Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial

Purpose: The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m² given days 1–5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50–100 mg/m²/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors. Methods: Belinostat was administered days 1–5 and 13-cRA days 1–14, every 21 days. Dose-limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity grade ≥ 3 not resolving to grade ≤ 1 within 1 week or non-hematologic toxicity grade ≥ 3 (except controlled nausea and vomiting and transient liver function abnormalities) attributable to belinostat. Results: Among 51 patients, two DLTs were observed: grade 3 hypersensitivity with dizziness and hypoxia at 1700 mg/m²/day belinostat with 100 mg/m²/day 13-cRA, and grade 3 allergic reaction at 2000 mg/m²/day belinostat with 100 mg/m²/day 13-cRA. The MTD was not reached. Pharmacokinetics of belinostat may be non-linear at high doses. Ten patients had stable disease, including one with neuroendocrine pancreatic cancer for 56 cycles, one with breast cancer for 12 cycles, and one with lung cancer for 8 cycles. Partial responses included a patient with keratinizing squamous cell carcinoma of the tonsils, and a patient with lung cancer. Conclusions: The combination of belinostat 2000 mg/m² days 1–5 and 13-cRA 100 mg/m² days 1–14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single-agent MTD of belinostat.