Combination Chemotherapy, Autologous Stem Cell Transplant, and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma

Study Overview
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Brief Summary
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This phase III trial is studying the side effects and how well giving combination chemotherapy together with autologous stem cell transplant and/or radiation therapy works in treating young patients with extraocular retinoblastoma. Giving chemotherapy before an autologous stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and/or bone marrow and stored. More chemotherapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Radiation therapy uses high energy x-rays to kill tumor cells. Giving radiation therapy after combination chemotherapy and/or autologous stem cell transplant may kill any remaining tumor cells.

Detailed Description
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OBJECTIVES: I. To estimate the proportion of 3 groups of patients with extraocular retinoblastoma (stage 2 and 3: regional extra-ocular disease;, stage 4a: disseminated metastatic disease not involving the central nervous system [CNS]; or stage 4b: patients with CNS disease) who achieve long-term event-free survival after treatment with aggressive multimodality therapy compared to historical controls. II. To estimate the response rate to the induction phase of the regimen. III. To evaluate the toxicities associated with this regimen. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive vincristine intravenously (IV) on days 0, 7, and 14, cisplatin IV over 6 hours on day 0, cyclophosphamide IV over 1 hour and etoposide IV over 1 hour on days 1 and 2, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of induction chemotherapy, patients with stage 2 or 3 disease who have at least a partial response proceed to radiotherapy. Patients with stage 4a or 4b disease who have at least a partial response proceed to high-dose consolidation chemotherapy and autologous stem cell infusion. STEM CELL HARVESTING (stage 4a or 4b disease only): Peripheral blood stem cells (preferred) or bone marrow cells are collected after at least 1 course of induction chemotherapy. HIGH-DOSE CONSOLIDATION CHEMOTHERAPY (stage 4a or 4b disease only): Patients receive carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3. AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous stem cell infusion on day 0. Patients then receive filgrastim subcutaneously (SC) beginning on day 1 and continuing until blood counts recover. RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement) undergo radiotherapy to sites that were initially involved beginning within 42 days after the start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease undergo radiotherapy to sites initially involved based on response beginning approximately 42 days after autologous stem cell infusion. Patients with stage 4a disease who achieve a complete response to induction chemotherapy or with less than 5 mm of residual tumor at the time of planned irradiation, or patients with stage 4b disease who achieve a complete response to induction chemotherapy do not undergo radiotherapy. After completion of study therapy, patients are followed every 3 months for 1 year and then annually thereafter for 9 years.

Official Title
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A Trial of Intensive Multi-Modality Therapy for Extra-Ocular Retinoblastoma

Conditions
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Extraocular Retinoblastoma

Intervention / Treatment
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* Procedure: Autologous Bone Marrow Transplantation
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Carboplatin
* Drug: Cisplatin
* Drug: Cyclophosphamide
* Drug: Etoposide
* Biological: Filgrastim
* Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation
* Radiation: Radiation Therapy
* Drug: Thiotepa
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologic or cytologic verification of extra-ocular retinoblastoma; extra-ocular disease includes orbital disease, optic nerve involvement at the surgical margin, regional nodal disease, and/or overt distant metastatic disease (at sites such as bone, bone marrow, liver and/or the central nervous system); patients with trilateral retinoblastoma will also be included in this protocol Patients with a CNS lesion consistent with trilateral or stage 4b disease may be enrolled without tissue confirmation if (1) unequivocal leptomeningeal disease is present on brain or spine magnetic resonance imaging (MRI) scan and/or (2) the primary tumor is at least 2 cm in diameter, predominantly solid, and demonstrates enhancement on the post-gadolinium images; however, even in such cases surgery should be given serious consideration Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age No prior chemotherapy or radiotherapy for the extra-ocular retinoblastoma may have been administered prior to entering this study; prior treatment (chemotherapy and/or radiation therapy) for intra-ocular retinoblastoma is permissible Peripheral absolute neutrophil count (ANC) >= 750/uL If the ANC and/or platelet count are not adequate, but due to bone marrow metastatic disease, these criteria will be waived Platelet count >= 75,000/uL (transfusion independent) If the ANC and/or platelet count are not adequate, but due to bone marrow metastatic disease, these criteria will be waived Creatinine clearance OR radioisotope glomerular filtration rate >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows: 0.4 mg/dL (1 month to < 6 months of age) 0.5 mg/dL (6 months to < 1 year of age) 0.6 mg/dL (1 years to < 2 years of age) 0.8 mg/dL (2 years to < 6 years of age) 1.0 mg/dL (6 years to < 10 years of age) 1.2 mg/dL (10 years to < 13 years of age) 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age) 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age) Total bilirubin =< 1.5 times upper limit of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) for human studies must be met

Ages Eligible for Study
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Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, radiotherapy, autologous SCI)<br>INDUCTION: Patients receive vincristine IV; cisplatin IV; cyclophosphamide IV; and G-CSF SC beginning on day 3 and continuing until blood counts recover. CONSOLIDATION (stage 4a or 4b disease only): Patients receive carboplatin IV; thiotepa IV; and etoposide IV. AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous stem cell infusion on day 0 and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement) undergo radiotherapy to sites that were initially involved beginning within 42 days after the start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease undergo radiotherapy to sites initially involved based on response beginning approximately 42 days after autologous stem cell infusion. | Procedure: Autologous Bone Marrow Transplantation<br>* Undergo peripheral blood stem cell or bone marrow transplant<br>* Other names: Autologous Marrow Transplantation;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo peripheral blood stem cell or bone marrow transplant<br>* Other names: Stem Cell Transplantation, Autologous;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given SC<br>* Other names: Tevagrastim;Procedure: In Vitro-Treated Peripheral Blood Stem Cell Transplantation<br>* Undergo peripheral blood stem cell or bone marrow transplant<br>* Other names: in vitro-treated peripheral blood progenitor cell transplantation;Radiation: Radiation Therapy<br>* Undergo radiotherapy<br>* Other names: Therapy, Radiation;Drug: Thiotepa<br>* Given IV<br>* Other names: WR 45312;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | The probability of surviving patients who did not experience events at 1 year following enrollment. An event is defined as relapse, second malignancy, or death from any cause. | At 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate to the Induction Phase of the Regimen | This study used a modified version of the international criteria for neuroblastoma response. The response rate to the induction phase of the regimen and a corresponding 95% confidence interval will be calculated for all strata combined. | 12 weeks after participant received the first dose | 
| Percentage of Participants With Adverse Events as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Grade 3 and higher toxicities will be descriptively summarized. | Up to 30 days after completion of study treatment |