Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia.
OBJECTIVE
DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP).


METHODS
DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m(2)/day for 5 days (3.0 mg/m(2)/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy.


RESULTS
Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m(2)/day for 5 days, two of three treated at 1.2 mg/m(2)/day for 5 days, and one of six treated at 0.9 mg/m(2)/day for 7 days. The recommended Phase II dose was 0.9 mg/m(2)/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model.


CONCLUSIONS
Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. fgiles@mdanderson.org
Francis J
FJ
Giles
Jorge E
JE
Cortes
Deborah A
DA
Thomas
Guillermo
G
Garcia-Manero
Stephan
S
Faderl
Sima
S
Jeha
Robert L
RL
De Jager
Hagop M
HM
Kantarjian
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D016879:Salvage Therapy; D013280:Stomatitis / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C095887:exatecan; D002166:Camptothecin