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

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, 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

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.

Figures

Figure 1
Figure 1
Efficacy of BelCaP in a patient with rectal cancer. Response in a patient with metastatic rectal carcinoma treated with BelCaP showing an adrenal metastasis at baseline, (A) (encircled in red) measuring 7.7 cm, and after six cycles, (B) measuring 3.6 cm. The patient also had retroperitoneal lymph node metastases and with this, showed a confirmed PR. (See online version for color information).
Figure 2
Figure 2
Waterfall plot showing best response in individual patients evaluable for responses assessment by RECIST 1.0 criteria. In all14 patients completed the first two cycles and were evaluable for response and featured in this plot. Dotted lines at +20% and −30% indicate the % level at which disease progression and disease response has occurred, respectively.

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