A Phase II Trial of All-Trans-Retinoic Acid in Combination With Interferon-Alpha 2a in Children With Recurrent Neuroblastoma or Wilms' Tumor
Summary
A body of preclinical data has provided a strong rationale for evaluating the combination of IFN-alpha with retinoic acid. The two drugs have different mechanisms of action and, when used in combination, show enhanced activity in both adult and pediatric tumor cell lines.
The combination of the antiproliferative and differentiation inducing effect of retinoids together with the antiproliferative, immunostimulatory and differentiation-potentiating effects of IFN-alpha warrant clinical investigation of this combination for the treatment of refractory pediatric malignancies.
Description
A body of preclinical data has provided a strong rationale for evaluating the combination of IFN-alpha with retinoic acid. The two drugs have different mechanisms of action and, when used in combination, show enhanced activity in both adult and pediatric tumor cell lines. In the pediatric phase I trial which administered ATRA for 3 consecutive days/week repeated weekly, the AUC of ATRA decreased on day 1 to day 3 of drug administration but returned to day 1 levels at the beginning of subsequent weeks. This intermittent schedule of ATRA administration allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. The combination of ATRA/IFN-alpha 2a has demonstrated clinical activity in the pediatric phase I trial in neuroblastoma and Wilms' tumor. The combination of the antiproliferative and differentiation inducing effect of retinoids together with the antiproliferative, immunostimulatory and differentiation-potentiating effects of IFN-alpha warrant clinical investigation of this combination for the treatment of refractory pediatric malignancies.
Study Design
Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment
Conditions
Nephroblastoma
Intervention
IFN-alpha with retinoic acid
Location
National Cancer Institute (NCI)
Bethesda
Maryland
United States
20892
Status
Completed
Source
National Institutes of Health Clinical Center (CC)
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00001509
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Receptors, Retinoic Acid
Proteins in the nucleus or cytoplasm that specifically bind RETINOIC ACID or RETINOL and trigger changes in the behavior of cells. Retinoic acid receptors, like steroid receptors, are ligand-activated transcription regulators. Several types have been recognized.
Retinoid X Receptors
A subtype of RETINOIC ACID RECEPTORS that are specific for 9-cis-retinoic acid which function as nuclear TRANSCRIPTION FACTORS that regulate multiple signalling pathways.
Prostaglandins F
(9 alpha,11 alpha,13E,15S)-9,11,15-Trihydroxyprost-13-en-1-oic acid (PGF(1 alpha)); (5Z,9 alpha,11,alpha,13E,15S)-9,11,15-trihydroxyprosta-5,13-dien-1-oic acid (PGF(2 alpha)); (5Z,9 alpha,11 alpha,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oic acid (PGF(3 alpha)). A family of prostaglandins that includes three of the six naturally occurring prostaglandins. All naturally occurring PGF have an alpha configuration at the 9-carbon position. They stimulate uterine and bronchial smooth muscle and are often used as oxytocics.
Nephroblastoma Overexpressed Protein
A CCN protein family member found at high levels in NEPHROBLASTOMA cells. It is found both intracellularly and in the EXTRACELLULAR MATRIX and may play a role in the regulation of CELL PROLIFERATION and EXTRACELLULAR MATRIX synthesis.
Prostaglandins E
(11 alpha,13E,15S)-11,15-Dihydroxy-9-oxoprost-13-en-1-oic acid (PGE(1)); (5Z,11 alpha,13E,15S)-11,15-dihydroxy-9-oxoprosta-5,13-dien-1-oic acid (PGE(2)); and (5Z,11 alpha,13E,15S,17Z)-11,15-dihydroxy-9-oxoprosta-5,13,17-trien-1-oic acid (PGE(3)). Three of the six naturally occurring prostaglandins. They are considered primary in that no one is derived from another in living organisms. Originally isolated from sheep seminal fluid and vesicles, they are found in many organs and tissues and play a major role in mediating various physiological activities.
Clinical Trials
A Phase I Trial of Tamoxifen and 9-Cis-Retinoic Acid in Breast Cancer Patients
This is a dosage escalation study to estimate the maximum tolerated dose of 9-cis-retinoic acid given in combination with tamoxifen. Groups of 3 to 6 patients receive oral 9-cis-retinoic...
Feasibility of Retinoic Acid Treatment in Emphysema (FORTE)
To conduct feasibility studies on the use of retinoids in the treatment of emphysema. Specific objectives are to identify optimal patient populations, retinoids, doses, dosing schedules, r...
ZD6474 Alone and in Combination With Retinoic Acid in Pediatric Neuroblastoma
The goal of this clinical research study is to find the highest safe dose of the drug ZactimaTM (ZD6474) in patients with neuroblastoma or medulloblastoma that has gotten worse, has come b...
The purpose of this study is to assess the effects of the combination of all-trans retinoic acid in combination with one of two schedules of Bryostatin 1 in patients with myelodysplasia an...
This is a study looking at all-trans retinoic acid in combination with standard induction and consolidation therapy in older patients with newly diagnosed acute myeloid leukemia (AML).
PubMed Articles
Direct visualization of retinoic acid in the rat hypothalamus: An immunohistochemical study.
In order to increase our knowledge about the distribution of vitamins in the mammalian brain, we have developed a highly specific antiserum directed against retinoic acid with good affinity (10(-8)M),...
Vitamin A and its metabolite, retinoic acid (RA) are implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we showed RA was also required to elic...
In addition to estrogen receptor modulators, retinoic acid and other retinoids are promising agents to prevent breast cancer. Retinoic acid and estrogen exert antagonistic regulations on the transcrip...
Recent genetic studies in mice have established that the nuclear receptor coregulator Trim24/Tif1α suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor α (Rara)-dependent transcripti...
The objective of the study was to elucidate mRNA expression of CYP26b1 (cytochrome P450, family 26, subfamily B, polypeptide 1) and signalling molecules ALDH1 (aldehyde dehydrogenase 1), CRABPII (cell...
