Fenretinide in Children With Recurrent/Resistant ALL, AML, and NHL

Study Overview
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Brief Summary
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The purposee of this study is to determine the safety and dosing of Fenretinide when given continuously for 5 days, every 3 weeks, in pediatric patients with recurrent and/or resistant acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and non-Hodgkin's lymphoma (NHL).

Detailed Description
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Fenretinide is a cytotoxic retinoid that has activity against a variety of cell lines in vitro in a dose-related manner. The exact mechanism of fenretinide cytotoxicity in leukemia and lymphoma cell lines is not known, but may include the de novo ceramide synthesis of ceramides and the generation of reactive oxygen species. The malignancy-specific nature of fenretinide-induced ceramides suggests that combinations of the drug with other ceramide modulating agents may have a favorable therapeutic index. In this study, the primary aims are to define the maximum tolerated dose, toxicity profile, and pharmacokinetics of IV fenretinide when given continuously in pediatric patients with ALL, AML, and NHL. The drug will be administered via a central venous or percutaneous indwelling central catheter in an inpatient hospital setting.

Official Title
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A Phase I Study of Intravenous (Emulsion) Fenretinide (4-HPR, NSC 374551) in Children With Recurrent or Resistant Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), and Non-Hodgkin's Lymphoma (NHL) IND #70,058

Conditions
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Acute Myelogenous Leukemia, Acute Lymphoblastic Leukemia, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Fenretinide
* Drug: Cytarabine
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with relapsed or refractory ALL, AML, or NHL Must have had two or more therapeutic attempts for treating/curing disease Must have fully recoved from acute toxic effects of all prior therapy Karnofsky of greater than 50% for older than 10 years of age and Lansky greater than 50% for younger than 10 years. Exclusion Criteria: Grade 2 Pruritus or Rash (all forms) Grade 3 Dry Skin that is refractory to topical medical management Cardiac Fractional Shortening < 27% on echocardiogram Left Ventricular Ejection Fraction < 45% on echocardiogram Known allergy to egg products or soy bean oil Renal, Liver, and Pancreatic function: serum creatinine > 1.5X ULN direct bilirubin > 1.5X ULN ALT or AST > 2.5X ULN Serum trigylcerides > 2.5X ULN for age Lipase > 1.5X ULN for age History of pancreatitis

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: Combination of Fenretinide, Cytarabine, and Methotrexate<br>IV for 7 days for each 21 day cycle | Drug: Fenretinide<br>* 925 mg/m2 IV continuous infusion X 5 days for 6 cycles. Dose escalation will occur on a 3X3 basis.<br>* Other names: N-(4-hydroxyphenyl) retinamide, 4-HPR;Drug: Cytarabine<br>* dosing depending on age - will be administed intrathecally for all CNS negative subjects on day 0 and 15 of course 1, then on day 8 of each remaining cycle for CNS negative AML. For CNS positive ALL, NHL, and AML, will be administered alone on day 0 for and in combination with methotrexate and hydrocortisone on day 8, 15, 22 of cycle 1 and repeated on day 8 of each remaining cycle<br>* Other names: Ara-C, Cytosine Arabinoside, Cytosar;Drug: Methotrexate<br>* Dose depends on subject age - for CNS positive patients, will be given in combination with cytarabine and hydrocortisone on days 8, 15, and 22 during course 1. For courses 2-6, will be administered intrathecally on day 8 for CNS negative ALL and NHL. For patients who are CNS positive, it will be given in combination with cytarabine and hydrocortisone on day 8 of courses 2-6.<br>* Other names: MTX, Amethopterin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine maximum tolerated dose |  | end of study | 
| Define systemic toxicities |  | end of study | 
| Determine plasma pharmacokinetics |  | end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the response rate to IV Fenretinide |  | end of study | 
| Determine bioavailability of fenretinide and metabolites | To determine the bioavailability to cancer or peripheral blood mononuclear cells (PBMC) cells of fenretinide and metabolites delivered/obtained as an intravenous emulsion. To determine alterations to sphingolipid levels in PBMC and/or circulating leukemia blasts induced by fenretinide. | end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leukemia,lymphoma