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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37 schema:keywords Bayesian phase I dose-finding trial
38 CMML
39 I dose-finding trial
40 acute leukemia
41 acute myeloid leukemia
42 advanced acute leukemia
43 advanced acute myeloid leukemia
44 anasarque
45 aspergillosis
46 blast clearance
47 blast crisis
48 blood blast clearance
49 cells
50 chronic phase
51 clearance
52 complete remission
53 consecutive days
54 crisis
55 daily dose
56 daily subcutaneous injections
57 days
58 distribution
59 dose
60 dose escalation
61 dose levels
62 dose-finding trial
63 dose-limiting toxicity
64 escalation
65 haematemesis
66 homoharringtonine
67 hyperglycaemia
68 hyperosmolar
69 injection
70 leukaemic cells
71 leukemia
72 levels
73 life-threatening pulmonary aspergillosis
74 maximum-tolerated dose
75 myeloid leukemia
76 myelosuppression
77 pain
78 patients
79 pharmacokinetic study
80 phase
81 phase I
82 phase I dose-finding trials
83 plasma clearance
84 pulmonary aspergillosis
85 rash
86 remission
87 scalp pain
88 schedule
89 semisynthetic homoharringtonine
90 sequential Bayesian phase I dose-finding trial
91 skin rash
92 ssHHT
93 starting dose
94 state
95 steady state
96 study
97 subcutaneous injection
98 subsequent dose escalation
99 toxicity
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101 volume
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