169. Phase I and pharmacokinetic evaluation of all-trans retinoic acid in pediatric patients and pharmacokinetic evaluation in the nonhuman primate

1992 ◽  
Vol 46 (5-7) ◽  
pp. 325
Author(s):  
MA Smith ◽  
PC Adamson ◽  
FM Baus ◽  
L Aronson ◽  
RF Murphy ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Nonhuman Primate ◽  
Pediatric Patients ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Pharmacokinetic Evaluation

Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

1992 ◽  
Vol 10 (11) ◽  
pp. 1666-1673 ◽  
Author(s):  
M A Smith ◽  
P C Adamson ◽  
F M Balis ◽  
J Feusner ◽  
L Aronson ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Pediatric Patients ◽  
Day Treatment ◽  
Pseudotumor Cerebri ◽  
Pharmacokinetic Studies ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Pediatric Cancer Patients

PURPOSE Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy. PATIENTS AND METHODS A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed. RESULTS The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing. CONCLUSIONS The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.

Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

1997 ◽  
Vol 39 (4) ◽  
pp. 291-299 ◽  
Author(s):  
B. A. Conley ◽  
Merrill J. Egorin ◽  
Rajeshwari Sridhara ◽  
Rebecca Finley ◽  
Ramzi Hemady ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Retinoic Acid ◽  
Phase I ◽  
Phase I Clinical Trial ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Phase I evaluation of all-trans-retinoic acid in adults with solid tumors.

1993 ◽  
Vol 11 (5) ◽  
pp. 959-966 ◽  
Author(s):  
J S Lee ◽  
R A Newman ◽  
S M Lippman ◽  
M H Huber ◽  
T Minor ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Squamous Cell ◽  
Peak Plasma ◽  
Maximum Tolerated Dose ◽  
Skin Reactions ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

PURPOSE Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing. PATIENTS AND METHODS Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity. RESULTS Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated. CONCLUSION For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.

Treatment of Multiple Myeloma with All-Trans Retinoic Acid Alone and in Combination with Chemotherapy: a Phase I/II Trial

2004 ◽  
Vol 45 (4) ◽  
pp. 749-754 ◽  
Author(s):  
Kari Koskela ◽  
Tarja-Terttu Pelliniemi ◽  
Kari Pulkki ◽  
Kari Remes
Keyword(s):  
Multiple Myeloma ◽  
Retinoic Acid ◽  
Phase I ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Phase I trial of interferon ?2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma

Cancer ◽  
2002 ◽  
Vol 95 (6) ◽  
pp. 1220-1227 ◽  
Author(s):  
Jonathan S. Goldberg ◽  
Manuel Vargas ◽  
Alyssa S. Rosmarin ◽  
Matthew I. Milowsky ◽  
Nicholas Papanicoloau ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Retinoic Acid ◽  
Phase I ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Phase I Trial ◽  
Advanced Renal Cell Carcinoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Phase I/II study of intermittent all-trans-retinoic acid, alone and in combination with interferon alfa-2a, in patients with epidemic Kaposi's sarcoma.

1995 ◽  
Vol 13 (8) ◽  
pp. 1966-1974 ◽  
Author(s):  
J Bailey ◽  
J M Pluda ◽  
A Foli ◽  
M W Saville ◽  
S Bauza ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Kaposi's Sarcoma ◽  
Progressive Disease ◽  
Kaposi’S Sarcoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Immunodeficiency Virus ◽  
P24 Antigen ◽  
To Receive

PURPOSE A phase I/II study of oral all-trans-retinoic acid (ATRA; tretinoin), administered every other week alone and then in combination with interferon (IFN) alfa-2a, was undertaken to evaluate the activity, toxicity, and pharmacokinetics of this regimen in patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS). PATIENTS AND METHODS Thirteen patients with HIV-associated KS, eight of whom had more than 100 CD4 cells/microL, were entered. The protocol initially called for patients to receive 150 mg/m2/d of ATRA every other week. However, this regimen was associated with headaches, and the initial dose of ATRA was reduced to 40 mg/m2/d orally in three divided doses, increasing to a maximum of 100 mg/m2/d. After 12 weeks, IFN alfa-2a could be added. RESULTS The principal toxicities from ATRA were headaches (12 patients) and dry skin or lip (seven patients). Of 12 assessable patients, 10 had progressive disease and two had stable disease on ATRA alone. One of eight assessable patients who went on to receive ATRA plus IFN alfa-2a had partial response (PR). There were no overall changes in the serum HIV p24 antigen (Ag) level or CD4 count during treatment with ATRA alone. Peak ATRA levels decreased during the week of continuous ATRA therapy, but rebounded when treatment was resumed after a week without the drug. CONCLUSION Intermittent ATRA therapy was reasonably well tolerated and provided a means to circumvent the low plasma exposure found with continuous ATRA therapy. However, we were unable to document antitumor activity in patients with HIV-associated KS.

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