Phase I trial of ATRA-IV and Depakote in patients with advanced solid tumor malignancies.
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 <or=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.
David
Kevin A
KA
Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College - New York Presbyterian Hospital, New York, NY, USA.
Mongan
Nigel P
NP
Smith
Christopher
C
Gudas
Lorraine J
LJ
Nanus
David M
DM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016879:Salvage Therapy; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D014212:Tretinoin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014212:Tretinoin; D014635:Valproic Acid; D006655:Histone Deacetylases