A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2006-07-18

AUTHORS

V Lévy, S Zohar, C Bardin, A Vekhoff, D Chaoui, B Rio, O Legrand, S Sentenac, P Rousselot, E Raffoux, F Chast, S Chevret, J P Marie

ABSTRACT

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m−2 day−1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m−2 day−1. Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m−2 day−1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m−2, and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m−2 day−1. The mean half-life of ssHHT was 11.01±3.4 h, the volume of distribution at steady state was 2±1.4 l kg−1 and the plasma clearance was 11.6±10.4 l h−1. Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m−2 day−1. More... »

PAGES

253-259

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.bjc.6603265

DOI

http://dx.doi.org/10.1038/sj.bjc.6603265

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1030793270

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16847470


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30 schema:description To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m−2 day−1 was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m−2 day−1. Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m−2 day−1 for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m−2, and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m−2 day−1. The mean half-life of ssHHT was 11.01±3.4 h, the volume of distribution at steady state was 2±1.4 l kg−1 and the plasma clearance was 11.6±10.4 l h−1. Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m−2 day−1.
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42 aspergillosis
43 blast clearance
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45 cells
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47 clearance
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49 consecutive days
50 crisis
51 daily dose
52 daily subcutaneous injections
53 days
54 distribution
55 dose
56 dose escalation
57 dose levels
58 dose-finding trial
59 dose-limiting toxicity
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61 haematemesis
62 homoharringtonine
63 hyperglycaemia
64 hyperosmolar
65 injection
66 leukaemic cells
67 leukemia
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69 maximum-tolerated dose
70 myeloid leukemia
71 myelosuppression
72 pain
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74 pharmacokinetic study
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