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 > or =6 months.

CONCLUSION:

The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.

• Authors: U Lassen, L R Molife, M Sorensen, S-A Engelholm, L Vidal, R Sinha, R T Penson, P Buhl-Jensen, E Crowley, J Tjornelund, P Knoblauch, J S de Bono
• Journal: British journal of cancer (Br J Cancer) Vol. 103 Issue 1 Pg. 12-7 (Jun 29 2010) ISSN: 1532-1827 [Electronic] England
• PMID: 20588278 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Sulfonamides
• Carboplatin
• belinostat
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carboplatin (administration & dosage)
• Female
• Histone Deacetylase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Hydroxamic Acids (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Paclitaxel (administration & dosage)
• Sulfonamides