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

Sponsor

South Plains Oncology Consortium (Other)

Overall Status

Terminated

CT.gov ID

NCT01187810

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

1.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Acute Lymphoblastic Leukemia Non-Hodgkin's Lymphoma	Drug: Fenretinide Drug: Cytarabine Drug: Methotrexate	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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"

Study Start Date :

Aug 1, 2010

Actual Primary Completion Date :

Apr 1, 2018

Actual Study Completion Date :

Apr 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination of Fenretinide, Cytarabine, and Methotrexate IV for 7 days for each 21 day cycle	Drug: Fenretinide 925 mg/m2 IV continuous infusion X 5 days for 6 cycles. Dose escalation will occur on a 3X3 basis. Other Names: N-(4-hydroxyphenyl) retinamide, 4-HPR Drug: Cytarabine 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 Other Names: Ara-C, Cytosine Arabinoside, Cytosar Drug: Methotrexate 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. Other Names: MTX, Amethopterin

Arm

Intervention/Treatment

Experimental: Combination of Fenretinide, Cytarabine, and Methotrexate

IV for 7 days for each 21 day cycle

Drug: Fenretinide

925 mg/m2 IV continuous infusion X 5 days for 6 cycles. Dose escalation will occur on a 3X3 basis.

Other Names:

N-(4-hydroxyphenyl) retinamide, 4-HPR

Drug: Cytarabine

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

Other Names:

Ara-C, Cytosine Arabinoside, Cytosar

Drug: Methotrexate

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.

Other Names:

MTX, Amethopterin

Outcome Measures

Primary Outcome Measures

Determine maximum tolerated dose [end of study]
Define systemic toxicities [end of study]
Determine plasma pharmacokinetics [end of study]

Secondary Outcome Measures

Determine the response rate to IV Fenretinide [end of study]
Determine bioavailability of fenretinide and metabolites [end of study]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
2	MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

South Plains Oncology Consortium

Investigators

Study Chair: Anna R Franklin, MD, M.D. Anderson Cancer Center
Study Chair: Barry J Maurer, MD, PhD, Texas Tech University Health Sciences Center
Study Director: Shengping Yang, PhD, Texas Tech University Health Sciences Center
Study Director: Min Kang, PharmD, Texas Tech University Health Sciences Center
Study Director: Patrick Reynolds, MD, PhD, Texas Tech University Health Sciences Center