Combination Chemotherapy and Cyclosporine Followed by Focal Therapy for Bilateral Retinoblastoma

Multicenter Phase II Study for International Intraocular Retinoblastoma Classification Groups B, C & D Tumors Treated With Carboplatin-Etoposide-Vincristine-Cyclosporine-Focal Therapy Multimodality Protocol (OCRN Multicenter RB 2003)

RATIONALE: Drugs used in chemotherapy, such as carboplatin, etoposide, and vincristine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sometimes when chemotherapy is given, it does not stop the growth of tumor cells. The tumor is said to be resistant to chemotherapy. Giving cyclosporine together with chemotherapy may reduce drug resistance and allow the tumor cells to be killed. Cryotherapy kills tumor cells by freezing them. Laser therapy uses light to kill tumor cells. Giving combination chemotherapy together with cyclosporine followed by cryotherapy and/or laser therapy may be an effective treatment for retinoblastoma.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with cyclosporine followed by cryotherapy and/or laser therapy works in treating patients with newly diagnosed retinoblastoma in both eyes.

Study Overview

• Status: Active, not recruiting
• Conditions: Retinoblastoma
• Intervention / Treatment: Biological: filgrastim; Drug: Carboplatin; Drug: Cyclosporine; Drug: Etoposide; Drug: vincristine sulfate; Procedure: cryosurgery; Procedure: laser therapy

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy of neoadjuvant high-dose carboplatin and etoposide, vincristine, and cyclosporine (CSA) followed by ophthalmic focal therapy comprising cryotherapy and/or laser therapy to historical world data of chemotherapy treatment without CSA, in terms of increasing the proportion of eyes that remain relapse free and do not require external beam radiotherapy and/or enucleation, in patients with newly diagnosed Group B, C, or D bilateral intraocular retinoblastoma.

Secondary

• Determine the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients receive high-dose carboplatin IV over 30 minutes on day 1; vincristine IV over 5 minutes and high-dose etoposide IV over 25 minutes on day 2; cyclosporine IV over 1 hour before chemotherapy and then over 2 hours after chemotherapy on days 1 and 2, and filgrastim (G-CSF) subcutaneously once daily beginning on day 3 and continuing until day 16 or until blood counts recover. Treatment repeats every 21 days for a total of 3 courses for patients with Group B disease and a total of 6 courses for patients with Group C or D disease.

Patients undergo eye examination under anesthesia (EUA) at initial staging and then before each course of chemotherapy. Patients with small peripheral tumors in eyes without retinal detachment undergo minimal focal therapy (mainly cryotherapy) during EUA at initial staging and then after chemotherapy courses 1 and 2. At EUA after the third and subsequent courses of chemotherapy, patients with tumors that have sufficiently reduced in size undergo additional cryotherapy or laser therapy. After completion of chemotherapy, patients with any suspicious, active, or reactivated tumor undergo additional cryotherapy and/or laser therapy during EUA approximately every 4-8 weeks (or at longer intervals) for up to 5 years (as needed).

After completion of study chemotherapy, patients are followed every 3 months for 2 years, every 6 months for 2 years, and then annually for 1 year.

PROJECTED ACCRUAL: A total of 71 patients will be accrued for this study within 2.4 years.

• Study Type: Interventional
• Enrollment (Estimated): 71
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's and Women's Hospital of British Columbia
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
• Chile
  • Santiago, Chile, 8500000
    • Hospital San Juan de Dios
• India
  • Chennai, India, 600 006
    • Sankara Nethralaya Super Specialty Clinic
• Singapore
  • Singapore, Singapore, 229899
    • Kandang Kerbau Women's and Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

>>INCLUSION CRITERIA<<

DISEASE CHARACTERISTICS:

• Clinical diagnosis of bilateral intraocular retinoblastoma (RB)

  • International Intraocular Retinoblastoma Classification (IIRC) Group B, C, or D disease in 1 or both eyes
  • IIRC Group E disease in 1 eye allowed provided the eye was enucleated at diagnosis AND there is no extraocular RB in the enucleated eye by histologic confirmation AND there is IIRC Group B, C, or D disease in the remaining eye

PATIENT CHARACTERISTICS:

Age

• Over 30 days

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• AST and ALT < 2 times upper limit of normal (ULN)
• Conjugated and unconjugated bilirubin < 2 times ULN

Renal

• Creatinine < 1.5 times ULN
• Glomerular filtration rate (GFR) ≥ 100 mL/min* NOTE: *A 4-hour IV hydration is allowed if GFR is low due to poor hydration or transient dehydration

Other

• Meets 1 of the following auditory criteria:

  • Normal audiogram
  • At least normal responses to speech by audiogram
  • Documentation of hearing by acoustic emission test
  • Recording of evoked potentials by auditory brain stem response

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics

  >>EXCLUSION CRITERIA<<

• IIRC Group A disease in 1 or both eyes
• unilateral RB
• extraocular or metastatic RB
• younger than 30 days
• Glomerular filtration rate (GFR) < 100 mL/min

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CEV Chemo + Cyclosporine & Focal Therapy; Systemic carboplatin (28 mg/kg/dose), etoposide (12 mg/kg/dose) and vincristine sulfate (0.025 mg/kg/dose for the first cycle and 0.05 mg/kg/dose for subsequent cycles if first cycle well-tolerated) chemotherapy given with cyclosporin A (33 mg/kg/dose). Following 4-6 cycles CEV chemotherapy (depending on tumor stage) given every 3 weeks, focal laser therapy and/or cryosurgery are applied for tumor consolidation. Filgrastim is given after each chemotherapy cycle to prevent severe neutropenia.

Biological: filgrastim; Given after chemo cycle for 7 days or until neutrophil counts return to normal.; Other Names: granulocyte colony-stimulating factor (G-CSF); Drug: Carboplatin; Given at 28 mg/kg/dose.; Drug: Cyclosporine; Given at 33 mg/kg/dose; Drug: Etoposide; Given at 12 mg/kg/dose; Drug: vincristine sulfate; Given at 0.025 mg/kg/dose for the first cycle and 0.05 mg/kg/dose for subsequent cycles if first cycle well-tolerated; Other Names: vincristine; Procedure: cryosurgery; Local application of extreme cold to destroy residual tumor.; Other Names: cryotherapy; Procedure: laser therapy; Local and precise application of laser beams to destroy residual tumor.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing efficacy of study treatment with historic world data, in terms of increasing the proportion of eyes that remains relapse-free while avoiding external beam radiation and/or enucleation	Efficacy	5 year follow-up per patient

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity during treatment	Toxicity	5 year follow-up per patient

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Terry Fox Foundation
• Investigators: Principal Investigator: Brenda L Gallie, MD, The Hospital for Sick Children; Principal Investigator: Elise Heon, MD, The Hospital for Sick Children; Study Chair: Helen SL Chan, MD, BS, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2004
• Primary Completion (Actual): April 20, 2016
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: May 3, 2005
• First Submitted That Met QC Criteria: May 3, 2005
• First Posted (Estimated): May 4, 2005

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: intraocular retinoblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Eye Diseases; Retinal Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Eye Diseases, Hereditary; Eye Neoplasms; Retinal Neoplasms; Retinoblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Adjuvants, Immunologic; Antifungal Agents; Calcineurin Inhibitors; Carboplatin; Etoposide; Lenograstim; Vincristine; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1000005587; HFSC-OCRN-RB-2003 (Other Identifier: The Hospital for Sick Children); CDR0000422340 (Other Identifier: The Hospital for Sick Children)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO