PHASE-I TRIAL OF 13-CIS-RETINOIC ACID IN CHILDREN WITH NEUROBLASTOMA FOLLOWING BONE-MARROW TRANSPLANTATION

Purpose: Treatment of neuroblastoma cell lines with 13-cis-retinoic acid (cis-RA) can cause sustained inhibition of proliferation. Since cis-RA has demonstrated clinical responses in neuroblastoma patients, it may be effective in preventing relapse after cytotoxic therapy. This phase I trial was designed to determine the maximal-tolerated dosage (MTD), toxicities, and pharmacokinetics of cis-RA administered on an intermittent schedule in children with neuroblastoma following bone marrow transplantation (BMT). Patients and Methods: Fifty-one assessable patients, 2 to 12 years of age, were treated with oral cis-RA administered in two equally divided doses daily for 2 weeks, followed by a 2-week rest period, for up to 12 courses, The dose was escalated from 100 to 200 mg/m(2)/d until dose-limiting toxicity (DLT) wets observed. A single intrapatient dose escalation was permitted. Results: The MTD of cis-RA was 160 mg/m(2)/d. Dose-limiting toxicities in six of nine patients at 200 mg/m(2)/d included hypercalcemia (n = 3), rash (n = 2), and anemia/thrombocytopenia/emesis/rash (n = 1). All toxicities resolved after cis-RA was discontinued. Three complete responses were observed in marrow metastases. Serum levels of 7.4 +/- 3.0 mu mol/L (peak) and 4.0 +/- 2.8 mu mol/L (trough) at the MTD were maintained during 14 days of therapy, The DLT correlated with serum levels greater than or equal to 10 mu mol/L. Conclusion: The MTD of cis-RA given on this intermittent schedule was 160 mg/m(2)/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels, Monitoring of serum calcium and cis-RA levels is indicated in future trials. J Clin Oncol 13:894-901, (C) 1995 by American Society of Clinical Oncology.