A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours

Abstract

Background:This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours.Methods:Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1–5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m−2) were administered 2–3 h after the end of the belinostat infusion.Results:In all 23 patients received 600–1000 mg m−2 per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m−2 per day for days 1–5, with paclitaxel (175 mg m−2) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting ⩾6 months.Conclusion:The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.

Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma

“…67 A Phase I study of solid tumors showed that the belinostat/ paclitaxel combination is tolerable in humans and thus feasible for further clinical study. 71 Recently approved nanoparticle formulations of vincristine and paclitaxel that increase efficacy and reduce toxicity 72,73 should make them safer to combine with other drugs such as belinostat. Using a preclinical model of aggressive DLBCL the current study has demonstrated the potential of combining MTAs with belinostat for treatment of relapsed/refractory DLBCL.…”

Synergistic interaction between the novel histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in platinum-sensitive and resistant ovarian carcinoma cells

“…Thus, combinations with other agents are required to optimise their efficacy [12]. HDACi have shown synergistic or additive antitumor effects with conventional anticancer drugs, targeted agents and radiation [7,[13][14][15][16][17].…”

Drug Monographs: Belinostat and Idelalisib

“…The steady state volume of distribution is 22.6 ± 9.7 L/m 2 with a clearance of 41.1 ± 22.2 L/h/m 2 . 4 In another report following a 30-minute infusion of 1,000 mg/m 2 , the peak concentration (C max ) is 32,124 ± 9,128 ng/mL. The AUC is 9,990 ± 3,420 ng•h/mL.…”