Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT00186888
First received: September 12, 2005
Last updated: June 19, 2014
Last verified: June 2014
  Purpose

Retinoblastoma is a childhood cancer which affects the retina of the eye. The retina is the light sensitive layer of tissue that lines the back of the eyeball; sends visual messages through the optic nerve to the brain. When only one eye is affected, this is known as unilateral retinoblastoma and when both eyes are affected, it is called bilateral retinoblastoma. Treatment for retinoblastoma is individualized for each patient and is based on the form and the stage of the disease (inside the eye or has moved outside). The main goal is always to cure the cancer, and save the life of the child. Treatments are also designed with the hope of saving the vision, while completely destroying the tumor. Therapies may involve surgery, chemotherapy, radiation, and other treatments called focal treatments. Focal treatments may be laser therapy, freezing, or heat treatments meant to shrink and kill the tumor.

In this study, researchers want to investigate how different participants respond to different therapies that are individualized specifically for them. Participants will be divided into three main groups, depending on whether the disease is unilateral or bilateral, and the stage of the disease. One of the main objectives of the study is to investigate how advanced tumors in children with bilateral disease respond to a new combination of chemotherapy with topotecan and vincristine, with G-CSF support. In order to improve results, some children with very advanced disease may receive carboplatin chemotherapy given around the eye at the same time that they receive topotecan by vein. Also, because children with retinoblastoma are diagnosed so early in life and the vision may be significantly impaired, this study will investigate how children develop and how the brain adjusts and compensates for the visual deficits. Finally, this study also investigates the biology of retinoblastoma, in order to understand better how this cancer develops.


Condition Intervention Phase
Retinoblastoma
Retinal Neoplasm
Procedure: Enucleation
Drug: Vincristine, Carboplatin
Procedure: Focal Therapies
Radiation: External Beam Radiation
Drug: Vincristine + Topotecan
Drug: Vincristine + Carboplatin + Etoposide
Drug: Vincristine + Cyclophosphamide + Doxorubicin
Drug: Vincristine+Carboplatin+Etoposide
Procedure: Periocular carboplatin
Other: G-CSF
Phase 3

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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Stratum B Response to Window Therapy [ Time Frame: Six weeks post window therapy ] [ Designated as safety issue: No ]
    The primary outcome is to estimate the proportion of stratum B patients responding to 2 courses of window therapy consisting of vincristine and topotecan. Complete Response is the complete regression of all apparent tumor masses in the funduscopic examination and by MRI and ultrasound (US). Partial Response is defined as greater than 50% (but less than 100%) reduction of the tumor masses in the funduscopic examination and by US and MRI, without the appearance of any new lesions. The response must persist for at least 4 weeks. Stratum A and C did not receive window therapy.


Secondary Outcome Measures:
  • Stratum B Response Rate of Early Stage Eyes to Window Therapy [ Time Frame: Six weeks post window therapy. ] [ Designated as safety issue: No ]
    To estimate the proportion of early stage eyes defined as Reese-Ellsworth Group I, II, or III eyes, that responded to 2 courses of window therapy which consisted of vincristine and topotecan

  • Relationship Between Topotecan Clearance (CL) and CYP3A4/5 Genotype in Stratum B Participants. [ Time Frame: Courses 1, 2, 5, and 8 ] [ Designated as safety issue: No ]
    Blood samples for pharmacokinetic studies were collected at 0 hour (pre-dose), 5 minutes, 1.5 and 2.5 hours after the end of topotecan dose on Course 1 Day 1, Course 2 Day 1, and if further studies were needed, Course 5 Day 1 and Course 8 Day 1. A blood sample for pharmacogenetic studies was collected during the course of therapy on protocol.

  • Relationship Between Topotecan Clearance (CL) and ABCG2/B1 Genotype in Stratum B Participants. [ Time Frame: Courses 1, 2, 5, and 8 ] [ Designated as safety issue: No ]
    Blood samples for pharmacokinetic studies were collected at 0 hour (pre-dose), 5 minutes, 1.5 and 2.5 hours after the end of topotecan dose on Course 1 Day 1, Course 2 Day 1, and if further studies were needed, Course 5 Day 1 and Course 8 Day 1. A blood sample for pharmacogenetic studies was collected during the course of therapy on protocol.


Enrollment: 107
Study Start Date: February 2005
Estimated Study Completion Date: November 2016
Primary Completion Date: November 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Stratum A
Patients with early bilateral or unilateral, or patients with bilateral that have already had the advanced eye enucleated. Treatment included vincristine and carboplatin for 8 courses, given at 3-4 week intervals. Focal therapies any time after second course can include cryotherapy, laser photocoagulation, thermotherapy, and plaque radiotherapy
Procedure: Enucleation

Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye.

For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye.

Drug: Vincristine, Carboplatin
(Stratum A subjects receive 8 courses every 3-4 weeks, Stratum B subjects receive this combination for Courses 3, 4, 6, 7, 9, and 10 after the window, if they respond to window therapy) Vincristine dosage< 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1.
Procedure: Focal Therapies
Method will be at the discretion of the treating team, used after second course of chemotherapy. Cryotherapy- freezing of affected tissue, Laser photocoagulation- using lasers to destroy affected tissue, Thermotherapy and thermochemotherapy- using heat or heat/chemotherapy combination to destroy diseased tissue, and Episcleral plaque brachytherapy- radiation insertions in the diseased area to destroy affected tissue.
Radiation: External Beam Radiation
44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease.
Other: G-CSF
G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir.
Stratum B

Patients with bilateral disease (at least one advanced stage eye), candidate for conservative management.

Treatment included window treatment with vincristine and topotecan, Followed by 3 more courses of vincristine-topotecan if they had a response to the window+ 6 courses of vincristine and carboplatin. If they do not respond to the window, they receive 6 courses of vincristine, carboplatin, and etoposide. Periocular injections of carboplatin are also given three times, depending on whether they respond to window.

Procedure: Enucleation

Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye.

For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye.

Drug: Vincristine, Carboplatin
(Stratum A subjects receive 8 courses every 3-4 weeks, Stratum B subjects receive this combination for Courses 3, 4, 6, 7, 9, and 10 after the window, if they respond to window therapy) Vincristine dosage< 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1.
Procedure: Focal Therapies
Method will be at the discretion of the treating team, used after second course of chemotherapy. Cryotherapy- freezing of affected tissue, Laser photocoagulation- using lasers to destroy affected tissue, Thermotherapy and thermochemotherapy- using heat or heat/chemotherapy combination to destroy diseased tissue, and Episcleral plaque brachytherapy- radiation insertions in the diseased area to destroy affected tissue.
Radiation: External Beam Radiation
44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease.
Drug: Vincristine + Topotecan
(Stratum B subjects receive two up-front courses of vincristine and topotecan, given in 21-day intervals, then those who respond receive 3 additional courses (courses 5, 8, and 11) after the window. Dosages are the same for both window and subsequent courses: Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Topotecan: TSE of 140 ± 20 ng/ml*hr, daily for 5 consecutive days, infused over 30 minutes.
Drug: Vincristine + Carboplatin + Etoposide

Stratum B patients that do not respond to window receive 6 courses of this combination.

Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1 Etoposide, < 12 months of age: 3.3 mg/kg/d i.v. days 1 - 3, ≥ 12 months of age: 100 mg/m2/d i.v. days 1 - 3

Procedure: Periocular carboplatin
Periocular (subtenon) carboplatin 20 mg, one injection, in courses 5, 8, and 11 in patients responding to the VT window, and in courses 1, 3, and 6 of VCE in patients not responding to the VT window, when active vitreous disease is present. Carboplatin 20 mg will be diluted in 2 mL of NS or D5W and given by subtenon administration while the patient is under general anesthesia.
Other: G-CSF
G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir.
Stratum C

Patients with advanced unilateral advanced intraocular disease. First intervention is enucleation.

If enucleated eye does not have disease outside the retina (low risk), no additional treatment is given.

For patients whose enucleated eye shows tumor outside the retina (intermediate risk), they will receive 4 courses of vincristine, cyclophosphamide, and doxorubicin followed by G-CSF.

For patients with high risk disease (involvement of the sclera, optic nerve at the level of the cut-end), treatment after enucleation is 6 courses of alternating chemotherapy with vincristine, carboplatin, etoposide (VCE) to alternate with vincristine, cyclophosphamide, and doxorubicin (VCD). High risk patients also receive external-beam radiation therapy.

Procedure: Enucleation

Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye.

For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye.

Radiation: External Beam Radiation
44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease.
Drug: Vincristine + Cyclophosphamide + Doxorubicin
(High risk Stratum C patients in courses 2, 4, and 6 after enucleation, intermediate risk stratum C patients for four consecutive courses after enucleation) Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Cyclophosphamide: < 12 months of age: 40 mg/kg i.v. day 1, ≥ 12 months of age: 1,200 mg/m2 i.v. day 1, MESNA 200 mg/m2 at 0, 3, 6, and 9 hours Doxorubicin < 12 months of age: 1.5 mg/kg i.v. day 1, ≥ 12 months of age: 45 mg/m2 i.v. day 1
Drug: Vincristine+Carboplatin+Etoposide
High risk Stratum C patients in courses 1, 3, and 5 after enucleation: Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1 Etoposide, < 12 months of age: 3.3 mg/kg/d i.v. days 1 - 3, ≥ 12 months of age: 100 mg/m2/d i.v. days 1 - 3
Other: G-CSF
G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir.

Detailed Description:

This study will determine the following:

PRIMARY OBJECTIVE:

  • To estimate the ocular survival and event-free survival of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments.

SECONDARY OBJECTIVES:

  • To estimate the ocular survival of eye and event-free survival of eye of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments.
  • To estimate the ocular survival and event free survival of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments.
  • To estimate the ocular survival and event free survival of eye of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments.
  • To estimate the ocular survival and event-free survival of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments.
  • To estimate the ocular survival of eye and event-free survival of eye of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments.
  • To estimate the response rate of early stage eyes (R-E I-III) in patients with contralateral advanced disease treated with vincristine and topotecan.
  • To estimate the ocular survival and event-free survival of early stage eyes (R-E I-III) of patients with contralateral advanced disease treated with vincristine and topotecan.
  • To describe the outcome of intraocular retinoblastoma with respect to the new International Classification for Intraocular Retinoblastoma and the AJCC.
  • To describe primary visual cortex function in patients with unilateral and bilateral retinoblastoma.
  • To describe the cognitive, adaptive, and social/emotional development of children with retinoblastoma.
  • To describe changes in the pineal gland during treatment in patients with bilateral retinoblastoma.
  • To assess the relation between CYP3A4/5 genotype and the pharmacokinetics and pharmacodynamics of topotecan.
  • To assess the relation between ABCG2 genotype and the pharmacokinetics and pharmacodynamics of topotecan.
  • To determine if carboplatin can produce changes in cochlear function that are detectable with measurement of otoacoustic emissions.
  • To evaluate the need for and feasibility of starting early intervention support during the first year after the diagnosis of retinoblastoma.

EXPLORATORY OBJECTIVES:

  • To provide insight into molecular pathogenesis of retinoblastoma.
  • To describe the incidence and type of germline mutations of the RB gene in patients with retinoblastoma.
  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must have newly diagnosed intraocular retinoblastoma, previously untreated. Patients previously diagnosed with unilateral retinoblastoma treated surgically (or with focal therapies), who develop asynchronous involvement of the contralateral eye, will be eligible for study.
  • Must have a life expectancy of at least 8 weeks.
  • Must have Performance Status (ECOG) of 0-2.
  • Patients must have an adequate liver function, as defined by bilirubin less than or equal to 3 x normal, and SGOT and SGPT less than or equal to 3x normal.
  • Patients must have adequate renal function as defined by serum creatinine less than or equal to 3x normal for age.
  • Legal guardians must sign an informed consent indicating that they are aware of this study, its possible benefits, and toxic side effects. Legal guardians will be given a copy of the consent form.

Exclusion Criteria:

  • Previously treated patients
  • Presence of metastatic disease or orbital involvement
  • Patients must not have an invasive infection at time of protocol entry.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00186888

Locations
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Sponsors and Collaborators
St. Jude Children's Research Hospital
Investigators
Principal Investigator: Ibrahim Qaddoumi, M.D. St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00186888     History of Changes
Other Study ID Numbers: RET5, P01CA023099
Study First Received: September 12, 2005
Results First Received: June 29, 2011
Last Updated: June 19, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by St. Jude Children's Research Hospital:
Cancer of the Eye
Eye Enucleation

Additional relevant MeSH terms:
Neoplasms
Eye Neoplasms
Retinoblastoma
Retinal Neoplasms
Neoplasms by Site
Eye Diseases
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Retinal Diseases
Cyclophosphamide
Etoposide phosphate
Doxorubicin
Etoposide
Vincristine
Carboplatin
Topotecan
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 29, 2014