's Research Hospital


Study Sponsor

Rachel C. Brennan, MD, Principal Investigator, St. Jude Children's Research Hospital


Verification Date

January 2021