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; Janice Marie Sorensen; S-A Engelholm; L Vidal; R Sinha; R T Penson; P Buhl-Jensen; E Crowley; J Tjornelund; P Knoblauch; J S de Bono; P Buhl-Jensen

doi:http://dx.doi.org/10.1038/sj.bjc.6605726

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, Janice Marie Sorensen, S-A Engelholm, L Vidal, R Sinha, R T Penson, P Buhl-Jensen, E Crowley, J Tjornelund, P Knoblauch, J S de Bono, P Buhl-Jensen

63 Citations (Scopus)

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.

Original language	English
Journal	B J C
Volume	103
Issue number	1
Pages (from-to)	12-7
Number of pages	6
ISSN	0007-0920
DOIs	https://doi.org/10.1038/sj.bjc.6605726
Publication status	Published - 29 Jun 2010

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Lassen, U., Molife, L. R., Sorensen, J. M., Engelholm, S-A., Vidal, L., Sinha, R., Penson, R. T., Buhl-Jensen, P., Crowley, E., Tjornelund, J., Knoblauch, P., de Bono, J. S., & Buhl-Jensen, P. (2010). 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. B J C, 103(1), 12-7. https://doi.org/10.1038/sj.bjc.6605726

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. / Lassen, U; Molife, L R; Sorensen, Janice Marie et al.

In: B J C, Vol. 103, No. 1, 29.06.2010, p. 12-7.

Research output: Contribution to journal › Journal article › Research › peer-review

Lassen, U, Molife, LR, Sorensen, JM, Engelholm, S-A, Vidal, L, Sinha, R, Penson, RT, Buhl-Jensen, P, Crowley, E, Tjornelund, J, Knoblauch, P, de Bono, JS & Buhl-Jensen, P 2010, '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', B J C, vol. 103, no. 1, pp. 12-7. https://doi.org/10.1038/sj.bjc.6605726

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title = "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.",

author = "U Lassen and Molife, {L R} and Sorensen, {Janice Marie} and S-A Engelholm and L Vidal and R Sinha and Penson, {R T} and P Buhl-Jensen and E Crowley and J Tjornelund and P Knoblauch and {de Bono}, {J S} and P Buhl-Jensen",

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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 -

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

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