Phase I study of tamibarotene monotherapy in pediatric and young adult patients with recurrent/refractory solid tumors.

Purpose: Tamibarotene is a synthetic retinoid that inhibits proliferation and induces differentiation of malignant cells by binding to the retinoic acid receptor α/β. Previous in vitro studies have shown that some pediatric solid tumors with retinoic acid receptors differentiate in response to retinoic acid. We conducted a phase I dose-escalation study to determine the recommended dose of tamibarotene for further study in pediatric and young adult patients with recurrent/refractory solid tumors.

Methods: Pediatric and young adult patients with recurrent/refractory solid tumors were administered tamibarotene at 4, 6, 8, 10, and 12 mg/m/day for 14 or 21 days of a 28 day cycle. Safety, efficacy, and pharmacokinetics of tamibarotene were evaluated.

Results: Twenty-two patients (median age 8 years) were enrolled in this study. No dose-limiting toxicity (DLT) was encountered, and tamibarotene was generally well tolerated. Two patients experienced severe adverse events (AEs), leading to discontinuation of the treatment. One grade 4 venous thrombosis and one grade 2 erythema multiforme were observed, which promptly resolved after tamibarotene discontinuance. The grade 4 venous thrombosis was a severe AE but not DLT because it occurred after the evaluation period. Pharmacokinetic analyses showed a dose-dependent increase in the maximum drug concentration (C) and area under the concentration-time curve (AUC). None of the patients achieved a complete response or partial response. Seven patients had stable disease lasting longer than 18 weeks.

Conclusions: The recommended dose for phase II study of tamibarotene in pediatric and young adult patients with refractory solid tumors is 12 mg/m/day for 21 days in a 28 day cycle.