Phase I trial of ATRA-IV and depakote in patients with advanced solid tumor malignancies

Abstract

Retinoic acid derivatives have shown their greatest benefit in acute promyelocytic leukemia, but have also demonstrated pre-clinical anti-cancer effects in some solid tumors. Histone deacetylase inhibitors, by upregulating gene expression, are able to limit cancer cell proliferation and induce apoptosis. The combination of all-trans retinoic acid (ATRA) and the histone deacetylase inhibitor valproic acid has been previously studied in hematologic malignancies. We conducted a phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote®) in nine patients with advanced solid tumors refractory to prior therapy. Side effects attributed to therapy had a severity ≤grade 2 and included skin toxicity and thrombocytopenia. The best disease response seen was disease stabilization in one patient. Expression of cellular retinoic acid binding protein-2 in peripheral blood mononuclear cells was detected as a marker of drug effect. The maximum tolerated dose (MTD) of both drugs in combination could not be established due to early closure of the trial resulting from a halt in the commercial availability of ATRA-IV. © 2010 Landes Bioscience.