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

Area of Science:

• Oncology
• Pharmacology

Background:

• Retinoic acid derivatives show anti-cancer effects in solid tumors.
• Histone deacetylase inhibitors limit cancer cell proliferation and induce apoptosis.
• Combination of all-trans retinoic acid (ATRA) and valproic acid studied in hematologic malignancies.

Purpose of the Study:

• Evaluate safety and tolerability of liposomal ATRA (ATRA-IV) and divalproex sodium in advanced solid tumors.
• Determine the maximum tolerated dose (MTD) of the combination therapy.
• Assess preliminary efficacy and identify biomarkers of drug effect.

Main Methods:

• Phase I, two-step dose escalation trial.
• Nine patients with advanced solid tumors refractory to prior therapy.
• Combination of liposomal ATRA-IV and divalproex sodium administered.
• Monitoring for side effects, disease response, and cellular retinoic acid binding protein-2 expression.

Main Results:

• Side effects were mild (grade <=2), including skin toxicity and thrombocytopenia.
• One patient achieved disease stabilization.
• Cellular retinoic acid binding protein-2 expression detected as a marker of drug effect.
• Trial closed early due to commercial unavailability of ATRA-IV, MTD not established.

Conclusions:

• The combination of ATRA-IV and divalproex sodium was generally well-tolerated in patients with advanced solid tumors.
• Further investigation is warranted, but commercial unavailability of ATRA-IV halted the trial.
• Biomarker analysis suggests potential for retinoic acid pathway modulation.