Fenretinide in Treating Children With Recurrent or Resistant Neuroblastoma

Study Overview
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Brief Summary
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This phase II trial is studying how well fenretinide works in treating children with recurrent or resistant neuroblastoma. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

Detailed Description
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OBJECTIVES: Determine the response rate in pediatric patients with recurrent or resistant high-risk neuroblastoma treated with fenretinide. Determine the toxic effects of this drug in these patients. Determine the proportion of patients with disease detected only by bone marrow immunocytology, who clear all evidence of disease during treatment with this drug. Determine minimal residual disease response by marrow and meta-iodobenzylguanidine (MIBG) I 123 scan in patients treated with this drug. OUTLINE: Patients are stratified according to presence of measurable disease on CT scan/MRI (yes vs no). A third stratum of patients with tumor cells in bone marrow by immunocytology only is enrolled but is not evaluated for response. Patients receive oral fenretinide 3 times daily (or 2 times daily if over 18 years of age) on days 1-7. Treatment repeats every 3 weeks for up to 30 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum III who fail to achieve a complete response after 8 courses of therapy are removed from study. Patients are followed monthly until blood counts and visual acuity are stable or normalized and then every 6 months for 2 years and annually for 3 years. PROJECTED ACCRUAL: A total of 70 patients (25 each for strata I and II, 20 for stratum III) will be accrued for this study within 1-2 years.

Official Title
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A Phase II Study of Fenretinide (NSC# 374551, IND# 40294) in Children With Recurrent/Resistant High Risk Neuroblastoma

Conditions
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Recurrent Neuroblastoma

Intervention / Treatment
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* Drug: fenretinide
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of recurrent or resistant/refractory high-risk neuroblastoma by one or both of the following: Histological confirmation Demonstration of tumor cells in bone marrow with increased urinary catecholamines Stratum I: At least 1 unidimensionally measurable lesion* At least 20 mm by MRI and/or CT scan OR at least 10 mm by spiral CT scan Stratum II: Meets one or both of the following criteria: At least 1 site with positive uptake on meta-iodobenzylguanidine (MIBG) I 123 scan Tumor in bilateral bone marrow aspirate/biopsy by routine morphology (no NSE staining only) Stratum III: At least 5 tumor cells/10^6 mononuclear cells in the bone marrow by immunocytology only (on 2 successive bone marrows performed from 1 day to 4 weeks apart) Patients in first response (i.e., patients with persistent tumor at end of frontline therapy, but who have never had disease relapse or progression) must have histological* or morphological (by bone marrow) confirmation** of viable tumor on CT scan, MRI, or MIBG scan after completion of myeloablative therapy (for strata I and II) No catecholamine elevation only Performance status - 0-2 At least 2 months Hemoglobin greater than 7.5 g/dL (transfusion allowed) Bilirubin no greater than 1.5 times normal SGPT and SGOT less than 2.5 times normal Creatinine normal for age No hematuria or proteinuria greater than 1+ on urinalysis Calcium less than 11.6 mg/dL Triglycerides less than 300 mg/dL Not pregnant Negative pregnancy test Fertile patients must use effective contraception No seizure disorders unless on anticonvulsants and well controlled No skin toxicity greater than grade 1 Must be able to consume entire intact study capsule in the dosage prescribed for body surface area Recovered from prior immunotherapy At least 7 days since prior anticancer biologic therapy At least 2 days since prior growth factors Prior autologous stem cell transplantation allowed No prior allogeneic stem cell transplantation No concurrent immunomodulating agents At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered No concurrent anticancer chemotherapy No concurrent steroids Recovered from prior radiotherapy At least 4 weeks since prior radiotherapy to target lesion Prior radiotherapy to non target lesions allowed No concurrent radiotherapy to sole measurable lesion for symptom relief Concurrent palliative radiotherapy to non target or localized painful lesions allowed Prior tretinoin or isotretinoin allowed At least 2 weeks since other prior retinoids No prior fenretinide No concurrent supplemental oral or IV vitamin A, ascorbic acid, or vitamin E (except if contained in routine total parenteral nutrition [TPN] vitamin supplements) No concurrent drugs suspected of causing pseudotumor cerebri (e.g., tetracycline, nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, amiodarone, or vitamin A [except as part of routine TPN supplements]) No other concurrent anticancer agents

Ages Eligible for Study
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Maximum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (fenretinide)<br>Patients receive oral fenretinide 3 times daily (or 2 times daily if over 18 years of age) on days 1-7. Treatment repeats every 3 weeks for up to 30 courses in the absence of disease progression or unacceptable toxicity. | Drug: fenretinide<br>* Given orally<br>Other: pharmacological study<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | A responder is defined to be a patient who achieves a best overall response of complete response (CR), very good partial response (VGPR) or partial response (PR). | Up to 8 courses of therapy | 
| Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 | Assessed via a descriptive tabulation of the toxicity rates, overall and by stratum. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of fenretinide | Assessed via descriptive analysis of the steady state levels of fenretinide overall and by stratum | At baseline and during courses 1, 2, and 5 | 
| Plasma retinol levels | Assessed via descriptive analysis of the plasma retinol levels overall and by stratum. | At baseline and during courses 1, 2, and 5 | 
| Minimal residual disease (MRD) (Stratum 3) | Assessed by descriptive calculation of the proportion of responders. | Up to 5 years |