Protocol Number: 06-C-0227

Title:

Phase I Trial of Intravenous Fenretinide (4-HPR) for Patients with Hematologic Malignancies

Number:

06-C-0227

Summary:

Background:

-Fenretinide in pill form has killed or been shown to slow the growth of cancer cells in the laboratory. High doses of the drug were more effective at stopping cancer cells than lower doses; however, the higher doses of drug cannot be given in pill form.

-A new, intravenous (i.v.), form of the drug has been developed for giving it through the veins to permit higher doses.

Objectives:

-To find the highest safe dose of i.v. fenretinide that can be given to patients with blood or lymph node cancers and to examine the side effects of i.v. administration of the drug.

Eligibility:

-Patients 18 years of age and older with cancer of the blood or lymph nodes or with myeloproliferative disorders with a poor prognosis.

-Patients must have disease that is either resistant to treatment or has relapsed and for whom standard treatments are no longer effective.

Design:

-About 16 to 21 patients will participate in the study.

-The first patient in the study is given the lowest study dose of fenretinide. Subsequent patients receive increasingly higher doses as long as the side effects remain tolerable and until the maximum tolerated dose is reached.

-Fenretinide is given by continuous i.v. infusion over 5 days. If the side effects are tolerable and the disease does not worsen, a second dose is given 21 days after the first dose. Patients may receive a maximum of six 5-day infusions given every 21 days.

-Blood samples are collected frequently to determine how the body handles fenretinide and to monitor for drug side effects.

-Treatment response is monitored with physical examinations, blood and urine tests, imaging studies, such as CT and MRI scans, and possibly bone marrow biopsy or aspiration.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Patients must have a histologically or cytological confirmed hematology malignancy for which standard therapies do not exist or are no longer effective. Must have measurable or evaluable disease. Chronic hematologic malignancies such as CLL, CML, indolent NHL, or myeloproliferative disorders with poor prognosis are eligible, such as those failing 3 standard therapies.

Age 18 years or greater.

Patients must have adequate organ and marrow function as defined below:

-Absolute neutrophil count (AGC) greater than or equal to 1500, platelets greater than or equal to 75,000, unless due to direct bone marrow involvement of disease.

-Hemoglobin greater than or equal to 8.0 gm/dL, transfusion allowed.

-Serum creatinine less than or equal to 1.5x the upper limits of institutional normal (ULN).

-Total bilirubin less than or equal to 1.5x the upper limits of institutional normal.

-AST/ALT less than 2.5x the upper limits of institutional normal.

-Less than or equal to 5x ULN for patients with liver mets.

ECOG performance status of 0, 1, or 2, and estimated survival of at least 3 months.

Patients must be able to understand and agree to sign an IRB-approved informed consent form.

The effects of fenretinide on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry, for the duration of study, and for two months after study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

EXCLUSION CRITERIA: Patients will be excluded:

Who have received radiation therapy, chemotherapy, and other investigational agents within the 2 weeks of starting fenretinide. Patients must have recovered from toxicities of prior therapy.

Have uncontrolled systemic infections, coagulation disorders, or other major medical illnesses of the cardiovascular or respiratory systems.

Who are pregnant and/or lactating.

Who have had non-biopsy surgery in the last 20 days.

Who have active CNS disease or a history of cranial irradiation are excluded; patients with previously treated leptomeningeal disease or brain metastases without evidence of remaining tumor by PET, MRI scan, or spinal fluid will be eligible.

Patients with known allergy to egg products.

Patients known to be HIV-positive.

Who have hypertriglyceridemia requiring medication.

Patients concurrently taking the following drugs are excluded: antioxidants, herbal or other alternative therapy medications, vitamin supplements (especially vitamins A, C, and E), other than a standard dose multivitamin, cyclosporine A or analogue; verapamil; tamoxifen or analogue, ketoconazole, chlorpromazine; RU486; indomethacin; or sulfinpyrazone, tetracycline, nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, and amiodarone. If the patients discontinue usage of the above drugs, they can be eligible for enrollment into the study one week after the discontinuation. For patients requiring any of these mediations entry is permissible only with permission from the study chair.

Patients with an identified familial hyperlipidemia disorder.

Patients with poorly controlled diabetes mellitus with fasting serum glucose concentration over 200 mg/dl or a hemoglobin A1C over 7.5%.

Special Instructions:

Currently Not Provided

Keywords:

Retinoid

Cytotoxic

Lymphomas

Ceramide

Pharmacokinetics

Recruitment Keyword(s):

Hematologic Malignancy

Chronic Lymphocytic Leukemia

CLL

Chronic Myelogenous Leukemia

CML

Lymphoma

Non-Hodgkin Lymphoma

NHL

Condition(s):

Fenretinide

Investigational Drug(s):

Fenretinide (4-HPR)

Investigational Device(s):

None

Intervention(s):

Drug: Fenretinide (4-HPR)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Ponzoni M, Bocca P, Chiesa V, Decensi A, Pistoia V, Raffaghello L, Rozzo C, Montaldo PG. Differential effects of N-(4-hydroxyphenyl)retinamide and retinoic acid on neuroblastoma cells: apoptosis versus differentiation. Cancer Res. 1995 Feb 15;55(4):853-61.

Di Vinci A, Geido E, Infusini E, Giaretti W. Neuroblastoma cell apoptosis induced by the synthetic retinoid N-(4-hydroxyphenyl)retinamide.Int J Cancer. 1994 Nov 1;59(3):422-6.

Maurer BJ, Melton L, Billups C, Cabot MC, Reynolds CP. Synergistic cytotoxicity in solid tumor cell lines between N-(4-hydroxyphenyl)retinamide and modulators of ceramide metabolism. J Natl Cancer Inst. 2000 Dec 6;92(23):1897-909.

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