TY - JOUR
T1 - 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
AU - Lassen, U
AU - Molife, L R
AU - Sorensen, Janice Marie
AU - Engelholm, S-A
AU - Vidal, L
AU - Sinha, R
AU - Penson, R T
AU - Buhl-Jensen, P
AU - Crowley, E
AU - Tjornelund, J
AU - Knoblauch, P
AU - de Bono, J S
AU - Buhl-Jensen, P
PY - 2010/6/29
Y1 - 2010/6/29
N2 - 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.
AB - 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.
U2 - http://dx.doi.org/10.1038/sj.bjc.6605726
DO - http://dx.doi.org/10.1038/sj.bjc.6605726
M3 - Journal article
SN - 0007-0920
VL - 103
SP - 12
EP - 17
JO - The British journal of cancer. Supplement
JF - The British journal of cancer. Supplement
IS - 1
ER -
